Science.gov

Sample records for 6c reveals determinants

  1. Determination of C6-C10 aromatic hydrocarbons in water by purge-and-trap capillary gas chromatography

    USGS Publications Warehouse

    Eganhouse, R.P.; Dorsey, T.F.; Phinney, C.S.; Westcott, A.M.

    1993-01-01

    A method is described for the determination of the C6-C10 aromatic hydrocarbons in water based on purge-and-trap capillary gas chromatography with flame ionization and mass spectrometric detection. Retention time data and 70 eV mass spectra were obtained for benzene and all 35 C7-C10 aromatic hydrocarbons. With optimized chromatographic conditions and mass spectrometric detection, benzene and 33 of the 35 alkylbenzenes can be identified and measured in a 45-min run. Use of a flame ionization detector permits the simultaneous determination of benzene and 26 alkylbenzenes.

  2. Voltage-sensing phosphatase reveals temporal regulation of TRPC3/C6/C7 channels by membrane phosphoinositides.

    PubMed

    Itsuki, Kyohei; Imai, Yuko; Okamura, Yasushi; Abe, Kihachiro; Inoue, Ryuji; Mori, Masayuki X

    2012-01-01

    TRPC3/C6/C7 channels, a subgroup of classical/canonical TRP channels, are activated by diacylglycerol produced via activation of phospholipase C (PLC)-coupled receptors. Recognition of the physiological importance of these channels has been steadily growing, but the mechanism by which they are regulated remains largely unknown. We recently used a membrane-resident danio rerio voltage-sensing phosphatase (DrVSP) to study TRPC3/C6/C7 regulation and found that the channel activity was controlled by PtdIns(4,5)P(2)-DAG signaling in a self-limiting manner (Imai Y et al., the Journal of Physiology, 2012). In this addendum, we present the advantages of using DrVSP as a molecular tool to study PtdIns(4,5)P(2) regulation. DrVSP should be readily applicable for studying phosphoinositide metabolism-linked channel regulation as well as lipid dynamics. Furthermore, in comparison to other modes of self-limiting ion channel regulation, the regulation of TRPC3/C6/C7 channels seems highly susceptible to activation signal strength, which could potentially affect both open duration and the time to peak activation and inactivation. Dysfunction of such self-limiting regulation may contribute to the pathology of the cardiovascular system, gastrointestinal tract and brain, as these channels are broadly distributed and affected by numerous neurohormonal agonists.

  3. Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice.

    PubMed

    Bhusari, Sachin; Pandiri, Arun R; Nagai, Hiroaki; Wang, Yu; Foley, Julie; Hong, Hue-Hua L; Ton, Thai-Vu; DeVito, Michael; Shockley, Keith R; Peddada, Shyamal D; Gerrish, Kevin E; Malarkey, David E; Hooth, Michelle J; Sills, Robert C; Hoenerhoff, Mark J

    2015-12-01

    The cell of origin of hepatoblastoma (HB) in humans and mice is unknown; it is hypothesized to be a transformed hepatocyte, oval cell, or hepatic progenitor cell. In mice, current dogma is that HBs arise from preexisting hepatocellular neoplasms as a result of further neoplastic transformation. However, there is little evidence supporting this direct relationship. To better understand the relationship between hepatocellular carcinoma (HCC) and HB and determine molecular similarities between mouse and human HB, global gene expression analysis and targeted mutation analysis were performed using HB, HCC, and adjacent liver from the same animals in a recent National Toxicology Program bioassay. There were significant differences in Hras and Ctnnb1 mutation spectra, and by microarray, HBs showed dysregulation of embryonic development, stem cell pluripotency, and genomic imprinting compared to HCC. Meta-analysis showed similarities between HB, early mouse embryonic liver, and hepatocyte-derived stem/progenitor cells compared to HCC. Our data show that there are striking differences between HB and HCC and suggest that HB is a significantly different entity that may arise from a hepatic precursor cell. Furthermore, mouse HB is similar to the human disease at the pathway level and therefore is likely a relevant model for evaluating human cancer hazard.

  4. Determination of Hepatotoxicity and Its Underlying Metabolic Basis of 1,2-Dichloropropane in Male Syrian Hamsters and B6C3F1 Mice.

    PubMed

    Gi, Min; Fujioka, Masaki; Yamano, Shotaro; Shimomura, Eri; Ishii, Naomi; Kakehashi, Anna; Takeshita, Masanori; Wanibuchi, Hideki

    2015-05-01

    1,2-Dichloropropane (1,2-DCP) has recently been reclassified from not classifiable as to its carcinogenicity to humans (Group 3) to carcinogenic to humans (Group 1) by the International Agency for Research on Cancer. This was based on the findings of epidemiological studies in Japan that occupational exposure to paint stripers containing 1,2-DCP was associated with increased cholangiocarcinomas. It is known that 1,2-DCP is negative for cholangiocarcinogenicity in rats and mice. However, its toxicity and carcinogenicity has not been examined in hamsters and little is known about the regulation of its metabolism in hamsters. The purpose of this study was to determine the hepatobiliary toxicity of 1,2-DCP in hamsters and to characterize and compare the altered patterns of hepatic xenometabolic enzymes in hamsters and mice. Male Syrian hamsters and male B6C3F1 mice were treated with various doses of 1,2-DCP for 4 h or 3 days or 4 weeks. These experiments demonstrated that a high dose of 1,2-DCP induced centrilobular hepatocellular necrosis in hamsters. CYP2E1 is possibly the key enzyme responsible for bioactivation and the consequent hepatocytotoxicity of 1,2-DCP, and GSH conjugation catalyzed by GST-T1 may exert a cytoprotective role in hamsters and mice. Notably, the expression pattern of GST-T1 in bile duct epithelial cells differed between hamsters and mice: GST-T1 was expressed in bile duct epithelial cells of mice but not hamsters. This indicates that responses to 1,2-DCP in the bile duct of hamsters might differ from that of mice, and suggests that long-term studies are necessary to clarify the chalangiocarcinogenicity of 1,2-DCP in hamsters, though no biliary toxicity was observed in the present short-term experiments.

  5. Structural insights into the neutralization mechanism of monoclonal antibody 6C2 against ricin.

    PubMed

    Zhu, Yuwei; Dai, Jianxin; Zhang, Tiancheng; Li, Xu; Fang, Pengfei; Wang, Huajing; Jiang, Yongliang; Yu, Xiaojie; Xia, Tian; Niu, Liwen; Guo, Yajun; Teng, Maikun

    2013-08-30

    Ricin belongs to the type II ribosome-inactivating proteins that depurinate the universally conserved α-sarcin loop of rRNA. The RNA N-glycosidase activity of ricin also largely depends on the ribosomal proteins that play an important role during the process of rRNA depurination. Therefore, the study of the interaction between ricin and the ribosomal elements will be better to understand the catalysis mechanism of ricin. The antibody 6C2 is a mouse monoclonal antibody exhibiting unusually potent neutralizing ability against ricin, but the neutralization mechanism remains unknown. Here, we report the 2.8 Å crystal structure of 6C2 Fab in complex with the A-chain of ricin (RTA), which reveals an extensive antigen-antibody interface that contains both hydrogen bonds and van der Waals contacts. The complementarity-determining region loops H1, H2, H3, and L3 form a pocket to accommodate the epitope on the RTA (residues Asp(96)-Thr(116)). ELISA results show that Gln(98), Glu(99), Glu(102), and Thr(105) (RTA) are the key residues that play an important role in recognizing 6C2. With the perturbation of the 6C2 Fab-RTA interface, 6C2 loses its neutralization ability, measured based on the inhibition of protein synthesis in a cell-free system. Finally, we propose that the neutralization mechanism of 6C2 against ricin is that the binding of 6C2 hinders the interaction between RTA and the ribosome and the surface plasmon resonance and pulldown results confirm our hypothesis. In short, our data explain the neutralization mechanism of mAb 6C2 against ricin and provide a structural basis for the development of improved antibody drugs with better specificity and higher affinity.

  6. Solvation Thermodynamic Properties of Hydrogen Sulfide in [C4mim][PF6], [C4mim][BF4], and [C4mim][Cl] Ionic Liquids, Determined by Molecular Simulations.

    PubMed

    Sánchez-Badillo, Joel; Gallo, Marco; Alvarado, Sandra; Glossman-Mitnik, Daniel

    2015-08-20

    Removal of hydrogen sulfide (H2S) and acid gases from natural gas is accomplished by absorption processes using a solvent. The gas solubility in a liquid can be used to measure the degree of removal of the gas and is quantified by the Henry's constant, the free energy of solvation at infinite dilution, or the excess chemical potential. In this work, Henry's constants and thermodynamic properties of solvation of H2S were calculated in three ionic liquids: [C4mim][PF6], [C4mim][BF4], and [C4mim][Cl] ([C4mim], 1-butyl-3-methyl imidazolium). The first step in this work was the evaluation of the force fields for the gas and condensed phases in order to obtain accurate values for the excess chemical potential for H2S on each ionic liquid using free energy perturbation techniques. In the H2S-[C4mim][PF6] and H2S-[C4mim][BF4] systems, the results obtained by molecular simulation agree with the experimental values reported in the literature. However, the solvation free energy calculated for the H2S-[C4mim][Cl] system can be considered predictive because of the lack of experimental data at the simulated conditions. Based on these results, the best solvent for removing H2S is [C4mim][Cl] because it has the highest affinity for this species (lowest value of the Henry's constant). Also, solvation thermodynamic properties such as enthalpy and entropy were calculated in order to evaluate their contribution to the free energy of solvation.

  7. Pathogenicity determinants in smut fungi revealed by genome comparison.

    PubMed

    Schirawski, Jan; Mannhaupt, Gertrud; Münch, Karin; Brefort, Thomas; Schipper, Kerstin; Doehlemann, Gunther; Di Stasio, Maurizio; Rössel, Nicole; Mendoza-Mendoza, Artemio; Pester, Doris; Müller, Olaf; Winterberg, Britta; Meyer, Elmar; Ghareeb, Hassan; Wollenberg, Theresa; Münsterkötter, Martin; Wong, Philip; Walter, Mathias; Stukenbrock, Eva; Güldener, Ulrich; Kahmann, Regine

    2010-12-10

    Biotrophic pathogens, such as the related maize pathogenic fungi Ustilago maydis and Sporisorium reilianum, establish an intimate relationship with their hosts by secreting protein effectors. Because secreted effectors interacting with plant proteins should rapidly evolve, we identified variable genomic regions by sequencing the genome of S. reilianum and comparing it with the U. maydis genome. We detected 43 regions of low sequence conservation in otherwise well-conserved syntenic genomes. These regions primarily encode secreted effectors and include previously identified virulence clusters. By deletion analysis in U. maydis, we demonstrate a role in virulence for four previously unknown diversity regions. This highlights the power of comparative genomics of closely related species for identification of virulence determinants.

  8. Proximity Labeling Reveals Molecular Determinants of FGFR4 Endosomal Transport.

    PubMed

    Haugsten, Ellen Margrethe; Sørensen, Vigdis; Kunova Bosakova, Michaela; de Souza, Gustavo Antonio; Krejci, Pavel; Wiedlocha, Antoni; Wesche, Jørgen

    2016-10-07

    The fibroblast growth factor receptors (FGFRs) are important oncogenes promoting tumor progression in many types of cancer, such as breast, bladder, and lung cancer as well as multiple myeloma and rhabdomyosarcoma. However, little is known about how these receptors are internalized and down-regulated in cells. We have here applied proximity biotin labeling to identify proteins involved in FGFR4 signaling and trafficking. For this purpose we fused a mutated biotin ligase, BirA*, to the C-terminal tail of FGFR4 (FGFR4-BirA*) and the fusion protein was stably expressed in U2OS cells. Upon addition of biotin to these cells, proteins in proximity to the FGFR4-BirA* fusion protein became biotinylated and could be isolated and identified by quantitative mass spectrometry. We identified in total 291 proteins, including 80 proteins that were enriched in samples where the receptor was activated by the ligand (FGF1), among them several proteins previously found to be involved in FGFR signaling (e.g., FRS2, PLCγ, RSK2 and NCK2). Interestingly, many of the identified proteins were implicated in endosomal transport, and by precise annotation we were able to trace the intracellular pathways of activated FGFR4. Validating the data by confocal and three-dimensional structured illumination microscopy analysis, we concluded that FGFR4 uses clathrin-mediated endocytosis for internalization and is further sorted from early endosomes to the recycling compartment and the trans-Golgi network. Depletion of cells for clathrin heavy chain led to accumulation of FGFR4 at the cell surface and increased levels of active FGFR4 and PLCγ, while AKT and ERK signaling was diminished, demonstrating that functional clathrin-mediated endocytosis is required for proper FGFR4 signaling. Thus, this study reveals proteins and pathways involved in FGFR4 transport and signaling that provide possible targets and opportunities for therapeutic intervention in FGFR4 aberrant cancer.

  9. VEGF Production by Ly6C+high Monocytes Contributes to Ventilator-Induced Lung Injury

    PubMed Central

    Lin, Chin-Kuo; Li, Jhy-Ming; Chen, Mei-Hsin; Tsai, Mei-Ling; Chang, Chih-Ching

    2016-01-01

    Background Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C+high monocytes are involved in the pathogenesis of VILI. In this study, we investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI. Methods A clinically relevant two-hit mouse model of VILI, with intravenous lipopolysaccharide (LPS, 20 ng/mouse) immediately before high tidal volume (HTV, 20 mL/kg) ventilation (LPS+HTV), was established. Blood gas and respiratory mechanics were measured to ensure the development of VILI. Flow cytometry and histopathological analyses revealed pulmonary infiltration of leukocytes subsets. Clodronate liposomes were intravenously injected to deplete pulmonary monocytes. In vitro endothelial cell permeability assay with sorted Ly6C+high monocytes condition media assessed the role of Ly6C+high monocytes in vascular permeability. Results LPS+HTV significantly increased total proteins, TNF-α, IL-6, vascular endothelial growth factor (VEGF) and mononuclear cells in the bronchoalveolar lavage fluid (BALF). Pulmonary Ly6C+high monocytes (SSClowCD11b+F4/80+Ly6C+high), but not Ly6C+low monocytes (SSClowCD11b+F4/80+Ly6C+low), were significantly elevated starting at 4 hr. Clodronate liposomes were able to significantly reduce pulmonary Ly6C+high monocytes, and VEGF and total protein in BALF, and restore PaO2/FiO2. There was a strong correlation between pulmonary Ly6C+high monocytes and BALF VEGF (R2 = 0.8791, p<0.001). Moreover, sorted Ly6C+high monocytes were able to produce VEGF, resulting in an increased permeability of endothelial cell monolayer in an in vitro endothelial cell permeability assay. Conclusion VEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung

  10. LY6G6C — EDRN Public Portal

    Cancer.gov

    LY6G6C, a cell membrane protein, is highly expressed at the leading edges of cells, on filopodia. The LY6G6C gene belongs to a cluster of leukocyte antigen-6 (LY6) genes located in the major histocompatibility complex (MHC) class III region on chromosome 6. Members of the LY6 superfamily typically contain 70 to 80 amino acids, including 8 to 10 cysteines. LY6G6C is attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor that is directly involved in signal transduction.

  11. Feedback Control of Sex Determination by Dosage Compensation Revealed through Caenorhabditis Elegans Sdc-3 Mutations

    PubMed Central

    DeLong, L.; Plenefisch, J. D.; Klein, R. D.; Meyer, B. J.

    1993-01-01

    In Caenorhabditis elegans, sex determination and dosage compensation are coordinately controlled through a group of genes that respond to the primary sex determination signal. Here we describe a new gene, sdc-3, that also controls these processes. In contrast to previously described genes, the sex determination and dosage compensation activities of sdc-3 are separately mutable, indicating that they function independently. Paradoxically, the sdc-3 null phenotype fails to reveal the role of sdc-3 in sex determination: sdc-3 null mutations that lack both activities disrupt dosage compensation but cause no overt sexual transformation. We demonstrate that the dosage compensation defect of sdc-3 null alleles suppresses their sex determination defect. This self-suppression phenomenon provides a striking example of how a disruption in dosage compensation can affect sexual fate. We propose that the suppression occurs via a feedback mechanism that acts at an early regulatory step in the sex determination pathway to promote proper sexual identity. PMID:8462848

  12. Interleukin-6 c.-174G>C Polymorphism and Periodontitis in a Brazilian Population

    PubMed Central

    Gabriela Teixeira, Fernanda; Mendonça, Samir Andrade; Menezes Oliveira, Kamilla; Barbosa dos Santos, Djanilson; Miranda Marques, Lucas; Mendonça Amorim, Maise; de Souza Gestinari, Raquel

    2014-01-01

    Aim. Periodontitis is an inflammatory disease that affects the teeth supporting structures, triggered by periodontal pathogens, and is influenced by environmental and genetic factors. Genes encoding molecules related to the immune response, such as cytokine, are the main candidates for polymorphisms analysis and may be possibly associated with this pathology. A G/C promoter polymorphism on the IL6 gene has been shown to affect basal IL-6 levels. The aim of this study was to investigate the association between the IL6 c.-174G>C polymorphism and periodontitis in individuals from Vitória da Conquista, Bahia, Brazil. Material and Methods. Three hundred and thirty individuals (134 cases, 196 controls) were genotyped for the IL6 c.-174G>C by MS-PCR technique. Concentrations of salivary IL-6 were determined by ELISA method. Results. The IL6 c.-174G>C polymorphism was associated with periodontitis when comparing the distribution of genotypes between patients with periodontitis and control subjects. The GC genotype appeared as a protective factor for periodontitis. Results showed increased levels of salivary IL-6 in periodontitis patients. Nevertheless, there was no relationship between the concentrations of IL-6 and genotypes when comparing the case and control groups. Conclusions. Our data indicate an association between IL6 c.-174G>C polymorphism and periodontitis and showed that IL-6 may be considered an important marker for periodontitis. PMID:25548674

  13. Multilocus Sex Determination Revealed in Two Populations of Gynodioecious Wild Strawberry, Fragaria vesca subsp. bracteata

    PubMed Central

    Ashman, Tia-Lynn; Tennessen, Jacob A.; Dalton, Rebecca M.; Govindarajulu, Rajanikanth; Koski, Matthew H.; Liston, Aaron

    2015-01-01

    Gynodioecy, the coexistence of females and hermaphrodites, occurs in 20% of angiosperm families and often enables transitions between hermaphroditism and dioecy. Clarifying mechanisms of sex determination in gynodioecious species can thus illuminate sexual system evolution. Genetic determination of gynodioecy, however, can be complex and is not fully characterized in any wild species. We used targeted sequence capture to genetically map a novel nuclear contributor to male sterility in a self-pollinated hermaphrodite of Fragaria vesca subsp. bracteata from the southern portion of its range. To understand its interaction with another identified locus and possibly additional loci, we performed crosses within and between two populations separated by 2000 km, phenotyped the progeny and sequenced candidate markers at both sex-determining loci. The newly mapped locus contains a high density of pentatricopeptide repeat genes, a class commonly involved in restoration of fertility caused by cytoplasmic male sterility. Examination of all crosses revealed three unlinked epistatically interacting loci that determine sexual phenotype and vary in frequency between populations. Fragaria vesca subsp. bracteata represents the first wild gynodioecious species with genomic evidence of both cytoplasmic and nuclear genes in sex determination. We propose a model for the interactions between these loci and new hypotheses for the evolution of sex determining chromosomes in the subdioecious and dioecious Fragaria. PMID:26483011

  14. Multilocus Sex Determination Revealed in Two Populations of Gynodioecious Wild Strawberry, Fragaria vesca subsp. bracteata.

    PubMed

    Ashman, Tia-Lynn; Tennessen, Jacob A; Dalton, Rebecca M; Govindarajulu, Rajanikanth; Koski, Matthew H; Liston, Aaron

    2015-10-19

    Gynodioecy, the coexistence of females and hermaphrodites, occurs in 20% of angiosperm families and often enables transitions between hermaphroditism and dioecy. Clarifying mechanisms of sex determination in gynodioecious species can thus illuminate sexual system evolution. Genetic determination of gynodioecy, however, can be complex and is not fully characterized in any wild species. We used targeted sequence capture to genetically map a novel nuclear contributor to male sterility in a self-pollinated hermaphrodite of Fragaria vesca subsp. bracteata from the southern portion of its range. To understand its interaction with another identified locus and possibly additional loci, we performed crosses within and between two populations separated by 2000 km, phenotyped the progeny and sequenced candidate markers at both sex-determining loci. The newly mapped locus contains a high density of pentatricopeptide repeat genes, a class commonly involved in restoration of fertility caused by cytoplasmic male sterility. Examination of all crosses revealed three unlinked epistatically interacting loci that determine sexual phenotype and vary in frequency between populations. Fragaria vesca subsp. bracteata represents the first wild gynodioecious species with genomic evidence of both cytoplasmic and nuclear genes in sex determination. We propose a model for the interactions between these loci and new hypotheses for the evolution of sex determining chromosomes in the subdioecious and dioecious Fragaria.

  15. Mutagenicity of furan in female Big Blue B6C3F1 mice

    PubMed Central

    Terrell, Ashley N.; Huynh, Mailee; Grill, Alex E.; Kovi, Ramesh C.; O’Sullivan, M. Gerard; Guttenplan, Joseph B.; Ho, Yen-Yi; Peterson, Lisa A.

    2014-01-01

    Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII trans-gene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell

  16. Mutagenicity of furan in female Big Blue B6C3F1 mice.

    PubMed

    Terrell, Ashley N; Huynh, Mailee; Grill, Alex E; Kovi, Ramesh C; O'Sullivan, M Gerard; Guttenplan, Joseph B; Ho, Yen-Yi; Peterson, Lisa A

    2014-08-01

    Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII transgene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell

  17. Structure determination of archaea-specific ribosomal protein L46a reveals a novel protein fold

    SciTech Connect

    Feng, Yingang; Song, Xiaxia; Lin, Jinzhong; Xuan, Jinsong; Cui, Qiu; Wang, Jinfeng

    2014-07-18

    Highlights: • The archaea-specific ribosomal protein L46a has no homology to known proteins. • Three dimensional structure and backbone dynamics of L46a were determined by NMR. • The structure of L46a represents a novel protein fold. • A potential rRNA-binding surface on L46a was identified. • The potential position of L46a on the ribosome was proposed. - Abstract: Three archaea-specific ribosomal proteins recently identified show no sequence homology with other known proteins. Here we determined the structure of L46a, the most conserved one among the three proteins, from Sulfolobus solfataricus P2 using NMR spectroscopy. The structure presents a twisted β-sheet formed by the N-terminal part and two helices at the C-terminus. The L46a structure has a positively charged surface which is conserved in the L46a protein family and is the potential rRNA-binding site. Searching homologous structures in Protein Data Bank revealed that the structure of L46a represents a novel protein fold. The backbone dynamics identified by NMR relaxation experiments reveal significant flexibility at the rRNA binding surface. The potential position of L46a on the ribosome was proposed by fitting the structure into a previous electron microscopy map of the ribosomal 50S subunit, which indicated that L46a contacts to domain I of 23S rRNA near a multifunctional ribosomal protein L7ae.

  18. Genome sequencing and analysis reveals possible determinants of Staphylococcus aureus nasal carriage

    PubMed Central

    Sivaraman, Karthikeyan; Venkataraman, Nitya; Tsai, Jennifer; Dewell, Scott; Cole, Alexander M

    2008-01-01

    Background Nasal carriage of Staphylococcus aureus is a major risk factor in clinical and community settings due to the range of etiologies caused by the organism. We have identified unique immunological and ultrastructural properties associated with nasal carriage isolates denoting a role for bacterial factors in nasal carriage. However, despite extensive molecular level characterizations by several groups suggesting factors necessary for colonization on nasal epithelium, genetic determinants of nasal carriage are unknown. Herein, we have set a genomic foundation for unraveling the bacterial determinants of nasal carriage in S. aureus. Results MLST analysis revealed no lineage specific differences between carrier and non-carrier strains suggesting a role for mobile genetic elements. We completely sequenced a model carrier isolate (D30) and a model non-carrier strain (930918-3) to identify differential gene content. Comparison revealed the presence of 84 genes unique to the carrier strain and strongly suggests a role for Type VII secretion systems in nasal carriage. These genes, along with a putative pathogenicity island (SaPIBov) present uniquely in the carrier strains are likely important in affecting carriage. Further, PCR-based genotyping of other clinical isolates for a specific subset of these 84 genes raise the possibility of nasal carriage being caused by multiple gene sets. Conclusion Our data suggest that carriage is likely a heterogeneic phenotypic trait and implies a role for nucleotide level polymorphism in carriage. Complete genome level analyses of multiple carriage strains of S. aureus will be important in clarifying molecular determinants of S. aureus nasal carriage. PMID:18808706

  19. Identification of Sex-Specific Markers Reveals Male Heterogametic Sex Determination in Pseudobagrus ussuriensis.

    PubMed

    Pan, Zheng-Jun; Li, Xi-Yin; Zhou, Feng-Jian; Qiang, Xiao-Gang; Gui, Jian-Fang

    2015-08-01

    Comprehending sex determination mechanism is a first step for developing sex control breeding biotechnologies in fish. Pseudobagrus ussuriensis, one of bagrid catfishes in Bagridae, had been observed to have about threefold size dimorphism between males and females, but its sex determination mechanism had been unknown. In this study, we firstly used the amplified fragment length polymorphism (AFLP)-based screening approach to isolate a male-specific DNA fragment and thereby identified a 10,569 bp of male-specific sequence and a 10,365 bp of female-related sequence by genome walking in the bagrid catfish, in which a substantial genetic differentiation with 96.35 % nucleotide identity was revealed between them. Subsequently, a high differentiating region of 650 bp with only 70.26 % nucleotide identity was found from the corresponding two sequences, and three primer pairs of male-specific marker, male and female-shared marker with different length products in male and female genomes, and female-related marker were designed. Significantly, when these markers were used to identify genetic sex of the bagrid catfish, only male individuals was detected to amplify the male-specific marker fragment, and female-related marker was discovered to produce dosage association in females and in males. Our current data provide significant genetic evidence that P. ussuriensis has heterogametic XY sex chromosomes in males and homogametic XX sex chromosomes in females. Therefore, sex determination mechanism of P. ussuriensis is male heterogametic XX/XY system.

  20. Transcription closed and open complex dynamics studies reveal balance between genetic determinants and co-factors.

    PubMed

    Sala, Adrien; Shoaib, Muhammad; Anufrieva, Olga; Mutharasu, Gnanavel; Jahan Hoque, Rawnak; Yli-Harja, Olli; Kandhavelu, Meenakshisundaram

    2015-05-19

    In E. coli, promoter closed and open complexes are key steps in transcription initiation, where magnesium-dependent RNA polymerase catalyzes RNA synthesis. However, the exact mechanism of initiation remains to be fully elucidated. Here, using single mRNA detection and dual reporter studies, we show that increased intracellular magnesium concentration affects Plac initiation complex formation resulting in a highly dynamic process over the cell growth phases. Mg2+ regulates transcription transition, which modulates bimodality of mRNA distribution in the exponential phase. We reveal that Mg2+ regulates the size and frequency of the mRNA burst by changing the open complex duration. Moreover, increasing magnesium concentration leads to higher intrinsic and extrinsic noise in the exponential phase. RNAP-Mg2+ interaction simulation reveals critical movements creating a shorter contact distance between aspartic acid residues and Nucleotide Triphosphate residues and increasing electrostatic charges in the active site. Our findings provide unique biophysical insights into the balanced mechanism of genetic determinants and magnesium ion in transcription initiation regulation during cell growth.

  1. Transcription closed and open complex dynamics studies reveal balance between genetic determinants and co-factors

    NASA Astrophysics Data System (ADS)

    Sala, Adrien; Shoaib, Muhammad; Anufrieva, Olga; Mutharasu, Gnanavel; Jahan Hoque, Rawnak; Yli-Harja, Olli; Kandhavelu, Meenakshisundaram

    2015-05-01

    In E. coli, promoter closed and open complexes are key steps in transcription initiation, where magnesium-dependent RNA polymerase catalyzes RNA synthesis. However, the exact mechanism of initiation remains to be fully elucidated. Here, using single mRNA detection and dual reporter studies, we show that increased intracellular magnesium concentration affects Plac initiation complex formation resulting in a highly dynamic process over the cell growth phases. Mg2+ regulates transcription transition, which modulates bimodality of mRNA distribution in the exponential phase. We reveal that Mg2+ regulates the size and frequency of the mRNA burst by changing the open complex duration. Moreover, increasing magnesium concentration leads to higher intrinsic and extrinsic noise in the exponential phase. RNAP-Mg2+ interaction simulation reveals critical movements creating a shorter contact distance between aspartic acid residues and Nucleotide Triphosphate residues and increasing electrostatic charges in the active site. Our findings provide unique biophysical insights into the balanced mechanism of genetic determinants and magnesium ion in transcription initiation regulation during cell growth.

  2. 6-C-methyl flavonoids isolated from Pinus densata inhibit the proliferation and promote the apoptosis of the HL-60 human promyelocytic leukaemia cell line.

    PubMed

    Yue, Rongcai; Li, Bo; Shen, Yunheng; Zeng, Huawu; Li, Bo; Yuan, Hu; He, Yiren; Shan, Lei; Zhang, Weidong

    2013-08-01

    Three structurally related 6-C-methyl flavonoids isolated from Pinus densata, including 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone (PD1), 5,7,4'-trihydroxy-3,8-dimethoxy-6-C-methylflavone (PD2), and 5,7,4'-trihydroxy-3-methoxy-6-C-methylflavone (PD3), were tested for their ability to inhibit the proliferation and promote the apoptosis of the HL-60 human leukaemia cell line. Cytotoxicity assays in the HL-60 human cancer cell line demonstrated that 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone exhibited the most potent cytotoxicity of the three structurally related 6-C-methyl flavonoids. 5,4'-Dihydroxy-3,7,8-trimethoxy-6-C-methylflavone inhibited the proliferation of HL-60 cells in a dose-dependent manner with an IC₅₀ of 7.91 µM (48 h treatment). Furthermore, 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone-induced apoptosis was associated with mitochondrial membrane disruption and cytochome c release. Flow cytometry analyses revealed an increase in the hypodiploid population in 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone-treated HL-60 cells. Treatment with a concentration of 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone that induced apoptosis activated caspase-3 but did not activate caspase-1. A caspase-3 inhibitor (Ac-DEVD-CHO), but not a caspase-1 inhibitor (Ac-YVAD-CHO), reversed the cytotoxic effects of 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone in HL-60 cells. These data demonstrated that 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone effectively induced the apoptosis of HL-60 cells and exhibited significant anticancer activity via the mitochondrial caspase-3-dependent apoptosis pathway.

  3. Determinants of spontaneous mutation in the bacterium Escherichia coli as revealed by whole-genome sequencing

    PubMed Central

    Foster, Patricia L.; Lee, Heewook; Popodi, Ellen; Townes, Jesse P.; Tang, Haixu

    2015-01-01

    A complete understanding of evolutionary processes requires that factors determining spontaneous mutation rates and spectra be identified and characterized. Using mutation accumulation followed by whole-genome sequencing, we found that the mutation rates of three widely diverged commensal Escherichia coli strains differ only by about 50%, suggesting that a rate of 1–2 × 10−3 mutations per generation per genome is common for this bacterium. Four major forces are postulated to contribute to spontaneous mutations: intrinsic DNA polymerase errors, endogenously induced DNA damage, DNA damage caused by exogenous agents, and the activities of error-prone polymerases. To determine the relative importance of these factors, we studied 11 strains, each defective for a major DNA repair pathway. The striking result was that only loss of the ability to prevent or repair oxidative DNA damage significantly impacted mutation rates or spectra. These results suggest that, with the exception of oxidative damage, endogenously induced DNA damage does not perturb the overall accuracy of DNA replication in normally growing cells and that repair pathways may exist primarily to defend against exogenously induced DNA damage. The thousands of mutations caused by oxidative damage recovered across the entire genome revealed strong local-sequence biases of these mutations. Specifically, we found that the identity of the 3′ base can affect the mutability of a purine by oxidative damage by as much as eightfold. PMID:26460006

  4. High-density linkage mapping revealed suppression of recombination at the sex determination locus in papaya.

    PubMed Central

    Ma, Hao; Moore, Paul H; Liu, Zhiyong; Kim, Minna S; Yu, Qingyi; Fitch, Maureen M M; Sekioka, Terry; Paterson, Andrew H; Ming, Ray

    2004-01-01

    A high-density genetic map of papaya (Carica papaya L.) was constructed using 54 F(2) plants derived from cultivars Kapoho and SunUp with 1501 markers, including 1498 amplified fragment length polymorphism (AFLP) markers, the papaya ringspot virus coat protein marker, morphological sex type, and fruit flesh color. These markers were mapped into 12 linkage groups at a LOD score of 5.0 and recombination frequency of 0.25. The 12 major linkage groups covered a total length of 3294.2 cM, with an average distance of 2.2 cM between adjacent markers. This map revealed severe suppression of recombination around the sex determination locus with a total of 225 markers cosegregating with sex types. The cytosine bases were highly methylated in this region on the basis of the distribution of methylation-sensitive and -insensitive markers. This high-density genetic map is essential for cloning of specific genes of interest such as the sex determination gene and for the integration of genetic and physical maps of papaya. PMID:15020433

  5. Epidemiology of pneumococcal serotype 6A and 6C among invasive and carriage isolates from Alaska, 1986–2009☆

    PubMed Central

    Rudolph, Karen; Bruce, Michael; Bruden, Dana; Zulz, Tammy; Wenger, Jay; Reasonover, Alisa; Harker-Jones, Marcella; Hurlburt, Debby; Hennessy, Thomas

    2015-01-01

    We investigated serotype 6A/6C invasive pneumococcal disease (IPD) incidence, genetic diversity, and carriage before and after 7-valent pneumococcal conjugate vaccine (PCV7) introduction in Alaska. IPD cases (1986–2009) were identified through population-based laboratory surveillance. Isolates were initially serotyped by conventional methods, and 6C isolates were differentiated from 6A by polymerase chain reaction. Among invasive and carriage isolates initially typed as 6A, 35% and 50% were identified as 6C, respectively. IPD rates caused by serotype 6A or 6C among children <5 years did not change from the pre- to post-PCV7 period (P = 0.71 and P = 0.09, respectively). Multilocus sequence typing of IPD isolates revealed 28 sequence types. The proportion of serotype 6A carriage isolates decreased from 7.4% pre-PCV7 to 1.8% (P < 0.001) during 2008–2009; the proportion of serotype 6C carriage isolates increased from 3.0% to 8.4% (P = 0.004) among children <5 years. Continued surveillance is warranted to monitor changes in serotype distribution and prevalence. PMID:23276772

  6. Molecular Dynamic Simulations Reveal the Structural Determinants of Fatty Acid Binding to Oxy-Myoglobin

    PubMed Central

    Chintapalli, Sree V.; Bhardwaj, Gaurav; Patel, Reema; Shah, Natasha; Patterson, Randen L.; van Rossum, Damian B.; Anishkin, Andriy; Adams, Sean H.

    2015-01-01

    The mechanism(s) by which fatty acids are sequestered and transported in muscle have not been fully elucidated. A potential key player in this process is the protein myoglobin (Mb). Indeed, there is a catalogue of empirical evidence supporting direct interaction of globins with fatty acid metabolites; however, the binding pocket and regulation of the interaction remains to be established. In this study, we employed a computational strategy to elucidate the structural determinants of fatty acids (palmitic & oleic acid) binding to Mb. Sequence analysis and docking simulations with a horse (Equus caballus) structural Mb reference reveals a fatty acid-binding site in the hydrophobic cleft near the heme region in Mb. Both palmitic acid and oleic acid attain a “U” shaped structure similar to their conformation in pockets of other fatty acid-binding proteins. Specifically, we found that the carboxyl head group of palmitic acid coordinates with the amino group of Lys45, whereas the carboxyl group of oleic acid coordinates with both the amino groups of Lys45 and Lys63. The alkyl tails of both fatty acids are supported by surrounding hydrophobic residues Leu29, Leu32, Phe33, Phe43, Phe46, Val67, Val68 and Ile107. In the saturated palmitic acid, the hydrophobic tail moves freely and occasionally penetrates deeper inside the hydrophobic cleft, making additional contacts with Val28, Leu69, Leu72 and Ile111. Our simulations reveal a dynamic and stable binding pocket in which the oxygen molecule and heme group in Mb are required for additional hydrophobic interactions. Taken together, these findings support a mechanism in which Mb acts as a muscle transporter for fatty acid when it is in the oxygenated state and releases fatty acid when Mb converts to deoxygenated state. PMID:26030763

  7. Mechanical and nonlinear elastic characteristics of polycrystalline AMg6 aluminum alloy and n-AMg6/C60 nanocomposite

    NASA Astrophysics Data System (ADS)

    Korobov, A. I.; Kokshaiskii, A. I.; Prokhorov, V. M.; Evdokimov, I. A.; Perfilov, S. A.; Volkov, A. D.

    2016-12-01

    The influence of nanostructuring on the mechanical and nonlinear elastic characteristics of polycrystalline AMg6 aluminum alloy and n-AMg6/C60 nanocomposite has been experimentally studied. The independent second- and third-order elastic coefficients are measured via the ultrasonic method. The thir-dorder elastic coefficients have been evaluated via the Tearstone-Bragger approach from the experimentally established velocities of shear and longitudinal bulk acoustic waves as the functions of the uniaxial compression in the studied samples. The nonlinear elastic properties are examined via the spectral acoustic technique in AMg6 aluminum alloy and n-AMg6/C60 nanocomposite, and the nonlinear acoustic parameters are determined.

  8. Determinants of National Fire Plan Fuels Treatment Expenditures: A Revealed Preference Analysis for Northern New Mexico

    NASA Astrophysics Data System (ADS)

    Shepherd, Curt; Grimsrud, Kristine; Berrens, Robert P.

    2009-10-01

    The accumulation of fire fuels in forests throughout the world contributes significantly to the severity of wildfires. To combat the threat of wildfire, especially in the wildland-urban interface (WUI), US federal land management agencies have implemented a number of forest restoration and wildfire risk reduction programs. In the spirit of revealed preference analyses, the objective of this study is to investigate the pattern and determinants of National Fire Plan (NFP) expenditures for fuel reduction treatments in northern New Mexico (USA). Estimation results from a set of Generalized Estimating Equations models are mixed with respect to risk reduction hypotheses, and also raise issues regarding how risk reduction should be defined for a region characterized by both pockets of urban sprawl into the WUI and large areas of chronic rural poverty. Program preferences for project funding under the federal Collaborative Forest Restoration Program in New Mexico are shown to be distinctly different (e.g., exhibiting greater concern for social equity) than for other NFP-funded projects.

  9. 17 CFR 270.6c-3 - Exemptions for certain registered variable life insurance separate accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Exemptions for certain registered variable life insurance separate accounts. 270.6c-3 Section 270.6c-3 Commodity and Securities... 1940 § 270.6c-3 Exemptions for certain registered variable life insurance separate accounts. A...

  10. 17 CFR 270.6c-3 - Exemptions for certain registered variable life insurance separate accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Exemptions for certain registered variable life insurance separate accounts. 270.6c-3 Section 270.6c-3 Commodity and Securities... 1940 § 270.6c-3 Exemptions for certain registered variable life insurance separate accounts. A...

  11. A compendium of nucleosome and transcript profiles reveals determinants of chromatin architecture and transcription.

    PubMed

    van Bakel, Harm; Tsui, Kyle; Gebbia, Marinella; Mnaimneh, Sanie; Hughes, Timothy R; Nislow, Corey

    2013-05-01

    Nucleosomes in all eukaryotes examined to date adopt a characteristic architecture within genes and play fundamental roles in regulating transcription, yet the identity and precise roles of many of the trans-acting factors responsible for the establishment and maintenance of this organization remain to be identified. We profiled a compendium of 50 yeast strains carrying conditional alleles or complete deletions of genes involved in transcriptional regulation, histone biology, and chromatin remodeling, as well as compounds that target transcription and histone deacetylases, to assess their respective roles in nucleosome positioning and transcription. We find that nucleosome patterning in genes is affected by many factors, including the CAF-1 complex, Spt10, and Spt21, in addition to previously reported remodeler ATPases and histone chaperones. Disruption of these factors or reductions in histone levels led genic nucleosomes to assume positions more consistent with their intrinsic sequence preferences, with pronounced and specific shifts of the +1 nucleosome relative to the transcription start site. These shifts of +1 nucleosomes appear to have functional consequences, as several affected genes in Ino80 mutants exhibited altered expression responses. Our parallel expression profiling compendium revealed extensive transcription changes in intergenic and antisense regions, most of which occur in regions with altered nucleosome occupancy and positioning. We show that the nucleosome-excluding transcription factors Reb1, Abf1, Tbf1, and Rsc3 suppress cryptic transcripts at their target promoters, while a combined analysis of nucleosome and expression profiles identified 36 novel transcripts that are normally repressed by Tup1/Cyc8. Our data confirm and extend the roles of chromatin remodelers and chaperones as major determinants of genic nucleosome positioning, and these data provide a valuable resource for future studies.

  12. A Compendium of Nucleosome and Transcript Profiles Reveals Determinants of Chromatin Architecture and Transcription

    PubMed Central

    van Bakel, Harm; Tsui, Kyle; Gebbia, Marinella; Mnaimneh, Sanie; Hughes, Timothy R.; Nislow, Corey

    2013-01-01

    Nucleosomes in all eukaryotes examined to date adopt a characteristic architecture within genes and play fundamental roles in regulating transcription, yet the identity and precise roles of many of the trans-acting factors responsible for the establishment and maintenance of this organization remain to be identified. We profiled a compendium of 50 yeast strains carrying conditional alleles or complete deletions of genes involved in transcriptional regulation, histone biology, and chromatin remodeling, as well as compounds that target transcription and histone deacetylases, to assess their respective roles in nucleosome positioning and transcription. We find that nucleosome patterning in genes is affected by many factors, including the CAF-1 complex, Spt10, and Spt21, in addition to previously reported remodeler ATPases and histone chaperones. Disruption of these factors or reductions in histone levels led genic nucleosomes to assume positions more consistent with their intrinsic sequence preferences, with pronounced and specific shifts of the +1 nucleosome relative to the transcription start site. These shifts of +1 nucleosomes appear to have functional consequences, as several affected genes in Ino80 mutants exhibited altered expression responses. Our parallel expression profiling compendium revealed extensive transcription changes in intergenic and antisense regions, most of which occur in regions with altered nucleosome occupancy and positioning. We show that the nucleosome-excluding transcription factors Reb1, Abf1, Tbf1, and Rsc3 suppress cryptic transcripts at their target promoters, while a combined analysis of nucleosome and expression profiles identified 36 novel transcripts that are normally repressed by Tup1/Cyc8. Our data confirm and extend the roles of chromatin remodelers and chaperones as major determinants of genic nucleosome positioning, and these data provide a valuable resource for future studies. PMID:23658529

  13. The human splicing code reveals new insights into the genetic determinants of disease

    PubMed Central

    Xiong, Hui Y.; Alipanahi, Babak; Lee, Leo J.; Bretschneider, Hannes; Merico, Daniele; Yuen, Ryan K.C.; Hua, Yimin; Gueroussov, Serge; Najafabadi, Hamed S.; Hughes, Timothy R.; Morris, Quaid; Barash, Yoseph; Krainer, Adrian R.; Jojic, Nebojsa; Scherer, Stephen W.; Blencowe, Benjamin J.; Frey, Brendan J.

    2015-01-01

    Introduction Advancing whole-genome precision medicine requires understanding how gene expression is altered by genetic variants, especially those that are outside of protein-coding regions. We developed a computational technique that scores how strongly genetic variants alter RNA splicing, a critical step in gene expression whose disruption contributes to many diseases, including cancers and neurological disorders. A genome-wide analysis reveals tens of thousands of variants that alter splicing and are enriched with a wide range of known diseases. Our results provide insight into the genetic basis of spinal muscular atrophy, hereditary nonpolyposis colorectal cancer and autism spectrum disorder. Methods We used machine learning to derive a computational model that takes as input DNA sequences and applies general rules to predict splicing in human tissues. Given a test variant, our model computes a score that predicts how much the variant disrupts splicing. The model was derived in such a way that it can be used to study diverse diseases and disorders, and to determine the consequences of common, rare, and even spontaneous variants. Results Our technique is able to accurately classify disease-causing variants and provides insights into the role of aberrant splicing in disease. We scored over 650,000 DNA variants and found that disease-causing variants have higher scores than common variants and even those associated with disease in genome-wide association studies. Our model predicts substantial and unexpected aberrant splicing due to variants within introns and exons, including those far from the splice site. For example, among intronic variants that are more than 30 nucleotides away from a splice site, known disease variants alter splicing nine times more often than common variants; among missense exonic disease variants, those that least impact protein function are over five times more likely to alter splicing than other variants. Autism has been associated with

  14. Colocalization of WT1 and cell proliferation reveals conserved mechanisms in temperature-dependent sex determination.

    PubMed

    Schmahl, Jennifer; Yao, Humphrey H; Pierucci-Alves, Fernando; Capel, Blanche

    2003-04-01

    During vertebrate development the gonad has two possible fates, the testis or the ovary. The choice between these fates is made by a variety of sex-determining mechanisms, from the sex-determining gene on the Y chromosome (Sry) in mammals, to nongenetic temperature-dependent systems in many reptiles. Despite the differences in the mechanisms at the top of the sex-determining cascade, the resulting morphology and many genes involved in early testis and ovarian development are common to most vertebrates, leading to the hypothesis that the underlying processes of sex determination are conserved. In this study, we examined the early steps of gonad development in the red-eared slider turtle (Trachemys scripta), a species that uses the temperature of egg incubation to determine sex. A dramatic increase in cell proliferation was observed in the male gonad during the earliest stages of sex determination. Using the localization of Wilms' Tumor suppressor 1 (WT1), we determined that this proliferation increase occurred in a population that contained pre-Sertoli cells. The proliferation of pre-Sertoli cells has been documented during sex determination in both mice and alligators, suggesting that proliferation of this cell type has an important role in vertebrate testis organogenesis and the determination of male fate.

  15. 77 FR 34121 - Culturally Significant Objects Imported for Exhibition Determinations: “Revealing the African...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-08

    ... Renaissance Europe'' SUMMARY: Notice is hereby given of the following determinations: Pursuant to the... Presence in Renaissance Europe'' imported from abroad for temporary exhibition within the United...

  16. 78 FR 55772 - Culturally Significant Object Imported for Exhibition Determinations: “Beauty Revealed: Images of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-11

    ... Qing Dynasty Chinese Painting'' SUMMARY: Notice is hereby given of the following determinations...: Images of Women in Qing Dynasty Chinese Painting,'' imported from abroad for temporary exhibition...

  17. Association of the CYP2B6 c.516G>T polymorphism with high blood propofol concentrations in women from northern Greece.

    PubMed

    Mastrogianni, Orthodoxia; Gbandi, Emma; Orphanidis, Amvrosios; Raikos, Nikolaos; Goutziomitrou, Evangelia; Kolibianakis, Efstratios M; Tarlatzis, Basil C; Goulas, Antonis

    2014-01-01

    Cytochrome P450 2B6 (CYP2B6) is responsible for the initial biotransformation of profol, an extensively metabolized intravenous anesthetic. In this study we examined the effect of the apparently functional CYP2B6 c.516G>T polymorphism on the distribution of propofol concentrations, quantified by GC/MS analysis following a single bolus dose, in the blood of 44 Greek women undergoing oocyte retrieval. Univariate analysis using age, height, weight and smoking status as covariates, as well as the Mann-Whitney non-parametric test, revealed a strong trend of association of the T allele with high propofol concentrations determined in whole blood, shortly after a single bolus dose. Propofol concentrations which were higher than one standard deviation of the mean were almost invariably associated with carriage of the T allele.

  18. The small 6C RNA of Corynebacterium glutamicum is involved in the SOS response.

    PubMed

    Pahlke, Jennifer; Dostálová, Hana; Holátko, Jiří; Degner, Ursula; Bott, Michael; Pátek, Miroslav; Polen, Tino

    2016-09-01

    The 6C RNA family is a class of small RNAs highly conserved in Actinobacteria, including the genera Mycobacterium, Streptomyces and Corynebacterium whose physiological function has not yet been elucidated. We found that strong transcription of the cgb_03605 gene, which encodes 6C RNA in C. glutamicum, was driven by the SigA- and SigB-dependent promoter Pcgb_03605. 6C RNA was detected at high level during exponential growth phase (180 to 240 molcules per cell) which even increased at the entry of the stationary phase. 6C RNA level did not decrease within 240 min after transcription had been stopped with rifampicin, which suggests high 6C RNA stability. The expression of cgb_03605 further increased approximately twofold in the presence of DNA-damaging mitomycin C (MMC) and nearly threefold in the absence of LexA. Deletion of the 6C RNA gene cgb_03605 resulted in a higher sensitivity of C. glutamicum toward MMC and UV radiation. These results indicate that 6C RNA is involved in the DNA damage response. Both 6C RNA level-dependent pausing of cell growth and branched cell morphology in response to MMC suggest that 6C RNA may also be involved in a control of cell division.

  19. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

    PubMed

    Xiong, Hui Y; Alipanahi, Babak; Lee, Leo J; Bretschneider, Hannes; Merico, Daniele; Yuen, Ryan K C; Hua, Yimin; Gueroussov, Serge; Najafabadi, Hamed S; Hughes, Timothy R; Morris, Quaid; Barash, Yoseph; Krainer, Adrian R; Jojic, Nebojsa; Scherer, Stephen W; Blencowe, Benjamin J; Frey, Brendan J

    2015-01-09

    To facilitate precision medicine and whole-genome annotation, we developed a machine-learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of more than 650,000 intronic and exonic variants revealed widespread patterns of mutation-driven aberrant splicing. Intronic disease mutations that are more than 30 nucleotides from any splice site alter splicing nine times as often as common variants, and missense exonic disease mutations that have the least impact on protein function are five times as likely as others to alter splicing. We detected tens of thousands of disease-causing mutations, including those involved in cancers and spinal muscular atrophy. Examination of intronic and exonic variants found using whole-genome sequencing of individuals with autism revealed misspliced genes with neurodevelopmental phenotypes. Our approach provides evidence for causal variants and should enable new discoveries in precision medicine.

  20. Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+ Monocytes into Macrophages

    PubMed Central

    Laoui, Damya; Van Overmeire, Eva; Guilliams, Martin; Schouppe, Elio; Tacke, Frank; deVries, Carlie J.; De Baetselier, Patrick; Beschin, Alain

    2015-01-01

    Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C– monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C– monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C– monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C– monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C– monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C– monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C– monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C– or Ly6C

  1. Ly6C+ monocyte efferocytosis and cross-presentation of cell-associated antigens

    PubMed Central

    Larson, S R; Atif, S M; Gibbings, S L; Thomas, S M; Prabagar, M G; Danhorn, T; Leach, S M; Henson, P M; Jakubzick, C V

    2016-01-01

    Recently it was shown that circulating Ly6C+ monocytes traffic from tissue to the draining lymph nodes (LNs) with minimal alteration in their overall phenotype. Furthermore, in the steady state, Ly6C+ monocytes are as abundant as classical dendritic cells (DCs) within the draining LNs, and even more abundant during inflammation. However, little is known about the functional roles of constitutively trafficking Ly6C+ monocytes. In this study we investigated whether Ly6C+ monocytes can efferocytose (acquire dying cells) and cross-present cell-associated antigen, a functional property particularly attributed to Batf3+ DCs. We demonstrated that Ly6C+ monocytes intrinsically efferocytose and cross-present cell-associated antigen to CD8+ T cells. In addition, efferocytosis was enhanced upon direct activation of the Ly6C+ monocytes through its corresponding TLRs, TLR4 and TLR7. However, only ligation of TLR7, and not TLR4, enhanced cross-presentation by Ly6C+ monocytes. Overall, this study outlines two functional roles, among others, that Ly6C+ monocytes have during an adaptive immune response. PMID:26990659

  2. 40 CFR 721.2088 - Carboxylic acids, (C6-C9) branched and linear.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... linear. 721.2088 Section 721.2088 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.2088 Carboxylic acids, (C6-C9) branched and linear. (a) Chemical... as carboxylic acids, (C6-C9) branched and linear (PMNs P-93-313, 314, 315, and 316) are subject...

  3. 40 CFR 721.2088 - Carboxylic acids, (C6-C9) branched and linear.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... linear. 721.2088 Section 721.2088 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.2088 Carboxylic acids, (C6-C9) branched and linear. (a) Chemical... as carboxylic acids, (C6-C9) branched and linear (PMNs P-93-313, 314, 315, and 316) are subject...

  4. 40 CFR 721.2088 - Carboxylic acids, (C6-C9) branched and linear.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... linear. 721.2088 Section 721.2088 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.2088 Carboxylic acids, (C6-C9) branched and linear. (a) Chemical... as carboxylic acids, (C6-C9) branched and linear (PMNs P-93-313, 314, 315, and 316) are subject...

  5. 40 CFR 721.2088 - Carboxylic acids, (C6-C9) branched and linear.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... linear. 721.2088 Section 721.2088 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.2088 Carboxylic acids, (C6-C9) branched and linear. (a) Chemical... as carboxylic acids, (C6-C9) branched and linear (PMNs P-93-313, 314, 315, and 316) are subject...

  6. Revealing the Complexity of Health Determinants in Resource-poor Settings

    PubMed Central

    Lewis, Fraser I.; McCormick, Benjamin J. J.

    2012-01-01

    An epidemiologic systems analysis of diarrhea in children in Pakistan is presented. Application of additive Bayesian network modeling to 2005–2006 data from the Pakistan Social and Living Standards Measurement Survey reveals the complexity of child diarrhea as a disease system. The key distinction between standard analytical approaches, such as multivariable regression, and Bayesian network analyses is that the latter attempt to not only identify statistically associated variables but also, additionally and empirically, separate these into those directly and indirectly dependent upon the outcome variable. Such discrimination is vastly more ambitious but has the potential to reveal far more about key features of complex disease systems. Additive Bayesian network analyses across 41 variables from the Pakistan Social and Living Standards Measurement Survey identified 182 direct dependencies but with only 3 variables: 1) access to a dry pit latrine (protective; odds ratio = 0.67); 2) access to an atypical water source (protective; odds ratio = 0.49); and 3) no formal garbage collection (unprotective; odds ratio = 1.32), supported as directly dependent with the presence of diarrhea. All but 2 of the remaining variables were also, in turn, directly or indirectly dependent upon these 3 key variables. These results are contrasted with the use of a standard approach (multivariable regression). PMID:23139247

  7. Genome Mining for Radical SAM Protein Determinants Reveals Multiple Sactibiotic-Like Gene Clusters

    PubMed Central

    Murphy, Kiera; O'Sullivan, Orla; Rea, Mary C.; Cotter, Paul D.; Ross, R. Paul; Hill, Colin

    2011-01-01

    Thuricin CD is a two-component bacteriocin produced by Bacillus thuringiensis that kills a wide range of clinically significant Clostridium difficile. This bacteriocin has recently been characterized and consists of two distinct peptides, Trnβ and Trnα, which both possess 3 intrapeptide sulphur to α-carbon bridges and act synergistically. Indeed, thuricin CD and subtilosin A are the only antimicrobials known to possess these unusual structures and are known as the sactibiotics (sulplur to alpha carbon-containing antibiotics). Analysis of the thuricin CD-associated gene cluster revealed the presence of genes encoding two highly unusual SAM proteins (TrnC and TrnD) which are proposed to be responsible for these unusual post-translational modifications. On the basis of the frequently high conservation among enzymes responsible for the post-translational modification of specific antimicrobials, we performed an in silico screen for novel thuricin CD–like gene clusters using the TrnC and TrnD radical SAM proteins as driver sequences to perform an initial homology search against the complete non-redundant database. Fifteen novel thuricin CD–like gene clusters were identified, based on the presence of TrnC and TrnD homologues in the context of neighbouring genes encoding potential bacteriocin structural peptides. Moreover, metagenomic analysis revealed that TrnC or TrnD homologs are present in a variety of metagenomic environments, suggesting a widespread distribution of thuricin-like operons in a variety of environments. In-silico analysis of radical SAM proteins is sufficient to identify novel putative sactibiotic clusters. PMID:21760885

  8. The Rrp6 C-terminal domain binds RNA and activates the nuclear RNA exosome

    PubMed Central

    Wasmuth, Elizabeth V.; Lima, Christopher D.

    2017-01-01

    The eukaryotic RNA exosome is an essential, multi-subunit complex that catalyzes RNA turnover, maturation, and quality control processes. Its non-catalytic donut-shaped core includes 9 subunits that associate with the 3′ to 5′ exoribonucleases Rrp6, and Rrp44/Dis3, a subunit that also catalyzes endoribonuclease activity. Although recent structures and biochemical studies of RNA bound exosomes from S. cerevisiae revealed that the Exo9 central channel guides RNA to either Rrp6 or Rrp44 using partially overlapping and mutually exclusive paths, several issues related to RNA recruitment remain. Here, we identify activities for the highly basic Rrp6 C-terminal tail that we term the ‘lasso’ because it binds RNA and stimulates ribonuclease activities associated with Rrp44 and Rrp6 within the 11-subunit nuclear exosome. Stimulation is dependent on the Exo9 central channel, and the lasso contributes to degradation and processing activities of exosome substrates in vitro and in vivo. Finally, we present evidence that the Rrp6 lasso may be a conserved feature of the eukaryotic RNA exosome. PMID:27899565

  9. Genomic analysis reveals major determinants of cis-regulatory variation in Capsella grandiflora

    PubMed Central

    Steige, Kim A.; Laenen, Benjamin; Reimegård, Johan; Slotte, Tanja

    2017-01-01

    Understanding the causes of cis-regulatory variation is a long-standing aim in evolutionary biology. Although cis-regulatory variation has long been considered important for adaptation, we still have a limited understanding of the selective importance and genomic determinants of standing cis-regulatory variation. To address these questions, we studied the prevalence, genomic determinants, and selective forces shaping cis-regulatory variation in the outcrossing plant Capsella grandiflora. We first identified a set of 1,010 genes with common cis-regulatory variation using analyses of allele-specific expression (ASE). Population genomic analyses of whole-genome sequences from 32 individuals showed that genes with common cis-regulatory variation (i) are under weaker purifying selection and (ii) undergo less frequent positive selection than other genes. We further identified genomic determinants of cis-regulatory variation. Gene body methylation (gbM) was a major factor constraining cis-regulatory variation, whereas presence of nearby transposable elements (TEs) and tissue specificity of expression increased the odds of ASE. Our results suggest that most common cis-regulatory variation in C. grandiflora is under weak purifying selection, and that gene-specific functional constraints are more important for the maintenance of cis-regulatory variation than genome-scale variation in the intensity of selection. Our results agree with previous findings that suggest TE silencing affects nearby gene expression, and provide evidence for a link between gbM and cis-regulatory constraint, possibly reflecting greater dosage sensitivity of body-methylated genes. Given the extensive conservation of gbM in flowering plants, this suggests that gbM could be an important predictor of cis-regulatory variation in a wide range of plant species. PMID:28096395

  10. Genomic analysis reveals major determinants of cis-regulatory variation in Capsella grandiflora.

    PubMed

    Steige, Kim A; Laenen, Benjamin; Reimegård, Johan; Scofield, Douglas G; Slotte, Tanja

    2017-01-31

    Understanding the causes of cis-regulatory variation is a long-standing aim in evolutionary biology. Although cis-regulatory variation has long been considered important for adaptation, we still have a limited understanding of the selective importance and genomic determinants of standing cis-regulatory variation. To address these questions, we studied the prevalence, genomic determinants, and selective forces shaping cis-regulatory variation in the outcrossing plant Capsella grandiflora We first identified a set of 1,010 genes with common cis-regulatory variation using analyses of allele-specific expression (ASE). Population genomic analyses of whole-genome sequences from 32 individuals showed that genes with common cis-regulatory variation (i) are under weaker purifying selection and (ii) undergo less frequent positive selection than other genes. We further identified genomic determinants of cis-regulatory variation. Gene body methylation (gbM) was a major factor constraining cis-regulatory variation, whereas presence of nearby transposable elements (TEs) and tissue specificity of expression increased the odds of ASE. Our results suggest that most common cis-regulatory variation in C. grandiflora is under weak purifying selection, and that gene-specific functional constraints are more important for the maintenance of cis-regulatory variation than genome-scale variation in the intensity of selection. Our results agree with previous findings that suggest TE silencing affects nearby gene expression, and provide evidence for a link between gbM and cis-regulatory constraint, possibly reflecting greater dosage sensitivity of body-methylated genes. Given the extensive conservation of gbM in flowering plants, this suggests that gbM could be an important predictor of cis-regulatory variation in a wide range of plant species.

  11. Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology.

    PubMed

    Gibson, Molly K; Forsberg, Kevin J; Dantas, Gautam

    2015-01-01

    Antibiotic resistance is a dire clinical problem with important ecological dimensions. While antibiotic resistance in human pathogens continues to rise at alarming rates, the impact of environmental resistance on human health is still unclear. To investigate the relationship between human-associated and environmental resistomes, we analyzed functional metagenomic selections for resistance against 18 clinically relevant antibiotics from soil and human gut microbiota as well as a set of multidrug-resistant cultured soil isolates. These analyses were enabled by Resfams, a new curated database of protein families and associated highly precise and accurate profile hidden Markov models, confirmed for antibiotic resistance function and organized by ontology. We demonstrate that the antibiotic resistance functions that give rise to the resistance profiles observed in environmental and human-associated microbial communities significantly differ between ecologies. Antibiotic resistance functions that most discriminate between ecologies provide resistance to β-lactams and tetracyclines, two of the most widely used classes of antibiotics in the clinic and agriculture. We also analyzed the antibiotic resistance gene composition of over 6000 sequenced microbial genomes, revealing significant enrichment of resistance functions by both ecology and phylogeny. Together, our results indicate that environmental and human-associated microbial communities harbor distinct resistance genes, suggesting that antibiotic resistance functions are largely constrained by ecology.

  12. Seasonal determinations of algal virus decay rates reveal overwintering in a temperate freshwater pond.

    PubMed

    Long, Andrew M; Short, Steven M

    2016-07-01

    To address questions about algal virus persistence (i.e., continued existence) in the environment, rates of decay of infectivity for two viruses that infect Chlorella-like algae, ATCV-1 and CVM-1, and a virus that infects the prymnesiophyte Chrysochromulina parva, CpV-BQ1, were estimated from in situ incubations in a temperate, seasonally frozen pond. A series of experiments were conducted to estimate rates of decay of infectivity in all four seasons with incubations lasting 21 days in spring, summer and autumn, and 126 days in winter. Decay rates observed across this study were relatively low compared with previous estimates obtained for other algal viruses, and ranged from 0.012 to 11% h(-1). Overall, the virus CpV-BQ1 decayed most rapidly whereas ATCV-1 decayed most slowly, but for all viruses the highest decay rates were observed during the summer and the lowest were observed during the winter. Furthermore, the winter incubations revealed the ability of each virus to overwinter under ice as ATCV-1, CVM-1 and CpV-BQ1 retained up to 48%, 19% and 9% of their infectivity after 126 days, respectively. The observed resilience of algal viruses in a seasonally frozen freshwater pond provides a mechanism that can support the maintenance of viral seed banks in nature. However, the high rates of decay observed in the summer demonstrate that virus survival and therefore environmental persistence can be subject to seasonal bottlenecks.

  13. Molecular Determinants of Juvenile Hormone Action as Revealed by 3D QSAR Analysis in Drosophila

    PubMed Central

    Beňo, Milan; Farkaš, Robert

    2009-01-01

    Background Postembryonic development, including metamorphosis, of many animals is under control of hormones. In Drosophila and other insects these developmental transitions are regulated by the coordinate action of two principal hormones, the steroid ecdysone and the sesquiterpenoid juvenile hormone (JH). While the mode of ecdysone action is relatively well understood, the molecular mode of JH action remains elusive. Methodology/Principal Findings To gain more insights into the molecular mechanism of JH action, we have tested the biological activity of 86 structurally diverse JH agonists in Drosophila melanogaster. The results were evaluated using 3D QSAR analyses involving CoMFA and CoMSIA procedures. Using this approach we have generated both computer-aided and species-specific pharmacophore fingerprints of JH and its agonists, which revealed that the most active compounds must possess an electronegative atom (oxygen or nitrogen) at both ends of the molecule. When either of these electronegative atoms are replaced by carbon or the distance between them is shorter than 11.5 Å or longer than 13.5 Å, their biological activity is dramatically decreased. The presence of an electron-deficient moiety in the middle of the JH agonist is also essential for high activity. Conclusions/Significance The information from 3D QSAR provides guidelines and mechanistic scope for identification of steric and electrostatic properties as well as donor and acceptor hydrogen-bonding that are important features of the ligand-binding cavity of a JH target protein. In order to refine the pharmacophore analysis and evaluate the outcomes of the CoMFA and CoMSIA study we used pseudoreceptor modeling software PrGen to generate a putative binding site surrogate that is composed of eight amino acid residues corresponding to the defined molecular interactions. PMID:19547707

  14. Analysis on Population Level Reveals Trappability of Wild Rodents Is Determined by Previous Trap Occupant

    PubMed Central

    2015-01-01

    Live trapping is central to the study of small mammals. Thus, any bias needs to be understood and accounted for in subsequent analyses to ensure accurate population estimates. One rarely considered bias is the behavioural response of individuals to the trap, in particular the olfactory cues left behind by previous occupants (PO). We used a data set of 8,115 trap nights spanning 17 separate trapping sessions between August 2002 and November 2013 in Wytham Woods, Oxfordshire, UK to examine if the decision to enter a trap was affected by the PO, if this was detectable in traditional Capture-Mark-Recapture trapping data (i.e., individuals not uniquely marked), and if it was possible for this effect to bias the population estimates obtained. Data were collected on Apodemus sylvaticus, Myodes glareolus, and Microtus agrestis. Three Generalised Linear Models revealed a significant tendency for the three species to enter traps with same-species PO. With, for example, A. sylvaticus 9.1 times more likely to enter a same species PO trap compared to one that contained a M. agrestis in the grassland during the nocturnal period. Simulation highlighted that, when all other factors are equal, the species with the highest PO effect will have the highest capture rate and therefore return more accurate population estimates. Despite the large dataset, certain species-, sex-, and/ or age-combinations were under-represented, and thus no effects of any additional individual-specific characteristics could be evaluated. Uniquely marking individuals would allow for the PO effect to be disentangled from other biases such as trap-shyness and spatial heterogeneity, but may not be possible in all cases and will depend on the aims of the study and the resources available. PMID:26689683

  15. Association Studies and Legume Synteny Reveal Haplotypes Determining Seed Size in Vigna unguiculata.

    PubMed

    Lucas, Mitchell R; Huynh, Bao-Lam; da Silva Vinholes, Patricia; Cisse, Ndiaga; Drabo, Issa; Ehlers, Jeffrey D; Roberts, Philip A; Close, Timothy J

    2013-01-01

    Highly specific seed market classes for cowpea and other grain legumes exist because grain is most commonly cooked and consumed whole. Size, shape, color, and texture are critical features of these market classes and breeders target development of cultivars for market acceptance. Resistance to biotic and abiotic stresses that are absent from elite breeding material are often introgressed through crosses to landraces or wild relatives. When crosses are made between parents with different grain quality characteristics, recovery of progeny with acceptable or enhanced grain quality is problematic. Thus genetic markers for grain quality traits can help in pyramiding genes needed for specific market classes. Allelic variation dictating the inheritance of seed size can be tagged and used to assist the selection of large seeded lines. In this work we applied 1,536-plex SNP genotyping and knowledge of legume synteny to characterize regions of the cowpea genome associated with seed size. These marker-trait associations will enable breeders to use marker-based selection approaches to increase the frequency of progeny with large seed. For 804 individuals derived from eight bi-parental populations, QTL analysis was used to identify markers linked to 10 trait determinants. In addition, the population structure of 171 samples from the USDA core collection was identified and incorporated into a genome-wide association study which supported more than half of the trait-associated regions important in the bi-parental populations. Seven of the total 10 QTLs were supported based on synteny to seed size associated regions identified in the related legume soybean. In addition to delivering markers linked to major trait determinants in the context of modern breeding, we provide an analysis of the diversity of the USDA core collection of cowpea to identify genepools, migrants, admixture, and duplicates.

  16. New roles for Nanos in neural cell fate determination revealed by studies in a cnidarian.

    PubMed

    Kanska, Justyna; Frank, Uri

    2013-07-15

    Nanos is a pan-metazoan germline marker, important for germ cell development and maintenance. In flies, Nanos also acts in posterior and neural development, but these functions have not been demonstrated experimentally in other animals. Using the cnidarian Hydractinia we have uncovered novel roles for Nanos in neural cell fate determination. Ectopic expression of Nanos2 increased the numbers of embryonic stinging cell progenitors, but decreased the numbers of neurons. Downregulation of Nanos2 had the opposite effect. Furthermore, Nanos2 blocked maturation of committed, post-mitotic nematoblasts. Hence, Nanos2 acts as a switch between two differentiation pathways, increasing the numbers of nematoblasts at the expense of neuroblasts, but preventing nematocyte maturation. Nanos2 ectopic expression also caused patterning defects, but these were not associated with deregulation of Wnt signaling, showing that the basic anterior-posterior polarity remained intact, and suggesting that numerical imbalance between nematocytes and neurons might have caused these defects, affecting axial patterning only indirectly. We propose that the functions of Nanos in germ cells and in neural development are evolutionarily conserved, but its role in posterior patterning is an insect or arthropod innovation.

  17. NMR Structure of Francisella tularensis Virulence Determinant Reveals Structural Homology to Bet v1 Allergen Proteins.

    PubMed

    Zook, James; Mo, Gina; Sisco, Nicholas J; Craciunescu, Felicia M; Hansen, Debra T; Baravati, Bobby; Cherry, Brian R; Sykes, Kathryn; Wachter, Rebekka; Van Horn, Wade D; Fromme, Petra

    2015-06-02

    Tularemia is a potentially fatal bacterial infection caused by Francisella tularensis, and is endemic to North America and many parts of northern Europe and Asia. The outer membrane lipoprotein, Flpp3, has been identified as a virulence determinant as well as a potential subunit template for vaccine development. Here we present the first structure for the soluble domain of Flpp3 from the highly infectious Type A SCHU S4 strain, derived through high-resolution solution nuclear magnetic resonance (NMR) spectroscopy; the first structure of a lipoprotein from the genus Francisella. The Flpp3 structure demonstrates a globular protein with an electrostatically polarized surface containing an internal cavity-a putative binding site based on the structurally homologous Bet v1 protein family of allergens. NMR-based relaxation studies suggest loop regions that potentially modulate access to the internal cavity. The Flpp3 structure may add to the understanding of F. tularensis virulence and contribute to the development of effective vaccines.

  18. Synthetic CpG islands reveal DNA sequence determinants of chromatin structure

    PubMed Central

    Wachter, Elisabeth; Quante, Timo; Merusi, Cara; Arczewska, Aleksandra; Stewart, Francis; Webb, Shaun; Bird, Adrian

    2014-01-01

    The mammalian genome is punctuated by CpG islands (CGIs), which differ sharply from the bulk genome by being rich in G + C and the dinucleotide CpG. CGIs often include transcription initiation sites and display ‘active’ histone marks, notably histone H3 lysine 4 methylation. In embryonic stem cells (ESCs) some CGIs adopt a ‘bivalent’ chromatin state bearing simultaneous ‘active’ and ‘inactive’ chromatin marks. To determine whether CGI chromatin is developmentally programmed at specific genes or is imposed by shared features of CGI DNA, we integrated artificial CGI-like DNA sequences into the ESC genome. We found that bivalency is the default chromatin structure for CpG-rich, G + C-rich DNA. A high CpG density alone is not sufficient for this effect, as A + T-rich sequence settings invariably provoke de novo DNA methylation leading to loss of CGI signature chromatin. We conclude that both CpG-richness and G + C-richness are required for induction of signature chromatin structures at CGIs. DOI: http://dx.doi.org/10.7554/eLife.03397.001 PMID:25259796

  19. A recombination event in the 5' flanking region of the Ly-6C gene correlates with impaired expression in the NOD, NZB and ST strains of mice.

    PubMed Central

    Philbrick, W M; Maher, S E; Bridgett, M M; Bothwell, A L

    1990-01-01

    The murine alloantigen, Ly-6C, is found on 45% of bone marrow cells, 25% of splenocytes and 15% of lymph node cells in all inbred strains of mice tested, with the exception of NOD, NZB and ST. In these three strains, Ly-6C expression can be detected on only 5% of bone marrow cells and not at all on cells from spleen or lymph node. NOD and NZB, which are models for the autoimmune diseases, diabetes and lupus, respectively, also exhibit a depressed syngeneic mixed lymphocyte reaction. Southern blot analysis reveals a restriction fragment length polymorphism involving the Ly-6C gene which is unique to these three strains. Cloning of the affected genomic segment from the NOD mouse indicates the presence of an interruption in the flanking region of the Ly-6C gene at a point 475 bp upstream of the transcription initiation site and the consequent separation of distal 5' sequences from the body of the gene by at least 10 kb. Inspection of the recombination borders reveals a set of inverted copies of a mouse repetitive R element. Transfection of the Ly-6C genes from NOD and BALB/c into a murine carcinoma line indicates relative functional impairment of the NOD gene, thus paralleling performance in vivo. Images Fig. 2. PMID:2164472

  20. Clonal expansion of the macrolide resistant ST386 within pneumococcal serotype 6C in France.

    PubMed

    Janoir, Claire; Cohen, Robert; Levy, Corinne; Bingen, Edouard; Lepoutre, Agnès; Gutmann, Laurent; Varon, Emmanuelle

    2014-01-01

    In France, the use of the 7-valent pneumococcal conjugate vaccine (PCV7) lead to an overall significant decrease in PCV7 invasive pneumococcal disease (IPD) incidence. However, the decrease in vaccine serotype prevalence was partially counterbalanced by the serotype replacement phenomenon. In this study, we analyzed the role of the newly described serotype 6C as one of the replacement serotypes. This work was conducted on a large time scale from the early PCV7 era (2002-2003) to the PCV13 era (2010-2011), both on IPD strains recovered from the whole population and nasopharyngeal colonizing strains isolated in infant less than two years, who are known to be the main reservoir for pneumococci. Serotype 6C took advantage over 6A and 6B serotypes, which both decreased over time. A continuous and significant increase in 6C IPD was observed in adults along the study period; in contrast, in children less than two years, only an increase in 6C nasopharyngeal carriage was found, the prevalence of serotype 6C in IPD remaining very low over time. Among 101 6C invasive and colonizing strains studied by MLST, 24 STs were found to be related to three major clonal complexes, CC395, CC176, and CC315. STs related to CC176 tend to disappear after 2009 and were essentially replaced by ST386 (CC315), which dramatically increased over time. This clonal expansion may be explained by the erythromycin and tetracycline resistances associated with this clone. Finally, the decrease observed in nasopharyngeal 6C carriage since 2010, likely related to the PCV13 introduction in the French immunization schedule, is expected to lead to a decrease in 6C IPD in adults thereafter.

  1. Clonal Expansion of the Macrolide Resistant ST386 within Pneumococcal Serotype 6C in France

    PubMed Central

    Janoir, Claire; Cohen, Robert; Levy, Corinne; Bingen, Edouard; Lepoutre, Agnès; Gutmann, Laurent; Varon, Emmanuelle

    2014-01-01

    In France, the use of the 7-valent pneumococcal conjugate vaccine (PCV7) lead to an overall significant decrease in PCV7 invasive pneumococcal disease (IPD) incidence. However, the decrease in vaccine serotype prevalence was partially counterbalanced by the serotype replacement phenomenon. In this study, we analyzed the role of the newly described serotype 6C as one of the replacement serotypes. This work was conducted on a large time scale from the early PCV7 era (2002–2003) to the PCV13 era (2010–2011), both on IPD strains recovered from the whole population and nasopharyngeal colonizing strains isolated in infant less than two years, who are known to be the main reservoir for pneumococci. Serotype 6C took advantage over 6A and 6B serotypes, which both decreased over time. A continuous and significant increase in 6C IPD was observed in adults along the study period; in contrast, in children less than two years, only an increase in 6C nasopharyngeal carriage was found, the prevalence of serotype 6C in IPD remaining very low over time. Among 101 6C invasive and colonizing strains studied by MLST, 24 STs were found to be related to three major clonal complexes, CC395, CC176, and CC315. STs related to CC176 tend to disappear after 2009 and were essentially replaced by ST386 (CC315), which dramatically increased over time. This clonal expansion may be explained by the erythromycin and tetracycline resistances associated with this clone. Finally, the decrease observed in nasopharyngeal 6C carriage since 2010, likely related to the PCV13 introduction in the French immunization schedule, is expected to lead to a decrease in 6C IPD in adults thereafter. PMID:24603763

  2. Cytogenetic Insights into the Evolution of Chromosomes and Sex Determination Reveal Striking Homology of Turtle Sex Chromosomes to Amphibian Autosomes.

    PubMed

    Montiel, Eugenia E; Badenhorst, Daleen; Lee, Ling S; Literman, Robert; Trifonov, Vladimir; Valenzuela, Nicole

    2016-01-01

    Turtle karyotypes are highly conserved compared to other vertebrates; yet, variation in diploid number (2n = 26-68) reflects profound genomic reorganization, which correlates with evolutionary turnovers in sex determination. We evaluate the published literature and newly collected comparative cytogenetic data (G- and C-banding, 18S-NOR, and telomere-FISH mapping) from 13 species spanning 2n = 28-68 to revisit turtle genome evolution and sex determination. Interstitial telomeric sites were detected in multiple lineages that underwent diploid number and sex determination turnovers, suggesting chromosomal rearrangements. C-banding revealed potential interspecific variation in centromere composition and interstitial heterochromatin at secondary constrictions. 18S-NORs were detected in secondary constrictions in a single chromosomal pair per species, refuting previous reports of multiple NORs in turtles. 18S-NORs are linked to ZW chromosomes in Apalone and Pelodiscus and to X (not Y) in Staurotypus. Notably, comparative genomics across amniotes revealed that the sex chromosomes of several turtles, as well as mammals and some lizards, are homologous to components of Xenopus tropicalis XTR1 (carrying Dmrt1). Other turtle sex chromosomes are homologous to XTR4 (carrying Wt1). Interestingly, all known turtle sex chromosomes, except in Trionychidae, evolved via inversions around Dmrt1 or Wt1. Thus, XTR1 appears to represent an amniote proto-sex chromosome (perhaps linked ancestrally to XTR4) that gave rise to turtle and other amniote sex chromosomes.

  3. An ion selectivity filter in the extracellular domain of Cys-loop receptors reveals determinants for ion conductance.

    PubMed

    Hansen, Scott B; Wang, Hai-Long; Taylor, Palmer; Sine, Steven M

    2008-12-26

    Neurotransmitter binding to Cys-loop receptors promotes a prodigious transmembrane flux of several million ions/s, but to date, structural determinants of ion flux have been identified flanking the membrane-spanning region. Using x-ray crystallography, sequence analysis, and single-channel recording, we identified a novel determinant of ion conductance near the point of entry of permeant ions. Co-crystallization of acetylcholine-binding protein with sulfate anions revealed coordination of SO4(2-) with a ring of lysines at a position equivalent to 24 A above the lipid membrane in homologous Cys-loop receptors. Analysis of multiple sequence alignments revealed that residues equivalent to the ring of lysines are negatively charged in cation-selective receptors but are positively charged in anion-selective receptors. Charge reversal of side chains at homologous positions in the nicotinic receptor from the motor end plate decreases unitary conductance up to 80%. Selectivity filters stemming from transmembrane alpha-helices have similar pore diameters and compositions of amino acids. These findings establish that when the channel opens under a physiological electrochemical gradient, permeant ions are initially stabilized within the extracellular vestibule of Cys-loop receptors, and this stabilization is a major determinant of ion conductance.

  4. Denatured-state energy landscapes of a protein structural database reveal the energetic determinants of a framework model for folding.

    PubMed

    Wang, Suwei; Gu, Jenny; Larson, Scott A; Whitten, Steven T; Hilser, Vincent J

    2008-09-19

    Position-specific denatured-state thermodynamics were determined for a database of human proteins by use of an ensemble-based model of protein structure. The results of modeling denatured protein in this manner reveal important sequence-dependent thermodynamic properties in the denatured ensembles as well as fundamental differences between the denatured and native ensembles in overall thermodynamic character. The generality and robustness of these results were validated by performing fold-recognition experiments, whereby sequences were matched with their respective folds based on amino acid propensities for the different energetic environments in the protein, as determined through cluster analysis. Correlation analysis between structure and energetic information revealed that sequence segments destined for beta-sheet in the final native fold are energetically more predisposed to a broader repertoire of states than are sequence segments destined for alpha-helix. These results suggest that within the subensemble of mostly unstructured states, the energy landscapes are dominated by states in which parts of helices adopt structure, whereas structure formation for sequences destined for beta-strand is far less probable. These results support a framework model of folding, which suggests that, in general, the denatured state has evolutionarily evolved to avoid low-energy conformations in sequences that ultimately adopt beta-strand. Instead, the denatured state evolved so that sequence segments that ultimately adopt alpha-helix and coil will have a high intrinsic structure formation capability, thus serving as potential nucleation sites.

  5. Kinetics of Arsenic Methylation by Freshly Isolated B6C3F1 Mouse Hepatocytes

    SciTech Connect

    Kedderis, Gregory L.; Elmore, Amy R.; Crecelius, Eric A.; Yager, Janice W.; Goldsworthy, Thomas L.

    2006-06-10

    The toxic and carcinogenic effects of arsenic may be mediated by both inorganic and methylated arsenic species. The methylation of arsenicIII takes place via sequential oxidative methylation and reduction steps to form monomethylarsenic (MMA) and dimethylarsenic (DMA) species. The kinetics of arsenic methylation were determined in freshly isolated hepatocytes from male B6C3F1 mice. Hepatocytes (>90% viability) were isolated by collagenase perfusion and suspended in Williams Medium E with various concentrations of arsenicIII (sodium m-arsenite). Aliquots of the cell suspension were lysed with 1.0% Triton X-100 and analyzed for arsenic species by hydride generation-atomic absorption spectrometry. The formation of MMAIII from sodium arsenite (1 ?M) was linear with respect to time for >90 min. DMAIII formation did not become significant until 60 min. MMAV and DMAV were not consistently observed in the incubations. These results suggest that the reduction of MMAV to MMAIII is rapid relative to the methylation rate since MMAV was not observed as a major product of arsenicIII metabolism in mouse hepatocytes. Metabolism of arsenicV was not observed in mouse hepatocytes, consistent with inhibition of arsenicV active cellular uptake by phosphate in the medium. The formation of MMAIII increased with increasing arsenicIII concentrations up to approximately 2 ?M and declined thereafter. The concentration dependence is consistent with a saturable methylation reaction accompanied by substrate inhibition of the reaction by arsenicIII. Kinetic analysis of the data suggested an apparent KM of approximately 3.6 ?M arsenicIII, an apparent Vmax of approximately 38.9 ?g MMAIII formed/L/hr/million cells, and an apparent KI of approximately 1.3 ?M arsenicIII. The results of this study can be used in the physiologically based pharmacokinetic model for arsenic disposition in mice to predict the concentration of MMAIII in liver and other tissues.

  6. Integrating total quality management principles with the requirements of DOE Order 5700.6C

    SciTech Connect

    Hedges, D.

    1993-03-01

    The Department of Energy has recently required its field offices, contractors, and subcontractors to implement DOE Order 5700.6C, ``Quality Assurance,`` for all work on waste management contracts. The order restructures the 18 criteria of NQA-1 and focuses on the role of management in achieving and assuring quality, performance of activities to achieve and assure quality, and management`s assessment of its performance for the purpose of identifying improvements to be made. The DOE order also introduces elements of the total quality management (TQM) philosophy, which were not present in DOE Order 5700.6B. The research community within DOE has recently issued a document entitled DOE Order 5700.6C Implementation Guide, which is more explicit about the integration of TQM principles with the implementation of DOE Order 5700.6C in research facilities. The Environmental Protection Agency is sponsoring a quality assurance standard (ANSI/ASQC E-4) to replace EPA`s QAMS 005/80. The new standard is consistent with DOE Order 5700.6C, and it also stresses the integration of TQM principles within the quality assurance process. This paper discusses the intent and philosophy of the 10 criteria of the new DOE order, the status of ANSI/ASQC E-4, and how to effectively integrate TQM principles into the quality assurance process as the conversion is made from NQA-1 to DOE Order 5700.6C. The purpose and value of DOE Order 5700.6C Implementation Guide for research will also be discussed.

  7. Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection.

    PubMed

    Hodson, Charlotte; Purkiss, Andrew; Miles, Jennifer Anne; Walden, Helen

    2014-02-04

    The combination of an E2 ubiquitin-conjugating enzyme with an E3 ubiquitin-ligase is essential for ubiquitin modification of a substrate. Moreover, the pairing dictates both the substrate choice and the modification type. The molecular details of generic E3-E2 interactions are well established. Nevertheless, the determinants of selective, specific E3-E2 recognition are not understood. There are ∼40 E2s and ∼600 E3s giving rise to a possible ∼24,000 E3-E2 pairs. Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex, revealing a specific and extensive network of additional electrostatic and hydrophobic interactions. Furthermore, we show that these specific interactions are required for selection of Ube2T over other E2s by FANCL.

  8. PENTACHLOROPHENOL POTENTIATES BENZO[A]PYRENE DNA ADDUCT FORMATION IN ADULT BUT NOT INFANT B6C3F1 MALE MICE

    EPA Science Inventory

    Abstract

    The objective of this study is to determine whether pentachlorophenol (PCP) alters benzo[a]pyrene (B[a]P) induced DNA adduct formation in infant and adult B6C3Fl mice. Mice were exposed to 55 ug B[a]P/g body weight (BW) alone and in combination with several dose...

  9. Distinct patterns of compartmentalization and proteolytic stability of PDE6C mutants linked to achromatopsia.

    PubMed

    Cheguru, Pallavi; Majumder, Anurima; Artemyev, Nikolai O

    2015-01-01

    Phosphodiesterase-6 (PDE6) is an essential effector enzyme in vertebrate photoreceptor cells. Mutations in rod and cone PDE6 cause recessive retinitis pigmentosa and achromatopsia, respectively. The mechanisms of missense PDE6 mutations underlying severe visual disorders are poorly understood. To probe these mechanisms, we expressed seven known missense mutants of cone PDE6C in rods of transgenic Xenopus laevis and examined their stability and compartmentalization. PDE6C proteins with mutations in the catalytic domain, H602L and E790K, displayed modestly reduced proteolytic stability, but they were properly targeted to the outer segment of photoreceptor cells. Mutations in the regulatory GAF domains, R104W, Y323N, and P391L led to a proteolytic degradation of the proteins involving a cleavage in the GAFb domain. Lastly, the R29W and M455V mutations residing outside the conserved PDE6 domains produced a pattern of subcellular compartmentalization different from that of PDE6C. Thus, our results suggest a spectrum of mechanisms of missense PDE6C mutations in achromatopsia including catalytic defects, protein mislocalization, or a specific sequence of proteolytic degradation.

  10. 29 CFR 780.311 - Basic conditions of section 13(a)(6)(C).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Employment in Agriculture That Is Exempted From the Minimum Wage and Overtime Pay Requirements Under Section... 29 Labor 3 2012-07-01 2012-07-01 false Basic conditions of section 13(a)(6)(C). 780.311 Section 780.311 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF...

  11. 29 CFR 780.311 - Basic conditions of section 13(a)(6)(C).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Employment in Agriculture That Is Exempted From the Minimum Wage and Overtime Pay Requirements Under Section... 29 Labor 3 2011-07-01 2011-07-01 false Basic conditions of section 13(a)(6)(C). 780.311 Section 780.311 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF...

  12. 29 CFR 780.311 - Basic conditions of section 13(a)(6)(C).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Employment in Agriculture That Is Exempted From the Minimum Wage and Overtime Pay Requirements Under Section... 29 Labor 3 2013-07-01 2013-07-01 false Basic conditions of section 13(a)(6)(C). 780.311 Section 780.311 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF...

  13. 29 CFR 780.311 - Basic conditions of section 13(a)(6)(C).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Employment in Agriculture That Is Exempted From the Minimum Wage and Overtime Pay Requirements Under Section... 29 Labor 3 2010-07-01 2010-07-01 false Basic conditions of section 13(a)(6)(C). 780.311 Section 780.311 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF...

  14. 29 CFR 780.311 - Basic conditions of section 13(a)(6)(C).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Employment in Agriculture That Is Exempted From the Minimum Wage and Overtime Pay Requirements Under Section... 29 Labor 3 2014-07-01 2014-07-01 false Basic conditions of section 13(a)(6)(C). 780.311 Section 780.311 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF...

  15. Stimulatory effect of apigenin-6-C-beta-L-fucopyranoside on insulin secretion and glycogen synthesis.

    PubMed

    Cazarolli, Luisa Helena; Folador, Poliane; Moresco, Henrique Hunger; Brighente, Inês Maria Costa; Pizzolatti, Moacir Geraldo; Silva, Fátima Regina M Barreto

    2009-11-01

    In vivo and in vitro treatments were carried out to investigate the effects of apigenin-6-C-beta-L-fucopyranoside (1), isolated from Averrhoa carambola L. (Oxalidaceae), on serum glucose and insulin levels in hyperglycemic rats as well as its effect on glycogen synthesis in normal rat soleus muscle. Apigenin-6-C-beta-L-fucopyranoside showed an acute effect on blood glucose lowering in hyperglycemic rats and stimulated glucose-induced insulin secretion. A stimulatory effect of 1 on glycogen synthesis was observed when muscles were incubated with this flavonoid and also its effect was completely nullified by pre-treatment with insulin signal transduction inhibitors. Taking this into account, the MAPK-PP1 and PI3K-GSK3 pathways are involved in the apigenin-6-C-beta-L-fucopyranoside-induced increase in glycogen synthesis in muscle. This study provides evidence for dual effects of apigenin-6-C-beta-L-fucopyranoside as an antihyperglycemic (insulin secretion) as well as an insulinomimetic (glycogen synthesis) agent.

  16. Anti-hyperglycemic action of apigenin-6-C-β-fucopyranoside from Averrhoa carambola.

    PubMed

    Cazarolli, Luisa Helena; Kappel, Virgínia Demarchi; Pereira, Danielle Fontana; Moresco, Henrique Hunger; Brighente, Inês Maria Costa; Pizzolatti, Moacir Geraldo; Silva, Fátima Regina Mena Barreto

    2012-10-01

    A stimulatory effect of apigenin-6-C-β-fucopyranoside (1) on glucose uptake was observed when rat soleus muscle was incubated with 1, 10 and 100 μM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), and HNMPA(AM)₃, an insulin receptor tyrosine kinase activity inhibitor showed that apigenin-6-C-β-fucopyranoside triggers different metabolic pathways in skeletal muscle. The oral administration of crude extract, fractions and isolated flavonoids (apigenin-6-C-β-fucopyranoside (1) and apigenin-6-C-(2″-O-α-rhamnopyranosyl)-β-fucopyranoside (2)) from Averrhoa carambola leaves exhibited a potential hypoglycemic activity in hyperglycemic normal rats. Additionally, both flavonoids significantly increased the muscle and liver glycogen content after an acute treatment. The results indicate that A. carambola can be regarded as a potent antihyperglycemic agent with insulin secretagogue and insulin mimetic properties.

  17. Genome-Wide Association and Transcriptome Analyses Reveal Candidate Genes Underlying Yield-determining Traits in Brassica napus

    PubMed Central

    Lu, Kun; Peng, Liu; Zhang, Chao; Lu, Junhua; Yang, Bo; Xiao, Zhongchun; Liang, Ying; Xu, Xingfu; Qu, Cunmin; Zhang, Kai; Liu, Liezhao; Zhu, Qinlong; Fu, Minglian; Yuan, Xiaoyan; Li, Jiana

    2017-01-01

    Yield is one of the most important yet complex crop traits. To improve our understanding of the genetic basis of yield establishment, and to identify candidate genes responsible for yield improvement in Brassica napus, we performed genome-wide association studies (GWAS) for seven yield-determining traits [main inflorescence pod number (MIPN), branch pod number (BPN), pod number per plant (PNP), seed number per pod (SPP), thousand seed weight, main inflorescence yield (MIY), and branch yield], using data from 520 diverse B. napus accessions from two different yield environments. In total, we detected 128 significant single nucleotide polymorphisms (SNPs), 93 of which were revealed as novel by integrative analysis. A combination of GWAS and transcriptome sequencing on 21 haplotype blocks from samples pooled by four extremely high-yielding or low-yielding accessions revealed the differential expression of 14 crucial candiate genes (such as Bna.MYB83, Bna.SPL5, and Bna.ROP3) associated with multiple traits or containing multiple SNPs associated with the same trait. Functional annotation and expression pattern analyses further demonstrated that these 14 candiate genes might be important in developmental processes and biomass accumulation, thus affecting the yield establishment of B. napus. These results provide valuable information for understanding the genetic mechanisms underlying the establishment of high yield in B. napus, and lay the foundation for developing high-yielding B. napus varieties. PMID:28261256

  18. Crystal structure of pentapeptide-independent chemotaxis receptor methyltransferase (CheR) reveals idiosyncratic structural determinants for receptor recognition.

    PubMed

    Batra, Monu; Sharma, Rajesh; Malik, Anjali; Dhindwal, Sonali; Kumar, Pravindra; Tomar, Shailly

    2016-12-01

    Chemotactic methyltransferase, CheR catalyse methylation of specific glutamate residues in the cytoplasmic domain of methyl-accepting chemotactic protein receptors (MCPRs). The methylation of MCPRs is essential for the chemical sensing and chemotactic bacterial mobility towards favorable chemicals or away from unfavorable ones. In this study, crystal structure of B. subtilis CheR (BsCheR) in complex with S-adenosyl-l-homocysteine (SAH) has been determined to 1.8Å resolution. This is the first report of crystal structure belonging to the pentapeptide-independent CheR (PICheR) class. Till date, only one crystal structure of CheR from S. typhimurium (StCheR) belonging to pentapeptide-dependent CheR (PDCheR) class is available. Structural analysis of BsCheR reveals a helix-X-helix motif (HXH) with Asp53 as the linker residue in the N-terminal domain. The key structural features of the PDCheR β-subdomain involved in the formation of a tight complex with the pentapeptide binding motif in MCPRs were found to be absent in the structure of BsCheR. Additionally, isothermal titration calorimetry (ITC) experiments were performed to investigate S-adenosyl-(l)-methionine (SAM) binding affinity and KD was determined to be 0.32mM. The structure of BsCheR reveals that mostly residues of the large C-terminal domain contribute to SAH binding, with contributions of few residues from the linker region and the N-terminal domain. Structural investigations and sequence analysis carried out in this study provide critical insights into the distinct receptor recognition mechanism of the PDCheR and PICheR methyltransferase classes.

  19. 76 FR 39795 - Special Conditions: Pratt and Whitney Canada Model PT6C-67E Turboshaft Engine

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-07

    ... Whitney Canada Model PT6C-67E Turboshaft Engine AGENCY: Federal Aviation Administration (FAA), DOT. ACTION... Whitney Canada (PWC) model PT6C-67E engines. The engine model will have a novel or unusual design feature... PT6C-67E turboshaft engines. If Pratt and Whitney Canada applies later for a change to the...

  20. AEG-1 expression correlates with CD133 and PPP6c levels in human glioma tissues

    PubMed Central

    Guo, Jia; Chen, Xin; Xi, Ruxing; Chang, Yuwei; Zhang, Xuanwei; Zhang, Xiaozhi

    2014-01-01

    Abstract Astrocyte elevated gene-1 (AEG-1) is associated with tumor genesis and progression in a variety of human cancers. This study aimed to explore the significance of AEG-1 in glioma and investigate whether it correlated with radioresistance of glioma cells. Immunohistochemical staining showed that the intensity of AEG-1, CD133 and PPP6c protein expression in glioma tissues increased significantly, mainly in the cytoplasm. The expression rate of AEG-1, CD133 and PPP6c were 85.9% (67/78), 60.3% (47/78) and 65.8% (51/78), respectively. AEG-1 expression was correlated with age (r = 0.227, P = 0.045), clinical stage (r = 0.491, P<0.001) and clinical grade (r = 0.450, P<0.001). No correlation was found between AEG-1 expression and other clinicopathologic parameters (P>0.05). The expression of AEG-1 was positively correlated with the expression of CD133 (r = 0.240, P  =  0.035) and PPP6c (r =  0.250, P  =  0.027). In addition, retrieved data on TCGA implied co-occurrence of genomic alterations of AEG-1 and PPP6c in glioblastoma. Our findings indicate that AEG-1 is positively correlated with CD133 and AEG-1 expression. It may play an important role in the progression of glioma and may serve as potential novel marker of chemoresistance and radioresistance. PMID:25332711

  1. Dissociation of H{sub 2} on carbon doped aluminum cluster Al{sub 6}C

    SciTech Connect

    Yang, Huihui; Zhang, Yan; Chen, Hongshan

    2014-08-14

    The dissociation of H{sub 2} molecule is the first step for chemical storage of hydrogen, and the energy barrier of the dissociation is the key factor to decide the kinetics of the regeneration of the storage material. As a light element, aluminum is an important candidate component for storage materials with high gravimetric density. This paper investigates the adsorption and dissociation of H{sub 2} on carbon doping aluminum cluster Al{sub 6}C. The study shows that doping carbon into aluminum cluster can significantly change the electronic structure and increase the stability. Al{sub 6}C has a few stable isomers with close energies and their structures are quite flexible. The molecular adsorption of H{sub 2} on Al{sub 6}C is very weak, but the H{sub 2} molecule can be dissociated easily on this cluster. The stable product of the dissociated adsorption is searched and the different paths for the dissociation are investigated. During the dissociation of H{sub 2}, the structure of the cluster adjusts accordingly, and strong orbital interaction between the hydrogen and the cluster occurs. The calculated energy barrier for the dissociation is only 0.30 eV, which means the dissociation can take place at moderate temperatures.

  2. Developmental validation of the PowerPlex(®) Fusion 6C System.

    PubMed

    Ensenberger, Martin G; Lenz, Kristy A; Matthies, Learden K; Hadinoto, Gregory M; Schienman, John E; Przech, Angela J; Morganti, Michael W; Renstrom, Daniel T; Baker, Victoria M; Gawrys, Kori M; Hoogendoorn, Marlijn; Steffen, Carolyn R; Martín, Pablo; Alonso, Antonio; Olson, Hope R; Sprecher, Cynthia J; Storts, Douglas R

    2016-03-01

    The PowerPlex(®) Fusion 6C System is a 27-locus, six-dye, multiplex that includes all markers in the expanded CODIS core loci and increases overlap with STR database standards throughout the world. Additionally, it contains two, rapidly mutating, Y-STRs and is capable of both casework and database workflows, including direct amplification. A multi-laboratory developmental validation study was performed on the PowerPlex(®) Fusion 6C System. Here, we report the results of that study which followed SWGDAM guidelines and includes data for: species specificity, sensitivity, stability, precision, reproducibility and repeatability, case-type samples, concordance, stutter, DNA mixtures, and PCR-based procedures. Where appropriate we report data from both extracted DNA samples and direct amplification samples from various substrates and collection devices. Samples from all studies were separated on both Applied Biosystems 3500 series and 6-dye capable 3130 series Genetic Analyzers and data is reported for each. Together, the data validate the design and demonstrate the performance of the PowerPlex(®) Fusion 6C System.

  3. Cell surface glycoproteins from Thermoplasma acidophilum are modified with an N-linked glycan containing 6-C-sulfofucose.

    PubMed

    Vinogradov, Evgeny; Deschatelets, Lise; Lamoureux, Marc; Patel, Girishchandra B; Tremblay, Tammy-Lynn; Robotham, Anna; Goneau, Marie-France; Cummings-Lorbetskie, Cathy; Watson, David C; Brisson, Jean-Robert; Kelly, John F; Gilbert, Michel

    2012-09-01

    Thermoplasma acidophilum is a thermoacidophilic archaeon that grows optimally at pH 2 and 59°C. This extremophile is remarkable by the absence of a cell wall or an S-layer. Treating the cells with Triton X-100 at pH 3 allowed the extraction of all of the cell surface glycoproteins while keeping cells intact. The extracted glycoproteins were partially purified by cation-exchange chromatography, and we identified five glycoproteins by N-terminal sequencing and mass spectrometry of in-gel tryptic digests. These glycoproteins are positive for periodic acid-Schiff staining, have a high content of Asn including a large number in the Asn-X-Ser/Thr sequon and have apparent masses that are 34-48% larger than the masses deduced from their amino acid sequences. The pooled glycoproteins were digested with proteinase K and the purified glycopeptides were analyzed by NMR. Structural determination showed that the carbohydrate part was represented by two structures in nearly equal amounts, differing by the presence of one terminal mannose residue. The larger glycan chain consists of eight residues: six hexoses, one heptose and one sugar with an unusual residue mass of 226 Da which was identified as 6-deoxy-6-C-sulfo-D-galactose (6-C-sulfo-D-fucose). Mass spectrometry analyses of the peptides obtained by trypsin and chymotrypsin digestion confirmed the principal structures to be those determined by NMR and identified 14 glycopeptides derived from the main glycoprotein, Ta0280, all containing the Asn-X-Ser/Thr sequons. Thermoplasma acidophilum appears to have a "general" protein N-glycosylation system that targets a number of cell surface proteins.

  4. Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

    PubMed Central

    Huff, J E; Haseman, J K; DeMarini, D M; Eustis, S; Maronpot, R R; Peters, A C; Persing, R L; Chrisp, C E; Jacobs, A C

    1989-01-01

    Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence

  5. Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

    SciTech Connect

    Guo, Tai L.; Wang, Yunbiao; Xiong, Tao; Ling, Xiao; Zheng, Jianfeng

    2014-11-01

    Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiation of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet.

  6. A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration

    PubMed Central

    Zhang, Liyun; Xiang, Lue; Liu, Yiwen; Venkatraman, Prahatha; Chong, Leelyn; Cho, Jin; Bonilla, Sylvia; Jin, Zi-Bing; Pang, Chi Pui; Ko, Kam Ming; Ma, Ping

    2016-01-01

    Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants’ eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend

  7. Phosphorylation of eIF2α triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma.

    PubMed

    Wengrod, Jordan; Wang, Ding; Weiss, Sarah; Zhong, Hua; Osman, Iman; Gardner, Lawrence B

    2015-03-10

    Amino acid deprivation promotes the inhibition of the kinase complex mTORC1 (mammalian target of rapamycin complex 1) and activation of the kinase GCN2 (general control nonrepressed 2). Signaling pathways downstream of both kinases have been thought to independently induce autophagy. We showed that these two amino acid-sensing systems are linked. We showed that pharmacological inhibition of mTORC1 led to activation of GCN2 and phosphorylation of the eukaryotic initiation factor 2α (eIF2α) in a mechanism dependent on the catalytic subunit of protein phosphatase 6 (PP6C). Autophagy induced by pharmacological inhibition of mTORC1 required PP6C, GCN2, and eIF2α phosphorylation. Although some of the PP6C mutants found in melanoma did not form a strong complex with PP6 regulatory subunits and were rapidly degraded, these mutants paradoxically stabilized PP6C encoded by the wild-type allele and increased eIF2α phosphorylation. Furthermore, these PP6C mutations were associated with increased autophagy in vitro and in human melanoma samples. Thus, these data showed that GCN2 activation and phosphorylation of eIF2α in response to mTORC1 inhibition are necessary for autophagy. Additionally, we described a role for PP6C in this process and provided a mechanism for PP6C mutations associated with melanoma.

  8. Tumor induction by monoenergetic neutrons in B6C3F1 mice.

    PubMed

    Watanabe, Hiromitsu; Kashimoto, Naoki; Kajimura, Junko; Ishikawa, Masayori; Kamiya, Kenji

    2007-05-01

    This study was undertaken to investigate induction of tumors by monoenergetic neutrons in B6C3F1 mice. Individual groups of 6 week-old animals of both sexes (about 30 mice/group) were exposed to 0.5 Gy of various monoenergetic neutrons (dose rate 0.5 cGy/min) and then observed for 13 months. The incidences of tumors (mainly liver neoplasms) in non-irradiated male and female controls were 11% and 0%, respectively. In the irradiated animals, the incidences were 53%, 50%, 60% and 43% in males, and 75%, 81%, 71%, and 85% in females, after 0.18, 0.32, 0.6 and 1.0 MeV neutron exposure, respectively. There were no significant differences in the tumor induction rate among the different energy groups.

  9. Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

    PubMed Central

    Viringipurampeer, I A; Shan, X; Gregory-Evans, K; Zhang, J P; Mohammadi, Z; Gregory-Evans, C Y

    2014-01-01

    Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6cw59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6cw59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6cw59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment. PMID:24413151

  10. Genomic analysis of the Pacific oyster (Crassostrea gigas) reveals possible conservation of vertebrate sex determination in a mollusc.

    PubMed

    Zhang, Na; Xu, Fei; Guo, Ximing

    2014-09-11

    Despite the prevalence of sex in animal kingdom, we have only limited understanding of how sex is determined and evolved in many taxa. The mollusc Pacific oyster Crassostrea gigas exhibits complex modes of sexual reproduction that consists of protandric dioecy, sex change, and occasional hermaphroditism. This complex system is controlled by both environmental and genetic factors through unknown molecular mechanisms. In this study, we investigated genes related to sex-determining pathways in C. gigas through transcriptome sequencing and analysis of female and male gonads. Our analysis identified or confirmed novel homologs in the oyster of key sex-determining genes (SoxH or Sry-like and FoxL2) that were thought to be vertebrate-specific. Their expression profile in C. gigas is consistent with conserved roles in sex determination, under a proposed model where a novel testis-determining CgSoxH may serve as a primary regulator, directly or indirectly interacting with a testis-promoting CgDsx and an ovary-promoting CgFoxL2. Our findings plus previous results suggest that key vertebrate sex-determining genes such as Sry and FoxL2 may not be inventions of vertebrates. The presence of such genes in a mollusc with expression profiles consistent with expected roles in sex determination suggest that sex determination may be deeply conserved in animals, despite rapid evolution of the regulatory pathways that in C. gigas may involve both genetic and environmental factors.

  11. Genomic Analysis of the Pacific Oyster (Crassostrea gigas) Reveals Possible Conservation of Vertebrate Sex Determination in a Mollusc

    PubMed Central

    Zhang, Na; Xu, Fei; Guo, Ximing

    2014-01-01

    Despite the prevalence of sex in animal kingdom, we have only limited understanding of how sex is determined and evolved in many taxa. The mollusc Pacific oyster Crassostrea gigas exhibits complex modes of sexual reproduction that consists of protandric dioecy, sex change, and occasional hermaphroditism. This complex system is controlled by both environmental and genetic factors through unknown molecular mechanisms. In this study, we investigated genes related to sex-determining pathways in C. gigas through transcriptome sequencing and analysis of female and male gonads. Our analysis identified or confirmed novel homologs in the oyster of key sex-determining genes (SoxH or Sry-like and FoxL2) that were thought to be vertebrate-specific. Their expression profile in C. gigas is consistent with conserved roles in sex determination, under a proposed model where a novel testis-determining CgSoxH may serve as a primary regulator, directly or indirectly interacting with a testis-promoting CgDsx and an ovary-promoting CgFoxL2. Our findings plus previous results suggest that key vertebrate sex-determining genes such as Sry and FoxL2 may not be inventions of vertebrates. The presence of such genes in a mollusc with expression profiles consistent with expected roles in sex determination suggest that sex determination may be deeply conserved in animals, despite rapid evolution of the regulatory pathways that in C. gigas may involve both genetic and environmental factors. PMID:25213692

  12. Effect of denervation and reinnervation on oxidation of 6-(C-14) glucose by rat skeletal muscle homogenates

    NASA Technical Reports Server (NTRS)

    Dubois, D. C.; Max, S. R.

    1983-01-01

    The effects of denervation and reinnervation of the rat extensor digitorum longus muscle on the oxidation of 6-(C-14) glucose to (C-14)O2 is investigated. Results show that the rate of (C-14)O2 production decreased dramatically following denervation and the decrease became significant 20 days after nerve section. The changes which occurred prior to day 20 apparently reflected the decline of muscle mass. The decreased (C-14)O2 production was found to be due to reduced capacity of the enzymatic system, while there was no change in the apparent affinity for glucose. Results of mixing experiments showed that the loss of oxidative capacity following denervation is not caused by the production of soluble inhibitors by degenerating muscle. Measurements of the (C-14)O2 revealed that oxidative metabolism recovered during reinnervation. The specific activity in reinnervated muscles displayed an 'overshoot' of approximately 50 percent, which returned to control levels by day 60. The time-course of the denervation-mediated change indicates that altered oxidative capacity is secondary to events that initiate dennervation changes in muscle, although diminished oxidative capacity may be of considerable metabolic significance in denervated muscle.

  13. The fluorescence properties of the phenylated fullerenes C 70Ph 4, C 70Ph 6, C 70Ph 8, and C 70Ph 10 in room temperature solutions

    NASA Astrophysics Data System (ADS)

    Schwell, Martin; Gustavsson, Thomas; Marguet, Sylvie; Vaissière, Benoı̂t de La; Wachter, Norbert K.; Birkett, Paul R.; Mialocq, Jean-Claude; Leach, Sydney

    2001-12-01

    The emission and excitation spectra of four phenylated [70] fullerenes, C 70Ph 4, C 70Ph 6, C 70Ph 8, and C 70Ph 10 in cyclohexane and toluene solutions have been measured. The fluorescence spectra and related excited state properties are found to depend strongly on the number of attached phenyl groups, but with no systematic trends. Quantum yields and fluorescence lifetimes were measured for C 70Ph 6, C 70Ph 8, and C 70Ph 10, allowing the determination of S1 → S0 radiative transition rates kR. It is found that kR for C 70Ph 10 is about six times larger than for the other compounds. This is consistent with measured absorbtivities for these compounds. The particular character of C 70Ph 10 is also manifested by its higher intersystem crossing rate kISC.

  14. UMBILICAL CORD SERUM INTERLEUKIN-6, C-REACTIVE PROTEIN, AND MYELOPEROXIDASE CONCENTRATIONS AT BIRTH AND ASSOCIATION WITH NEONATAL MORBIDITIES AND LONG TERM NEURODEVELOPMENTAL OUTCOMES

    PubMed Central

    Sorokin, Yoram; Romero, Roberto; Mele, Lisa; Iams, Jay D.; Peaceman, Alan M.; Leveno, Kenneth J.; Harper, Margaret; Caritis, Steve N.; Mercer, Brian M.; Thorp, John M.; O’Sullivan, Mary Jo; Ramin, Susan M.; Carpenter, Marshall W.; Rouse, Dwight J.; Sibai, Baha

    2015-01-01

    OBJECTIVE To determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children. STUDY DESIGN Umbilical cord serum samples were collected at birth from 400 newborns delivered within a multicenter randomized controlled trial of repeated versus single course of antenatal corticosteroids (ACs), in women at increased risk for PTB. Newborns were followed through discharge and were evaluated between 36 and 42 months corrected age with neurological examination and Bayley Scales of Infant Development. Umbilical cord serum concentrations of IL-6, CRP, and MPO were determined using enzyme-linked immunoassays. Multivariate logistic regression analyses explored the relationship between umbilical cord serum IL-6, CRP and MPO levels, adverse newborn outcomes and PTB < 32 weeks of gestational age (GA). RESULTS Univariate analysis revealed that umbilical cord IL-6 above the 75th percentile was associated with increased respiratory distress syndrome (RDS) and chronic lung disease (CLD), but not with necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or neonatal sepsis; however, this association was not significant after adjusting for gestational age at delivery and treatment group. No significant associations between CRP or MPO, and RDS, CLD, NEC, sepsis or IVH were evident. Regression analysis revealed that CRP above the 75th percentile was associated with a decreased risk of CLD (O.R. 0.10, 95% C.I. 0.02–0.41). No associations between umbilical cord IL-6, CRP or MPO, and MDI < 70 or PDI < 70 were evident. Umbilical cord serum IL-6, CRP, and MPO, above the 75th percentile, were associated with more frequent PTB < 32 weeks GA. CONCLUSION Elevated umbilical cord serum concentration of CRP is associated with reduced risk for CLD even after adjusting for

  15. Regeneration of roots from callus reveals stability of the developmental program for determinate root growth in Sonoran Desert Cactaceae.

    PubMed

    Shishkova, Svetlana; García-Mendoza, Edith; Castillo-Díaz, Vicente; Moreno, Norma E; Arellano, Jesús; Dubrovsky, Joseph G

    2007-05-01

    In some Sonoran Desert Cactaceae the primary root has a determinate root growth: the cells of the root apical meristem undergo only a few cell division cycles and then differentiate. The determinate growth of primary roots in Cactaceae was found in plants cultivated under various growth conditions, and could not be reverted by any treatment tested. The mechanisms involved in root meristem maintenance and determinate root growth in plants remain poorly understood. In this study, we have shown that roots regenerated from the callus of two Cactaceae species, Stenocereus gummosus and Ferocactus peninsulae, have a determinate growth pattern, similar to that of the primary root. To demonstrate this, a protocol for root regeneration from callus was established. The determinate growth pattern of roots regenerated from callus suggests that the program of root development is very stable in these species. These findings will permit future analysis of the role of certain Cactaceae genes in the determinate pattern of root growth via the regeneration of transgenic roots from transformed calli.

  16. Combat Support Forces (1C6C) Naval Surface Forces Requirements-based Budget Determination for Assault Craft Unit ONE

    DTIC Science & Technology

    2009-06-01

    period of time. It is an instrument of planning, performance measurement, decision-making, and management control , as well as a statement of priorities...Dimmerling, 1997). In 1995, Fleming wrote of the importance of budgeting. She states that “budgeting is one of the important planning and control ...Landing Craft Air Cushioned (LCAC) hovercrafts out of its base at Marine Corps Base Camp Pendleton located in North San Diego County, California

  17. The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse

    SciTech Connect

    DeAngelo, A.B.; Daniel, F.B.; Stober, J.A.; Olson, G.R. )

    1991-02-01

    Groups of male B6C3F1 mice (N = 50) were provided drinking water containing 2 g/liter sodium chloride (control) and 0.05, 0.5, and 5 g/liter dichloroacetic acid (DCA). Treatment of 30 animals in each group was carried out to 60 or 75 weeks. In a separate experiment, mice exposed to 3.5 g/liter DCA and the corresponding acetic acid control group were killed at 60 weeks. Groups of 5 mice were killed at 4, 15, 30, and 45 weeks. Time-weighted mean daily doses of 7.6, 77, 410, and 486 mg/kg/day were calculated for 0.05, 0.5, 3.5, and 5 g/liter DCA treatments. Animals exposed to 3.5 and 5 g/liter DCA had final body weights that were 87 and 83%, respectively, of the control value. Relative liver weights of 136, 230, and 351% of the control value were measured for 0.5, 3.5, and 5 g/liter, respectively. At 60 weeks mice receiving 5.0 g/liter DCA had a 90% prevalence of liver neoplasia with a mean multiplicity of 4.50 tumors/animal. Exposure to 3.5 g/liter DCA for 60 weeks resulted in a 100% tumor prevalence with an average of 4.0 tumors/animal. The prevalence of liver neoplasia and tumor multiplicity at 60 and 75 weeks in the 0.05 g/liter DCA (24.1%; 0.31 tumors/animal) and in the 0.5 g/liter group (11.1%; 0.11 tumors/animal) did not differ significantly from the control value (7.1% and 0.07 tumors/animal). No liver tumors were found in the group treated with acetic acid. Hyperplastic nodules were seen in the 3.5 (58%; 0.92/animal) and 5 g/liter DCA groups (83%; 1.27/animal). There was a significant positive dose-related trend in the age-adjusted prevalence of liver tumors. These data confirm the hepatocarcinogenicity of DCA administered in the drinking water to male B6C3F1 mice for 60 weeks.

  18. Carcinogenicity of bisphenol-A in Fischer rats and B6C3F1 mice.

    PubMed

    Huff, J

    2001-11-01

    Bisphenol-A (BP-A; 4,4'-isopropylidenediphenol) is a monomer of plastics commonly used in various consumer products, and is used as an intermediate in the manufacture of epoxy, polycarbonate, and polyester-styrene resins. A National Toxicology Program carcinogenesis bioassay of BP-A (>98% pure) was conducted by feeding diets containing 0, 1000, or 2000 ppm BP-A to groups of 50 male and 50 female Fischer (F)344 rats; 0, 1000, or 5000 ppm to groups of 50 male B6C3F1 mice; and 0, 5000, or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 weeks. The mean body weights of the low- and high-dose rats and of female mice and high-dose male mice were lower than those of the controls throughout much of the study. Lower body weight gains in rats were likely caused by reduced food consumption. Survivals were comparable among groups. Regarding neoplasia, leukemias occurred at increased incidences in BP-A-dosed rats of both sexes: male, 13/50 controls vs 12/50 low-dose and 23/50 high-dose (P < 0.03); in females, the respective findings were 7/50, 13/50, and 12/50. Interstitial-cell tumors of the testes were increased in BP-A-dosed male rats: 35/49 controls vs 48/50 (P < 0.01) and 46/49 (P < 0.01); and an increasing trend was observed for mammary gland fibroadenomas in male rats (P < 0.05, 0/50 controls vs 0/50 and 4/50). In male mice, lymphomas/leukemias were increased: 2/49 controls vs 9/50 (P < 0.05) and 5/50. Multinucleated giant hepatocytes were observed in male mice (1/49 controls vs 41/49 and 41/50), whereas there was no increase of liver tumors. In their BP-A bioassay report, the National Toxicology Program concluded that there was no convincing evidence that BP-A was carcinogenic for rats or mice. However, the marginal increases in leukemias in male and female rats, along with increases in the combined incidence of lymphomas and leukemias in male mice, suggest that BP-A may be associated with increased cancers of the hematopoietic system. Increases in interstitial

  19. Acrylonitrile is a multisite carcinogen in male and female B6C3F1 mice.

    PubMed

    Ghanayem, Burhan I; Nyska, Abraham; Haseman, Joseph K; Bucher, John R

    2002-07-01

    Acrylonitrile is a heavily produced unsaturated nitrile, which is used in the production of synthetic fibers, plastics, resins, and rubber. Acrylonitrile is a multisite carcinogen in rats after exposure via gavage, drinking water, or inhalation. No carcinogenicity studies of acrylonitrile in a second animal species were available. The current studies were designed to assess the carcinogenicity of acrylonitrile in B6C3F1 mice of both sexes. Acrylonitrile was administered by gavage at 0, 2.5, 10, or 20 mg/kg/day, 5 days per week, for 2 years. Urinary thiocyanate and N-acetyl-S-(2-cyanoethyl)-L-cysteine were measured as markers of exposure to acrylonitrile. In general, there were dose-related increases in urinary thiocyanate and N-acetyl-S-(2-cyanoethyl)-L-cysteine concentrations in all dosed groups of mice and at all time points. Survival was significantly (p < 0.001) reduced in the top dose (20 mg/kg) group of male and female mice relative to controls. The incidence of forestomach papillomas and carcinomas was increased in mice of both sexes in association with an increase in forestomach epithelial hyperplasia. The incidence of Harderian gland adenomas and carcinomas was also markedly increased in the acrylonitrile-dosed groups. In female mice, the incidence of benign or malignant granulosa cell tumors (combined) in the ovary in the 10 mg/kg dose group was greater than that in the vehicle control group, but because of a lack of dose response, this was considered an equivocal finding. In addition, the incidences of atrophy and cysts in the ovary of the 10 and 20 mg/kg dose groups were significantly increased. The incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in female mice treated with acrylonitrile at 10 mg/kg/day for 2 years. This was also considered an equivocal result. In conclusion, these studies demonstrated that acrylonitrile causes multiple carcinogenic effects after gavage administration to male and female B6

  20. Oncogenic evaluation of tetrachlorvinphos in the B6C3F1 mouse.

    PubMed

    Parker, C M; Van Gelder, G A; Chai, E Y; Gellatly, J B; Serota, D G; Voelker, R W; Vesselinovitch, S D

    1985-10-01

    Groups of 80 male and 80 female B6C3F1 mice were fed diets containing 17.5, 64, 320, 1600, 8000, and 16000 ppm tetrachlorvinphos (TCVP) for up to 103 weeks. Another group of 80 male and 80 female mice were fed TCVP (16000 ppm) that was used in a previous bioassay. One hundred-sixty male and 160 female mice served as the control group. Ten treated and 20 control mice/sex/group were killed at 6, 12, and 18 months. It was estimated that the study maximum-tolerated dose was exceeded by three- and sixfold in the 8000- and 16000-ppm dose groups, respectively. Consequently, these exposures produced excessive cytotoxicity and regenerative changes in the liver and kidneys which were associated with sex-hormonal imbalance and metabolic overload in liver. A significant decrease (15-40%) in body weight was observed in mice fed 8000 and 16000 ppm TCVP. These treated mice did not gain weight during the study. Reduced food consumption and caloric intake throughout the study were probably responsible for the increased survival and the decreased incidence of spontaneous neoplasia in mice fed 8000 and 16000 ppm TCVP. Classification of pathologic lesions observed in these high-dose groups differed among study and consulting pathologists. The consultant and Shell pathologists concluded that the liver and kidney changes were causally related to excessive toxicity which was manifest primarily by hepatocellular hyperplasia and renal tubular adenoma. Study pathologist in accordance with his classification found statistically significant increases in hepatocellular carcinoma, hepatocellular adenoma or carcinoma, and renal tubular carcinoma in male mice fed 16000 ppm TCVP. The incidence of hepatic neoplasms as evaluated by the study pathologist in female mice fed 8000 and 16000 ppm TCVP although statistically significant was of questionable biologic significance when compared with historical female controls. The only statistically significant finding observed by the consulting pathologist

  1. Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

    PubMed Central

    Dümig, Michaela; O'Keeffe, Gráinne; Binder, Jasmin; Doyle, Sean; Beilhack, Andreas

    2016-01-01

    Fungal infections are of major relevance due to the increased numbers of immunocompromised patients, frequently delayed diagnosis, and limited therapeutics. To date, the growth and nutritional requirements of fungi during infection, which are relevant for invasion of the host, are poorly understood. This is particularly true for invasive pulmonary aspergillosis, as so far, sources of (macro)elements that are exploited during infection have been identified to only a limited extent. Here, we have investigated sulfur (S) utilization by the human-pathogenic mold Aspergillus fumigatus during invasive growth. Our data reveal that inorganic S compounds or taurine is unlikely to serve as an S source during invasive pulmonary aspergillosis since a sulfate transporter mutant strain and a sulfite reductase mutant strain are fully virulent. In contrast, the S-containing amino acid cysteine is limiting for fungal growth, as proven by the reduced virulence of a cysteine auxotroph. Moreover, phenotypic characterization of this strain further revealed the robustness of the subordinate glutathione redox system. Interestingly, we demonstrate that methionine synthase is essential for A. fumigatus virulence, defining the biosynthetic route of this proteinogenic amino acid as a potential antifungal target. In conclusion, we provide novel insights into the nutritional requirements of A. fumigatus during pathogenesis, a prerequisite to understanding and fighting infection. PMID:26787716

  2. Multiple-site carcinogenicity of benzene in fischer 344 rats and B6C3F1 mice

    SciTech Connect

    Huff, J.E.; Haseman, J.K.; DeMarini, D.M.; Eustis, S.; Maronpot, R.R.

    1989-01-01

    Two-year toxicology and carcinogenesis studies of benzene were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each of three exposure doses and vehicle controls. These studies were conducted because of large production volume and widespread human exposure to benzene, because of the epidemiologic association with leukemia, and because previous studies were considered inadequate for determining carcinogenicity. Doses of 0, 50, 100 or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. At week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the animals that died before week 103 had neoplasia. Benzene-associated nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found for rats and mice.

  3. Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice.

    PubMed

    Fang, Jia-Long; Vanlandingham, Michelle; da Costa, Gonçalo Gamboa; Beland, Frederick A

    2016-05-01

    Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [(14)C(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-∞) and the Cmax of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars.

  4. Subchronic studies of doxylamine in B6C3F1 mice.

    PubMed

    Jackson, C D; Blackwell, B N

    1988-02-01

    Doxylamine succinate, a histamine (H1) antagonist (antihistamine), was administered as an admixture in the feed to male and female B6C3F1 mice for 14 or 90 days. Dose levels of 0, 100, 250, 500, 1000, and 2000 ppm doxylamine were administered to males and females in the 14-day study while dose levels of 0, 80, 162, 325, 750, and 1500 ppm were administered to both sexes in the 90-day study. Little toxicity was seen in the 14-day study. Final body weights in the highest dose group were reduced 4.0 and 7.3% in males and females, respectively. Treatment-related histopathological changes in the 14-day study were limited to a very low incidence of hepatic necrosis in both sexes. There was little toxicity observed in the 90-day study and no clear dose response relative to weight gain was observed. Histologically, the liver was the only organ affected by doxylamine administration. The liver lesions consisted of hepatic cell cytomegaly and/or karyomegaly which varied from mild to severe and a possible dose-related hepatic necrosis.

  5. Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity.

    PubMed

    Ma, Siming; Upneja, Akhil; Galecki, Andrzej; Tsai, Yi-Miau; Burant, Charles F; Raskind, Sasha; Zhang, Quanwei; Zhang, Zhengdong D; Seluanov, Andrei; Gorbunova, Vera; Clish, Clary B; Miller, Richard A; Gladyshev, Vadim N

    2016-11-22

    Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences.

  6. Genesis of Kirsten murine sarcoma virus: sequence analysis reveals recombination points and potential leukaemogenic determinant on parental leukaemia virus genome.

    PubMed Central

    Norton, J D; Connor, J; Avery, R J

    1984-01-01

    The genome of Kirsten murine sarcoma virus was formed by recombination between Kirsten murine leukaemia virus sequences, and rat sequences derived from a retrovirus-like '30S' (VL30) genetic element encompassing the Kras oncogene. Using cloned DNAs we have determined the nucleotide sequences of the long terminal repeats and adjacent regions, extending across the points of recombination on the sarcoma and leukaemia virus genomes. Our results suggest that discrete regions of homology and other cryptic sequence features, may have constituted recombinational hot-spots involved in the genesis of the Kirsten murine sarcoma virus genome. We have also compared the sequence of the Kirsten murine leukaemia virus p15 env and adjacent long terminal repeat with the corresponding regions of the AKV and Gross A murine leukaemia virus genomes. This comparison has identified a leukaemogenic determinant in the U3 domain of the long terminal repeat, possibly within a enhancer-like sequence element. PMID:6091040

  7. Comparison of the aggregation of homologous β2-microglobulin variants reveals protein solubility as a key determinant of amyloid formation.

    PubMed

    Pashley, Clare L; Hewitt, Eric W; Radford, Sheena E

    2016-02-13

    The mouse and human β2-microglobulin protein orthologs are 70% identical in sequence and share 88% sequence similarity. These proteins are predicted by various algorithms to have similar aggregation and amyloid propensities. However, whilst human β2m (hβ2m) forms amyloid-like fibrils in denaturing conditions (e.g. pH2.5) in the absence of NaCl, mouse β2m (mβ2m) requires the addition of 0.3M NaCl to cause fibrillation. Here, the factors which give rise to this difference in amyloid propensity are investigated. We utilise structural and mutational analyses, fibril growth kinetics and solubility measurements under a range of pH and salt conditions, to determine why these two proteins have different amyloid propensities. The results show that, although other factors influence the fibril growth kinetics, a striking difference in the solubility of the proteins is a key determinant of the different amyloidogenicity of hβ2m and mβ2m. The relationship between protein solubility and lag time of amyloid formation is not captured by current aggregation or amyloid prediction algorithms, indicating a need to better understand the role of solubility on the lag time of amyloid formation. The results demonstrate the key contribution of protein solubility in determining amyloid propensity and lag time of amyloid formation, highlighting how small differences in protein sequence can have dramatic effects on amyloid formation.

  8. Genome editing reveals dmrt1 as an essential male sex-determining gene in Chinese tongue sole (Cynoglossus semilaevis)

    PubMed Central

    Cui, Zhongkai; Liu, Yun; Wang, Wenwen; Wang, Qian; Zhang, Ning; Lin, Fan; Wang, Na; Shao, Changwei; Dong, Zhongdian; Li, Yangzhen; Yang, Yingming; Hu, Mengzhu; Li, Hailong; Gao, Fengtao; Wei, Zhanfei; Meng, Liang; Liu, Yang; Wei, Min; Zhu, Ying; Guo, Hua; Cheng, Christopher H. K.; Schartl, Manfred; Chen, Songlin

    2017-01-01

    Chinese tongue sole is a marine fish with ZW sex determination. Genome sequencing suggested that the Z-linked dmrt1 is a putative male determination gene, but direct genetic evidence is still lacking. Here we show that TALEN of dmrt1 efficiently induced mutations of this gene. The ZZ dmrt1 mutant fish developed ovary-like testis, and the spermatogenesis was disrupted. The female-related genes foxl2 and cyp19a1a were significantly increased in the gonad of the ZZ dmrt1 mutant. Conversely, the male-related genes Sox9a and Amh were significantly decreased. The dmrt1 deficient ZZ fish grew much faster than ZZ male control. Notably, we obtained an intersex ZW fish with a testis on one side and an ovary on the other side. This fish was chimeric for a dmrt1 mutation in the ovary, and wild-type dmrt1 in the testis. Our data provide the first functional evidence that dmrt1 is a male determining gene in tongue sole. PMID:28205594

  9. Genome editing reveals dmrt1 as an essential male sex-determining gene in Chinese tongue sole (Cynoglossus semilaevis).

    PubMed

    Cui, Zhongkai; Liu, Yun; Wang, Wenwen; Wang, Qian; Zhang, Ning; Lin, Fan; Wang, Na; Shao, Changwei; Dong, Zhongdian; Li, Yangzhen; Yang, Yingming; Hu, Mengzhu; Li, Hailong; Gao, Fengtao; Wei, Zhanfei; Meng, Liang; Liu, Yang; Wei, Min; Zhu, Ying; Guo, Hua; Cheng, Christopher H K; Schartl, Manfred; Chen, Songlin

    2017-02-16

    Chinese tongue sole is a marine fish with ZW sex determination. Genome sequencing suggested that the Z-linked dmrt1 is a putative male determination gene, but direct genetic evidence is still lacking. Here we show that TALEN of dmrt1 efficiently induced mutations of this gene. The ZZ dmrt1 mutant fish developed ovary-like testis, and the spermatogenesis was disrupted. The female-related genes foxl2 and cyp19a1a were significantly increased in the gonad of the ZZ dmrt1 mutant. Conversely, the male-related genes Sox9a and Amh were significantly decreased. The dmrt1 deficient ZZ fish grew much faster than ZZ male control. Notably, we obtained an intersex ZW fish with a testis on one side and an ovary on the other side. This fish was chimeric for a dmrt1 mutation in the ovary, and wild-type dmrt1 in the testis. Our data provide the first functional evidence that dmrt1 is a male determining gene in tongue sole.

  10. Single molecule force spectroscopy reveals critical roles of hydrophobic core packing in determining the mechanical stability of protein GB1.

    PubMed

    Bu, Tianjia; Wang, Hui-Chuan Eileen; Li, Hongbin

    2012-08-21

    Understanding molecular determinants of protein mechanical stability is important not only for elucidating how elastomeric proteins are designed and functioning in biological systems but also for designing protein building blocks with defined nanomechanical properties for constructing novel biomaterials. GB1 is a small α/β protein and exhibits significant mechanical stability. It is thought that the shear topology of GB1 plays an important role in determining its mechanical stability. Here, we combine single molecule atomic force microscopy and protein engineering techniques to investigate the effect of side chain reduction and hydrophobic core packing on the mechanical stability of GB1. We engineered seven point mutants and carried out mechanical φ-value analysis of the mechanical unfolding of GB1. We found that three mutations, which are across the surfaces of two subdomains that are to be sheared by the applied stretching force, in the hydrophobic core (F30L, Y45L, and F52L) result in significant decrease in mechanical unfolding force of GB1. The mechanical unfolding force of these mutants drop by 50-90 pN compared with wild-type GB1, which unfolds at around 180 pN at a pulling speed of 400 nm/s. These results indicate that hydrophobic core packing plays an important role in determining the mechanical stability of GB1 and suggest that optimizing hydrophobic interactions across the surfaces that are to be sheared will likely be an efficient method to enhance the mechanical stability of GB1 and GB1 homologues.

  11. Toxicokinetics of acrylamide and glycidamide in B6C3F{sub 1} mice

    SciTech Connect

    Doerge, Daniel R. . E-mail: ddoerge@nctr.fda.gov; Young, John F.; McDaniel, L. Patrice; Twaddle, Nathan C.; Churchwell, Mona I.

    2005-02-01

    Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxic mechanisms, particularly toxicokinetics and bioavailability. This study compares the toxicokinetics of AA and its epoxide metabolite glycidamide (GA) in serum and tissues of male and female B6C3F1 mice following acute dosing by intravenous, gavage, and dietary routes at 0.1 mg/kg AA or intravenous and gavage dosing with an equimolar amount of GA. AA was rapidly absorbed from oral dosing, was widely distributed to tissues, was efficiently converted to GA, and increased levels of GA-DNA adducts were observed in liver after complete elimination from serum. GA dosing also resulted in rapid absorption, wide distribution to tissues, and produced liver DNA adduct levels that were approximately 40% higher than those from an equimolar dose of AA. While oral administration was found to attenuate AA bioavailability to 23% from the diet and to 32-52% from aqueous gavage, a first-pass effect or other kinetic change resulted in higher relative internal exposure to GA when compared to the intravenous route. A similar effect on relative GA exposure was also evident as the administered dose was reduced, which suggests that as dosing rate decreases, the conversion of AA to GA is more efficient. These findings are critical to the assessment of genotoxicity of AA at low doses in the food supply, which appears to depend on total exposure to GA.

  12. Nuclear transfer nTreg model reveals fate-determining TCR-β and novel peripheral nTreg precursors.

    PubMed

    Ku, Manching; Chang, Shih-En; Hernandez, Julio; Abadejos, Justin R; Sabouri-Ghomi, Mohsen; Muenchmeier, Niklas J; Schwarz, Anna; Valencia, Anna M; Kirak, Oktay

    2016-04-19

    To study the development and function of "natural-arising" T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3(+)CD4(+)Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) β-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR β-chain was able to provide stronger TCR signals. This TCR-β-driven mechanism would thus unify former per se contradicting hypotheses of TCR-dependent and -independent nTreg development. Strikingly, peripheral FoxP3(-)CD4(+)T cells expressing the same TCR as this somatic cell nuclear transfer nTreg model had a reduced capability to differentiate into Th1 cells but were poised to differentiate better into induced nTreg cells, both in vitro and in vivo, representing a novel peripheral precursor subset of nTreg cells to which we refer to as pre-nTreg cells.

  13. Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity

    PubMed Central

    Ma, Siming; Upneja, Akhil; Galecki, Andrzej; Tsai, Yi-Miau; Burant, Charles F; Raskind, Sasha; Zhang, Quanwei; Zhang, Zhengdong D; Seluanov, Andrei; Gorbunova, Vera; Clish, Clary B; Miller, Richard A; Gladyshev, Vadim N

    2016-01-01

    Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences. DOI: http://dx.doi.org/10.7554/eLife.19130.001 PMID:27874830

  14. Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant

    PubMed Central

    Yuchi, Zhiguang; Yuen, Siobhan M. Wong King; Lau, Kelvin; Underhill, Ainsley Q.; Cornea, Razvan L.; Fessenden, James D.; Van Petegem, Filip

    2015-01-01

    Ryanodine receptors (RyRs) form calcium release channels located in the membranes of the sarcoplasmic and endoplasmic reticulum. RyRs play a major role in excitation-contraction coupling and other Ca2+-dependent signalling events, and consist of several globular domains that together form a large assembly. Here we describe the crystal structures of the SPRY1 and tandem-repeat domains at 1.2–1.5 Å resolution, which reveal several structural elements not detected in recent cryo-EM reconstructions of RyRs. The cryo-EM studies disagree on the position of SPRY domains, which had been proposed based on homology modelling. Computational docking of the crystal structures, combined with FRET studies, show that the SPRY1 domain is located next to FK506-binding protein (FKBP). Molecular dynamics flexible fitting and mutagenesis experiments suggest a hydrophobic cluster within SPRY1 that is crucial for FKBP binding. A RyR1 disease mutation, N760D, appears to directly impact FKBP binding through interfering with SPRY1 folding. PMID:26245150

  15. TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination

    PubMed Central

    Berkseth, Matt; Ikegami, Kohta; Arur, Swathi; Lieb, Jason D.; Zarkower, David

    2013-01-01

    How sexual regulators translate global sexual fate into appropriate local sexual differentiation events is perhaps the least understood aspect of sexual development. Here we have used ChIP followed by deep sequencing (ChIP-seq) to identify direct targets of the nematode global sexual regulator Transformer 1 (TRA-1), a transcription factor acting at the interface between organism-wide and cell-specific sexual regulation to control all sex-specific somatic differentiation events. We identified 184 TRA-1–binding sites in Caenorhabditis elegans, many with temporal- and/or tissue-specific TRA-1 association. We also identified 78 TRA-1–binding sites in the related nematode Caenorhabditis briggsae, 19 of which are conserved between the two species. Some DNA segments containing TRA-1–binding sites drive male-specific expression patterns, and RNAi depletion of some genes adjacent to TRA-1–binding sites results in defects in male sexual development. TRA-1 binds to sites adjacent to a number of heterochronic regulatory genes, some of which drive male-specific expression, suggesting that TRA-1 imposes sex specificity on developmental timing. We also found evidence for TRA-1 feedback regulation of the global sex-determination pathway: TRA-1 binds its own locus and those of multiple upstream masculinizing genes, and most of these associations are conserved in C. briggsae. Thus, TRA-1 coordinates sexual development by reinforcing the sex-determination decision and directing downstream sexual differentiation events. PMID:24046365

  16. Functional analysis of all AGAMOUS subfamily members in rice reveals their roles in reproductive organ identity determination and meristem determinacy.

    PubMed

    Dreni, Ludovico; Pilatone, Alessandro; Yun, Dapeng; Erreni, Stefano; Pajoro, Alice; Caporali, Elisabetta; Zhang, Dabing; Kater, Martin M

    2011-08-01

    Reproductive organ development is one of the most important steps in the life cycle of plants. Studies using core eudicot species like thale cress (Arabidopsis thaliana) and snapdragon (Antirrhinum majus) have shown that MADS domain transcription factors belonging to the AGAMOUS (AG) subfamily regulate the identity of stamens, carpels, and ovules and that they are important for floral meristem determinacy. Here, we investigate the genetic interactions between the four rice (Oryza sativa) AG subfamily members, MADS3, MADS13, MADS21, and MADS58. Our data show that, in contrast with previous reports, MADS3 and MADS58 determine stamen and carpel identity and, together with MADS13, are important for floral meristem determinacy. In the mads3 mads58 double mutant, we observed a complete loss of reproductive organ identity and massive accumulation of lodicules in the third and fourth floral whorls. MADS21 is an AGL11 lineage gene whose expression is not restricted to ovules. Instead, its expression profile is similar to those of class C genes. However, our genetic analysis shows that MADS21 has no function in stamen, carpel, or ovule identity determination.

  17. EIGEN-6C4 - The latest combined global gravity field model including GOCE data up to degree and order 1949 of GFZ Potsdam and GRGS Toulouse

    NASA Astrophysics Data System (ADS)

    Förste, Christoph; Bruinsma, Sean; Abrikosov, Oleg; Flechtner, Frank; Marty, Jean-Charles; Lemoine, Jean-Michel; Dahle, Christoph; Neumayer, Hans; Barthelmes, Franz; König, Rolf; Biancale, Richard

    2014-05-01

    GFZ Potsdam and GRGS Toulouse have a long-time close cooperation in the field of global gravity field determination. Here we focus on (1) GOCE gravity field determination and (2) computation of high resolution combined gravity field models. Such data products play a fundamental role in geodesy and Earth sciences, ranging from practical purposes, like precise orbit determination, to scientific applications, like investigations of the density structure of the Earth's interior. Here we present our combined gravity field model EIGEN-6C4 which is the fourth release of EIGEN-6C (EIGEN = European Improved Gravity model of the Earth by New techniques). The first release of EIGEN-6C, published in 2011, was the first global combined gravity field model containing GOCE data. It was computed from a combination of LAGEOS, GRACE and GOCE data, augmented with DTU10 surface gravity data, and it is complete to degree and order 1440 (corresponding to 14 km spatial resolution). The combination of the different data types has been done on the basis of full normal equations up to maximum degree/order 370. The spherical harmonic coefficients of the shorter wavelengths were obtained from a block diagonal normal equation from the terrestrial data only. The subsequent releases EIGEN-6C2 (2012) and EIGEN-6C3stat (2013) were complete to degree and order 1949 (corresponding to approx. 10 km spatial resolution) and comprise extended measurement time spans for the LAGEOS/GRACE as well as for the GOCE data. Now we present the new release EIGEN-6C4. This time variable combined gravity field model is again developed to degree and order 1949 and comprises the new GRACE Release 03 from GRGS and gradiometer data almost of the entire GOCE mission (Sept. 2009-Sept. 2013). Our combination of GRACE and GOCE data allows the construction of an accurate satellite-only contribution to the final combined model up to degree and order 260, where the GOCE gradiometer data contribute only for degrees upwards of

  18. TNF-alpha-dependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice.

    PubMed

    Perides, George; Weiss, Eric R; Michael, Emily S; Laukkarinen, Johanna M; Duffield, Jeremy S; Steer, Michael L

    2011-04-15

    The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-α. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-α(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-α(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-α by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-α expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.

  19. Meta-GWAS and Meta-Analysis of Exome Array Studies Do Not Reveal Genetic Determinants of Serum Hepcidin

    PubMed Central

    Galesloot, Tessel E.; van Dijk, Freerk; Geurts-Moespot, Anneke J.; Girelli, Domenico; Kiemeney, Lambertus A. L. M.; Sweep, Fred C. G. J.; Swertz, Morris A.; van der Meer, Peter; Camaschella, Clara; Toniolo, Daniela; Vermeulen, Sita H.; van der Harst, Pim; Swinkels, Dorine W.

    2016-01-01

    Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants. PMID:27846281

  20. Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies.

    PubMed

    Kaufmann, Kristian W; Dawson, Eric S; Henry, L Keith; Field, Julie R; Blakely, Randy D; Meiler, Jens

    2009-02-15

    To identify potential determinants of substrate selectivity in serotonin (5-HT) transporters (SERT), models of human and Drosophila serotonin transporters (hSERT, dSERT) were built based on the leucine transporter (LeuT(Aa)) structure reported by Yamashita et al. (Nature 2005;437:215-223), PBDID 2A65. Although the overall amino acid identity between SERTs and the LeuT(Aa) is only 17%, it increases to above 50% in the first shell of the putative 5-HT binding site, allowing de novo computational docking of tryptamine derivatives in atomic detail. Comparison of hSERT and dSERT complexed with substrates pinpoints likely structural determinants for substrate binding. Forgoing the use of experimental transport and binding data of tryptamine derivatives for construction of these models enables us to critically assess and validate their predictive power: A single 5-HT binding mode was identified that retains the amine placement observed in the LeuT(Aa) structure, matches site-directed mutagenesis and substituted cysteine accessibility method (SCAM) data, complies with support vector machine derived relations activity relations, and predicts computational binding energies for 5-HT analogs with a significant correlation coefficient (R = 0.72). This binding mode places 5-HT deep in the binding pocket of the SERT with the 5-position near residue hSERT A169/dSERT D164 in transmembrane helix 3, the indole nitrogen next to residue Y176/Y171, and the ethylamine tail under residues F335/F327 and S336/S328 within 4 A of residue D98. Our studies identify a number of potential contacts whose contribution to substrate binding and transport was previously unsuspected.

  1. Analytical Interference in Serum Iron Determination Reveals Iron Versus Gadolinium Transmetallation With Linear Gadolinium-Based Contrast Agents

    PubMed Central

    Fretellier, Nathalie; Poteau, Nathalie; Factor, Cécile; Mayer, Jean-François; Medina, Christelle; Port, Marc; Idée, Jean-Marc; Corot, Claire

    2014-01-01

    Objectives The purposes of this study were to evaluate the risk for analytical interference with gadolinium-based contrast agents (GBCAs) for the colorimetric measurement of serum iron (Fe3+) and to investigate the mechanisms involved. Materials and Methods Rat serum was spiked with several concentrations of all molecular categories of GBCAs, ligands, or “free” soluble gadolinium (Gd3+). Serum iron concentration was determined by 2 different colorimetric methods at pH 4.0 (with a Vitros DT60 analyzer or a Cobas Integra 400 analyzer). Secondly, the cause of interference was investigated by (a) adding free soluble Gd3+ or Mn2+ to serum in the presence of gadobenic acid or gadodiamide and (b) electrospray ionization mass spectrometry. Results Spurious decrease in serum Fe3+ concentration was observed with all linear GBCAs (only with the Vitros DT60 technique occurring at pH 4.0) but not with macrocyclic GBCAs or with free soluble Gd3+. Spurious hyposideremia was also observed with the free ligands present in the pharmaceutical solutions of the linear GBCAs gadopentetic acid and gadodiamide (ie, diethylene triamine pentaacetic acid and calcium-diethylene triamine pentaacetic acid bismethylamide, respectively), suggesting the formation of Fe-ligand chelate. Gadobenic acid-induced interference was blocked in a concentration-dependent fashion by adding a free soluble Gd3+ salt. Conversely, Mn2+, which has a lower affinity than Gd3+ and Fe3+ for the ligand of gadobenic acid (ie, benzyloxypropionic diethylenetriamine tetraacetic acid), was less effective (interference was only partially blocked), suggesting an Fe3+ versus Gd3+ transmetallation phenomenon at pH 4.0. Similar results were observed with gadodiamide. Mass spectrometry detected the formation of Fe-ligand with all linear GBCAs tested in the presence of Fe3+ and the disappearance of Fe-ligand after the addition of free soluble Gd3+. No Fe-ligand chelate was found in the case of the macrocyclic GBCA gadoteric

  2. ESA's Release 5 Gravity Field Model by the Direct Approach and its Part in the Combined Model EIGEN-6C4

    NASA Astrophysics Data System (ADS)

    Foerste, C.; Bruinsma, S.; Abrikosov, O.; Lemoine, J. M.; Marty, J. C.; Flechtner, F.; Dahle, C.; Neumayer, H.; Barthelmes, F.; König, R.; Balmino, G.; Biancale, R.

    2014-12-01

    GFZ Potsdam and GRGS Toulouse have a close cooperation in the field of global gravity field determination and both are members of the European GOCE Gravity Consortium and compute gravity fields on behalf of the European Space Agency. Here we present release 5 of the GOCE gravity field model by means of the Direct Approach (GOCE-DIR5), which was made with the GOCE data from the entire mission (Nov09 - Oct13) as well as with LAGEOS and GRACE data. Compared to release 4, GOCE data at the lower mission altitudes are included and the max d/o has been increased to 300. The 3-axes GOCE gradiometer gave gravity gradients that are measured with a high accuracy only within its measurement bandwidth of ~ 0.005 to 0.1 Hz. Thus, the gradient observation equations must be filtered which was done by a band pass filter of 8-120 sec. The GOCE GPS-SST data are only used to geolocate the gradients. The low-to-medium degree spherical harmonic coefficients of the gravity field are determined using GRACE as well as LAGEOS data from GRGS Release 3. All data are combined at normal equation level and a regularized solution is obtained by Cholesky decomposition. The GOCE-DIR5 data were used to make our latest combined model EIGEN-6C4. This is the 4th release of EIGEN-6C which was the very first combined gravity field model using GOCE data. EIGEN-6C4 is complete to d/o 2190 and was made from the GOCE-DIR5 data combined with DTU10 and EGM2008 surface gravity data. The combination of the different data types has been done on the basis of full normal equations up to d/o 370. In contrast to GOCE-DIR5 the satellite normal equation for EIGEN-6C4 contains 5 types of time variable parameters for each coefficient up to d/o 80. The coefficients beyond deg 370 were obtained from a block diagonal normal equation from the terrestrial data only. The comparison of test results (orbit computation, GPS leveling, geostrophic current speeds based on SVP buoy velocity data) of GOCE-DIR5 and EIGEN-6C4 with

  3. Stochastic kinetics reveal imperative role of anisotropic interfacial tension to determine morphology and evolution of nucleated droplets in nematogenic films

    NASA Astrophysics Data System (ADS)

    Bhattacharjee, Amit Kumar

    2017-01-01

    For isotropic fluids, classical nucleation theory predicts the nucleation rate, barrier height and critical droplet size by ac- counting for the competition between bulk energy and interfacial tension. The nucleation process in liquid crystals is less understood. We numerically investigate nucleation in monolayered nematogenic films using a mesoscopic framework, in par- ticular, we study the morphology and kinetic pathway in spontaneous formation and growth of droplets of the stable phase in the metastable background. The parameter κ that quantifies the anisotropic elastic energy plays a central role in determining the geometric structure of the droplets. Noncircular nematic droplets with homogeneous director orientation are nucleated in a background of supercooled isotropic phase for small κ. For large κ, noncircular droplets with integer topological charge, accompanied by a biaxial ring at the outer surface, are nucleated. The isotropic droplet shape in a superheated nematic background is found to depend on κ in a similar way. Identical growth laws are found in the two cases, although an unusual two-stage mechanism is observed in the nucleation of isotropic droplets. Temporal distributions of successive events indi- cate the relevance of long-ranged elasticity-mediated interactions within the isotropic domains. Implications for a theoretical description of nucleation in anisotropic fluids are discussed.

  4. Stochastic kinetics reveal imperative role of anisotropic interfacial tension to determine morphology and evolution of nucleated droplets in nematogenic films

    PubMed Central

    Bhattacharjee, Amit Kumar

    2017-01-01

    For isotropic fluids, classical nucleation theory predicts the nucleation rate, barrier height and critical droplet size by ac- counting for the competition between bulk energy and interfacial tension. The nucleation process in liquid crystals is less understood. We numerically investigate nucleation in monolayered nematogenic films using a mesoscopic framework, in par- ticular, we study the morphology and kinetic pathway in spontaneous formation and growth of droplets of the stable phase in the metastable background. The parameter κ that quantifies the anisotropic elastic energy plays a central role in determining the geometric structure of the droplets. Noncircular nematic droplets with homogeneous director orientation are nucleated in a background of supercooled isotropic phase for small κ. For large κ, noncircular droplets with integer topological charge, accompanied by a biaxial ring at the outer surface, are nucleated. The isotropic droplet shape in a superheated nematic background is found to depend on κ in a similar way. Identical growth laws are found in the two cases, although an unusual two-stage mechanism is observed in the nucleation of isotropic droplets. Temporal distributions of successive events indi- cate the relevance of long-ranged elasticity-mediated interactions within the isotropic domains. Implications for a theoretical description of nucleation in anisotropic fluids are discussed. PMID:28054600

  5. Phylogenomics of Xanthomonas field strains infecting pepper and tomato reveals diversity in effector repertoires and identifies determinants of host specificity

    PubMed Central

    Schwartz, Allison R.; Potnis, Neha; Timilsina, Sujan; Wilson, Mark; Patané, José; Martins, Joaquim; Minsavage, Gerald V.; Dahlbeck, Douglas; Akhunova, Alina; Almeida, Nalvo; Vallad, Gary E.; Barak, Jeri D.; White, Frank F.; Miller, Sally A.; Ritchie, David; Goss, Erica; Bart, Rebecca S.; Setubal, João C.; Jones, Jeffrey B.; Staskawicz, Brian J.

    2015-01-01

    Bacterial spot disease of pepper and tomato is caused by four distinct Xanthomonas species and is a severely limiting factor on fruit yield in these crops. The genetic diversity and the type III effector repertoires of a large sampling of field strains for this disease have yet to be explored on a genomic scale, limiting our understanding of pathogen evolution in an agricultural setting. Genomes of 67 Xanthomonas euvesicatoria (Xe), Xanthomonas perforans (Xp), and Xanthomonas gardneri (Xg) strains isolated from diseased pepper and tomato fields in the southeastern and midwestern United States were sequenced in order to determine the genetic diversity in field strains. Type III effector repertoires were computationally predicted for each strain, and multiple methods of constructing phylogenies were employed to understand better the genetic relationship of strains in the collection. A division in the Xp population was detected based on core genome phylogeny, supporting a model whereby the host-range expansion of Xp field strains on pepper is due, in part, to a loss of the effector AvrBsT. Xp-host compatibility was further studied with the observation that a double deletion of AvrBsT and XopQ allows a host range expansion for Nicotiana benthamiana. Extensive sampling of field strains and an improved understanding of effector content will aid in efforts to design disease resistance strategies targeted against highly conserved core effectors. PMID:26089818

  6. Structural Ensembles of Membrane-bound α-Synuclein Reveal the Molecular Determinants of Synaptic Vesicle Affinity

    PubMed Central

    Fusco, Giuliana; De Simone, Alfonso; Arosio, Paolo; Vendruscolo, Michele; Veglia, Gianluigi; Dobson, Christopher M.

    2016-01-01

    A detailed characterisation of the molecular determinants of membrane binding by α-synuclein (αS), a 140-residue protein whose aggregation is associated with Parkinson’s disease, is of fundamental significance to clarify the manner in which the balance between functional and dysfunctional processes are regulated for this protein. Despite its biological relevance, the structural nature of the membrane-bound state αS remains elusive, in part because of the intrinsically dynamic nature of the protein and also because of the difficulties in studying this state in a physiologically relevant environment. In the present study we have used solid-state NMR and restrained MD simulations to refine structure and topology of the N-terminal region of αS bound to the surface of synaptic-like membranes. This region has fundamental importance in the binding mechanism of αS as it acts as to anchor the protein to lipid bilayers. The results enabled the identification of the key elements for the biological properties of αS in its membrane-bound state. PMID:27273030

  7. Sex determination by SRY PCR and sequencing of Tasmanian devil facial tumour cell lines reveals non-allograft transmission.

    PubMed

    Cui, Xianlan; Wang, Yunfeng; Hua, Bobby; Miller, Webb; Zhao, Yan; Cui, Hongyu; Kong, Xiangang

    2016-05-20

    Devil facial tumour disease (DFTD) is an infectious tumour disease and was hypothesised to be transmitted by allograft during biting based on two cytogenetic findings of DFTD tumours in 2006. It was then believed that DFTD tumours were originally from a female devil. In this study the devil sex-determining region Y (SRY) gene was PCR amplified and sequenced, and six pairs of devil SRY PCR primers were used for detection of devil SRY gene fragments in purified DFTD tumour cell lines. Using three pairs of devil SRY PCR primers, devil SRY gene sequence was detected by PCR and sequencing in genomic DNA of DFTD tumour cell lines from six male devils, but not from six female devils. Four out of six DFTD tumour cell lines from male devils contained nucleotides 288-482 of the devil SRY gene, and another two DFTD tumour cell lines contained nucleotides 381-577 and 493-708 of the gene, respectively. These results indicate that the different portions of the SRY gene in the DFTD tumours of the male devils were originally from the male hosts, rejecting the currently believed DFTD allograft transmission theory. The reasons why DFTD transmission was incorrectly defined as allograft are discussed.

  8. Chemical dampening of Ly6C(hi) monocytes in the periphery produces anti-depressant effects in mice.

    PubMed

    Zheng, Xiao; Ma, Sijing; Kang, An; Wu, Mengqiu; Wang, Lin; Wang, Qiong; Wang, Guangji; Hao, Haiping

    2016-01-19

    The involvement of systemic immunity in depression pathogenesis promises a periphery-targeting paradigm in novel anti-depressant discovery. However, relatively little is known about druggable targets in the periphery for mental and behavioral control. Here we report that targeting Ly6C(hi) monocytes in blood can serve as a strategy for anti-depressant purpose. A natural compound, ginsenoside Rg1 (Rg1), was firstly validated as a periphery-restricted chemical probe. Rg1 selectively suppressed Ly6C(hi) monocytes recruitment to the inflamed mice brain. The proinflammatory potential of Ly6C(hi) monocytes to activate astrocytes was abrogated by Rg1, which led to a blunted feedback release of CCL2 to recruit the peripheral monocytes. In vitro study demonstrated that Rg1 pretreatment on activated THP-1 monocytes retarded their ability to trigger CCL2 secretion from co-cultured U251 MG astrocytes. CCL2-triggered p38/MAPK and PI3K/Akt activation were involved in the action of Rg1. Importantly, in mice models, we found that dampening Ly6C(hi) monocytes at the periphery ameliorated depression-like behavior induced by neuroinflammation or chronic social defeat stress. Together, our work unravels that blood Ly6C(hi) monocytes may serve as the target to enable remote intervention on the depressed brain, and identifies Rg1 as a lead compound for designing drugs targeting peripheral CCL2 signals.

  9. The lignan, (-)-sesamin reveals cytotoxicity toward cancer cells: pharmacogenomic determination of genes associated with sensitivity or resistance.

    PubMed

    Saeed, Mohamed; Khalid, Hassan; Sugimoto, Yoshikazu; Efferth, Thomas

    2014-04-15

    (-)-Sesamin is a lignan present in sesam oil and a number of medicinal plants. It exerts various pharmacological effects, such as prevention of hyperlipidemia, hypertension, and carcinogenesis. Moreover, (-)-sesamin has chemopreventive and anticancer activity in vitro and in vivo. Multidrug resistance (MDR) of tumors leads to fatal treatment outcome in many patients and novel drugs able to kill multidrug-resistant cells are urgently needed. P-glycoprotein (MDR1/ABCB1) is the best known ATP-binding cassette (ABC) drug transporter mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. We found that the mRNA expressions of ABCB1 and ABCB5 were not related to the 50% inhibition concentrations (IC50) for (-)-sesamin in a panel of 55 cell lines of the National Cancer Institute, USA. Furthermore, (-)-sesamin inhibited ABCB1- or ABCB5-overexpressing cells with similar efficacy than their drug-sensitive parental counterparts. In addition to ABC transporter-mediated MDR, we attempted to identify other molecular determinants of (-)-sesamin resistance. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell panel. Twenty-three genes were identified, whose mRNA expression correlated with the IC50 values for (-)-sesamin. These genes code for proteins of different biological functions, i.e. ribosomal proteins, components of the mitochondrial respiratory chain, proteins involved in RNA metabolism, protein biosynthesis, or glucose and fatty acid metabolism. Subjecting this set of genes to cluster analysis showed that the cell lines were assembled in the resulting dendrogram according to their responsiveness to (-)-sesamin. In conclusion, (-)-sesamin is not involved in MDR mediated by ABCB1 or ABCB5 and may be valuable to bypass chemoresistance of refractory tumors. The microarray expression profile, which predicted sensitivity or resistance of tumor cells to (-)-sesamin

  10. Genome-wide mutagenesis of Xanthomonas axonopodis pv. citri reveals novel genetic determinants and regulation mechanisms of biofilm formation.

    PubMed

    Li, Jinyun; Wang, Nian

    2011-01-01

    Xanthomonas axonopodis pv. citri (Xac) causes citrus canker disease, a major threat to citrus production worldwide. Accumulating evidence suggests that the formation of biofilms on citrus leaves plays an important role in the epiphytic survival of this pathogen prior to the development of canker disease. However, the process of Xac biofilm formation is poorly understood. Here, we report a genome-scale study of Xac biofilm formation in which we identified 92 genes, including 33 novel genes involved in biofilm formation and 7 previously characterized genes, colR, fhaB, fliC, galU, gumD, wxacO, and rbfC, known to be important for Xac biofilm formation. In addition, 52 other genes with defined or putative functions in biofilm formation were identified, even though they had not previously reported been to be associated with biofilm formation. The 92 genes were isolated from 292 biofilm-defective mutants following a screen of a transposon insertion library containing 22,000 Xac strain 306 mutants. Further analyses indicated that 16 of the novel genes are involved in the production of extracellular polysaccharide (EPS) and/or lipopolysaccharide (LPS), 7 genes are involved in signaling and regulatory pathways, and 5 genes have unknown roles in biofilm formation. Furthermore, two novel genes, XAC0482, encoding a haloacid dehalogenase-like phosphatase, and XAC0494 (designated as rbfS), encoding a two-component sensor protein, were confirmed to be biofilm-related genes through complementation assays. Our data demonstrate that the formation of mature biofilm requires EPS, LPS, both flagellum-dependent and flagellum-independent cell motility, secreted proteins and extracellular DNA. Additionally, multiple signaling pathways are involved in Xac biofilm formation. This work is the first report on a genome-wide scale of the genetic processes of biofilm formation in plant pathogenic bacteria. The report provides significant new information about the genetic determinants and

  11. Determination of the physiological 2:2 TLR5:flagellin activation stoichiometry revealed by the activity of a fusion receptor

    SciTech Connect

    Ivičak-Kocjan, Karolina; Panter, Gabriela; Benčina, Mojca; Jerala, Roman

    2013-05-24

    Highlights: •The chimeric protein fusing flagellin to the TLR5 ectodomain is constitutively active. •Mutation P736H within the BB-loop of TLR5 TIR domain renders the receptor inactive. •The R90D mutation in flagellin inactivated autoactivation of the chimeric protein. •The 2:2 stoichiometry of the TLR5:flagellin complex is physiologically relevant. -- Abstract: Toll-like receptor 5 (TLR5) recognizes flagellin of most flagellated bacteria, enabling activation of the MyD88-dependent signaling pathway. The recently published crystal structure of a truncated zebrafish TLR5 ectodomain in complex with an inactive flagellin fragment indicated binding of two flagellin molecules to a TLR5 homodimer, however this complex did not dimerize in solution. In the present study, we aimed to determine the physiological stoichiometry of TLR5:flagellin activation by the use of a chimeric protein composed of an active flagellin fragment linked to the N-terminus of human TLR5 (SF-TLR5). This construct was constitutively active. Inactivation by the R90D mutation within flagellin demonstrated that autoactivation of the chimeric protein depended solely on the specific interaction between TLR5 and flagellin. Addition of wild-type hTLR5 substantially lowered autoactivation of SF-TLR5 in a concentration dependent manner, an effect which was reversible by the addition of exogenous Salmonella typhimurium flagellin, indicating the biological activity of a TLR5:flagellin complex with a 2:2 stoichiometry. These results, in addition to the combinations of inactive P736H mutation within the BB-loop of the TIR domain of TLR5 and SF-TLR5, further confirm the mechanism of TLR5 activation.

  12. Genome-Wide Mutagenesis of Xanthomonas axonopodis pv. citri Reveals Novel Genetic Determinants and Regulation Mechanisms of Biofilm Formation

    PubMed Central

    Li, Jinyun; Wang, Nian

    2011-01-01

    Xanthomonas axonopodis pv. citri (Xac) causes citrus canker disease, a major threat to citrus production worldwide. Accumulating evidence suggests that the formation of biofilms on citrus leaves plays an important role in the epiphytic survival of this pathogen prior to the development of canker disease. However, the process of Xac biofilm formation is poorly understood. Here, we report a genome-scale study of Xac biofilm formation in which we identified 92 genes, including 33 novel genes involved in biofilm formation and 7 previously characterized genes, colR, fhaB, fliC, galU, gumD, wxacO, and rbfC, known to be important for Xac biofilm formation. In addition, 52 other genes with defined or putative functions in biofilm formation were identified, even though they had not previously reported been to be associated with biofilm formation. The 92 genes were isolated from 292 biofilm-defective mutants following a screen of a transposon insertion library containing 22,000 Xac strain 306 mutants. Further analyses indicated that 16 of the novel genes are involved in the production of extracellular polysaccharide (EPS) and/or lipopolysaccharide (LPS), 7 genes are involved in signaling and regulatory pathways, and 5 genes have unknown roles in biofilm formation. Furthermore, two novel genes, XAC0482, encoding a haloacid dehalogenase-like phosphatase, and XAC0494 (designated as rbfS), encoding a two-component sensor protein, were confirmed to be biofilm-related genes through complementation assays. Our data demonstrate that the formation of mature biofilm requires EPS, LPS, both flagellum-dependent and flagellum-independent cell motility, secreted proteins and extracellular DNA. Additionally, multiple signaling pathways are involved in Xac biofilm formation. This work is the first report on a genome-wide scale of the genetic processes of biofilm formation in plant pathogenic bacteria. The report provides significant new information about the genetic determinants and

  13. Upregulation of estrogen receptor expression in the uterus of ovariectomized B6C3F1 mice and Ishikawa cells treated with bromoethane.

    PubMed

    Aoyama, Hiroaki; Couse, John F; Hewitt, Sylvia C; Haseman, Joseph K; He, Hong; Zheng, Xiaolin; Majstoravich, Sonja; Korach, Kenneth S; Dixon, D

    2005-12-15

    In a 2-year NTP bioassay, Bromoethane (BE) was found to induce endometrial neoplasms in the uterus of B6C3F1 mice [; ]. In women, hormonal influences, such as "unopposed" estrogenic stimulus, have been implicated as important etiologic factors in uterine cancer. BE, however, does not affect the serum concentrations of sex hormones in female B6C3F1 mice [] and the mechanism of BE-induced uterine carcinogenesis still remains unclear. In the present study, we examined the estrogenic effects of BE on the uterus of ovariectomized B6C3F1 mice and on Ishikawa cells. Groups of 6 mice were given daily s.c. injections of 0, 100, 500 or 1000 mg BE/kg for 3 consecutive days. Mice treated with 17beta-estradiol served as positive controls. Mice were necropsied 24 h after the final injection, and uteri were weighed and examined histologically and immunohistochemically along with the vagina. Changes observed in the estrogen-treated mice included increased uterine weights, edema and inflammation of the endometrium, increased epithelial layers of the uterine and vaginal lumens and keratinization of the vaginal epithelium. In the BE-treated mice, no such changes occurred; however, immunohistochemical staining of the uterus revealed a significant increase in immunoexpression of the estrogen receptor alpha (ERalpha) in the two higher dose groups. Analysis of mRNA also showed slightly increased uterine ERalpha expression in these groups. Upregulated expression of ERalpha was confirmed in BE-treated Ishikawa cells, in which Western blotting analyses identified an intense signal at approximately 66 kDa, which is consistent with ERalpha. These data suggest that upregulated expression of ERalpha may be important in the induction of endometrial neoplasms in BE-treated mice.

  14. Upregulation of estrogen receptor expression in the uterus of ovariectomized B6C3F1 mice and Ishikawa cells treated with bromoethane

    SciTech Connect

    Aoyama, Hiroaki; Couse, John F.; Hewitt, Sylvia C.; Haseman, Joseph K.; He, Hong; Zheng, Xiaolin; Majstoravich, Sonja; Korach, Kenneth S.; Dixon, D. . E-mail: dixon@niehs.nih.gov

    2005-12-15

    In a 2-year NTP bioassay, Bromoethane (BE) was found to induce endometrial neoplasms in the uterus of B6C3F1 mice [; ]. In women, hormonal influences, such as 'unopposed' estrogenic stimulus, have been implicated as important etiologic factors in uterine cancer. BE, however, does not affect the serum concentrations of sex hormones in female B6C3F1 mice [] and the mechanism of BE-induced uterine carcinogenesis still remains unclear. In the present study, we examined the estrogenic effects of BE on the uterus of ovariectomized B6C3F1 mice and on Ishikawa cells. Groups of 6 mice were given daily s.c. injections of 0, 100, 500 or 1000 mg BE/kg for 3 consecutive days. Mice treated with 17{beta}-estradiol served as positive controls. Mice were necropsied 24 h after the final injection, and uteri were weighed and examined histologically and immunohistochemically along with the vagina. Changes observed in the estrogen-treated mice included increased uterine weights, edema and inflammation of the endometrium, increased epithelial layers of the uterine and vaginal lumens and keratinization of the vaginal epithelium. In the BE-treated mice, no such changes occurred; however, immunohistochemical staining of the uterus revealed a significant increase in immunoexpression of the estrogen receptor alpha (ER{alpha}) in the two higher dose groups. Analysis of mRNA also showed slightly increased uterine ER{alpha} expression in these groups. Upregulated expression of ER{alpha} was confirmed in BE-treated Ishikawa cells, in which Western blotting analyses identified an intense signal at approximately 66 kDa, which is consistent with ER{alpha}. These data suggest that upregulated expression of ER{alpha} may be important in the induction of endometrial neoplasms in BE-treated mice.

  15. Surface effects on the structure and mobility of the ionic liquid C6C1ImTFSI in silica gels.

    PubMed

    Nayeri, Moheb; Aronson, Matthew T; Bernin, Diana; Chmelka, Bradley F; Martinelli, Anna

    2014-08-14

    We report on how the dynamical and structural properties of the ionic liquid 1-hexyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (C6C1ImTFSI) change upon different degrees of confinement in silica gels. The apparent diffusion coefficients of the individual ions are measured by (1)H and (19)F pulsed field gradient nuclear magnetic resonance (PFG-NMR) spectroscopy, while the intermolecular interactions in the ionogels are elucidated by Raman spectroscopy. In addition, the local structure of the ionic liquid at the silica interface is probed by solid-state NMR spectroscopy. Importantly, we extend this study to a wider range of ionic liquid-to-silica molar ratios (x) than has been investigated previously, from very low (high degree of confinement) to very high (liquid-like gels) ionic liquid contents. Diffusion NMR measurements indicate that a solvation shell, with a significantly lower mobility than the bulk ionic liquid, forms at the silica interface. Additionally, the diffusion of the C6C1Im(+) and TFSI(-) ions decreases more rapidly below an observed molar ratio threshold (x < 1), with the intrinsic difference in the self-diffusion coefficient between the cation and anion becoming less pronounced. For ionic liquid molar ratio of x < 1, Raman spectroscopy reveals a different conformational equilibrium for the TFSI(-) anions compared to the bulk ionic liquid, with an increased population of the cisoid isomers with respect to the transoid. Concomitantly, at these high degrees of confinement the TFSI(-) anion experiences stronger ion-ion interactions as indicated by the evolution of the TFSI(-) characteristic vibrational mode at ∼740 cm(-1). Furthermore, solid-state 2D (29)Si{(1)H} HETCOR NMR measurements establish the interactions of the ionic liquid species with the silica surface, where the presence of adsorbed water results in weaker interactions between (29)Si surface moieties and the hydrophobic alkyl protons of the cationic C6C1Im(+) molecules.

  16. Quality assurance grading guidelines for research and development at DOE facilities. DOE Order 5700.6C

    SciTech Connect

    Powell, T.B.; Morris, R.N.

    1992-10-01

    The quality assurance (QA) requirements for the US Department of Energy (DOE) are established in DOE Order 5700.6C. This order is applicable for all DOE departmental elements, management, and maintenance and operating contractors and requires that documented Quality Assurance Programs (QAPS) are prepared at all levels; it has one attachment. The DOE Office of Energy Research (DOE-ER) has issued a standard to ensure implementation of the full intent of this order in the ER community. This report discusses order 5700.6C in relation to research with DOE.

  17. Materials Data on CaH6C2O7 (SG:2) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-04-24

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  18. Materials Data on H6C6NO (SG:1) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-04-24

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  19. Materials Data on LiB6C (SG:38) by Materials Project

    SciTech Connect

    Kristin Persson

    2014-07-09

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  20. Materials Data on Mg(B6C)2 (SG:74) by Materials Project

    DOE Data Explorer

    Kristin Persson

    2014-07-09

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  1. Materials Data on SrH6C4O7 (SG:15) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-02-04

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  2. Materials Data on Th2Ru6C5 (SG:127) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-02-10

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  3. Materials Data on Y6C2I7 (SG:12) by Materials Project

    DOE Data Explorer

    Kristin Persson

    2014-11-02

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  4. Materials Data on Nb6C5 (SG:12) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-02-05

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  5. Materials Data on HRu6C16NO16 (SG:14) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-04-22

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  6. Materials Data on KH6C2S2NO4 (SG:14) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-04-22

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  7. Materials Data on ZnH6C2(NO)4 (SG:7) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-07-14

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  8. Dynamic and Flight Tests on Rubber-Cord and Oleo-Rubber-Disk Landing Gears for an F6C-4 Airplane

    NASA Technical Reports Server (NTRS)

    Peck, William C

    1932-01-01

    The investigation described in this report was conducted for the purpose of comparing an oleo-rubber-disk and a rubber-cord landing gear, built for use on an F6C-4 airplane. The investigation consisted of drop tests under various loading conditions and flight tests on an F6C-4 airplane. In the drop tests the total work done on each gear and the work done on each of the shock-absorbing units were determined. For both drop tests and flight tests the maximum loads and accelerations were determined. The comparative results showed that the oleo gear was slightly superior in reducing the ordinary landing shocks, that it had a greater capacity for work, and that it was very superior in the reduction of the rebound. The results further showed that for drops comparable to very severe landings, the rubber-cord gear was potentially more effective as a shock-reducing mechanism. However, due to the construction of this chassis, which limited the maximum elongation of the cords, this gear was incapable of withstanding as severe tests as the oleo gear. The action of the oleo gear was greatly inferior to the action of an ideal gear. The maximum accelerations encountered during the flight tests for severe landings were 3.64g for the rubber-cord gear and 2.27g for the oleo gear. These were less than those experienced in free drops of 7 inches on either gear.

  9. Small-angle neutron scattering analysis of Mn–C clusters in high-manganese 18Mn–0.6C steel

    SciTech Connect

    Kang, Mihyun; Shin, Eunjoo; Woo, Wanchuck; Lee, Young-Kook

    2014-10-15

    Nanometer-scale particles (Mn–C clusters) were analyzed quantitatively using small-angle neutron scattering in 18Mn–0.6C (wt.%) austenite high-manganese steel. The size, number, and volume fraction of the particles were determined as a function of strain (0, 5, 15, 30, 45, 50%) at different temperatures (25 and 100 °C). The diameter of the cluster ranges from 2 to 14 nm in the matrix. The total volume fraction of the cluster significantly increases from 2.7 × 10{sup −6} to 8.7 × 10{sup −6} as the strain increases. Such clustering phenomenon is correlated to the serration behavior under loading in high-manganese steels. - Highlights: • Show Mn-C clustering as function of strain in 18Mn-0.6C TWIP steel. • Determine the size, number, and volume fraction of clusters quantitatively. • Compare the clustering behavior at 25 and 100 °C.

  10. Immunotoxicological Profile of Chloroform in Female B6c3f1 Mice When Administered In Drinking Water

    EPA Science Inventory

    Chloroform can be formed as a disinfection by-product during water chlorination, one of the primary modalities for purifying municipal water supplies for human consumption. The goal of this study was to characterize the immunotoxic effects of chloroform in female B6C3F1 mice when...

  11. 17 CFR 270.6c-10 - Exemption for certain open-end management investment companies to impose deferred sales loads.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... management investment companies to impose deferred sales loads. 270.6c-10 Section 270.6c-10 Commodity and... ACT OF 1940 § 270.6c-10 Exemption for certain open-end management investment companies to impose... registered open-end management investment company, other than a registered separate account, and includes...

  12. 17 CFR 270.6c-10 - Exemption for certain open-end management investment companies to impose deferred sales loads.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... management investment companies to impose deferred sales loads. 270.6c-10 Section 270.6c-10 Commodity and... ACT OF 1940 § 270.6c-10 Exemption for certain open-end management investment companies to impose... registered open-end management investment company, other than a registered separate account, and includes...

  13. Comparison of the toxicity of several fumonisin derivatives in a 28-day feeding study with female B6C3F(1) mice.

    PubMed

    Howard, Paul C; Couch, Letha H; Patton, Ralph E; Eppley, Robert M; Doerge, Daniel R; Churchwell, Mona I; Marques, M Matilde; Okerberg, Carlin V

    2002-12-15

    Fumonisinmycotoxins are produced by Fusaria fungi that grow worldwide primarily on corn. Fumonisin B(1), the most predominant form in corn samples, is a renal carcinogen in male F344/N rats and a hepatocarcinogen in female B6C3F(1) mice when fed at concentrations higher than 50 ppm (70 micromol/kg) in the diet for 2 years. We sought to determine the relative toxicities of several naturally occurring fumonisin derivatives when included in the diet of female B6C3F(1) mice. Mice were fed diets containing fumonisin B(1), fumonisin B(2), fumonisin B(3), fumonisin P1, hydrolyzed-fumonisin B(1), N-(acetyl)fumonisin B(1), or N-(carboxymethyl)fumonisin B(1) (approximately 0, 14, 70, and 140 micromol/kg diet) for 28 days. None of the doses used caused a decrease in body weight gain over the 28 days. Serum levels of total bile acids, cholesterol, and alkaline phosphatase were increased only in mice receiving 72 and 143 micromol/kg fumonisin B(1), suggesting that only fumonisin B(1) was hepatotoxic in the mice. Corroborating this observation, the liver weight, relative to body weight, was decreased only in the mice that consumed 143 micromol/kg fumonisin B(1). Consistent with fumonisin B(1) inhibition of ceramide synthase, the liver sphinganine-to-sphingosine ratio was increased and the liver ceramide levels were decreased only in the mice receiving 72 and 143 micromol/kg fumonisin B(1). Increased hepatocellular apoptosis, hepatocellular hypertrophy, Kupffer cell hyperplasia, and macrophage pigmentation were detected in the mice consuming 72 and 143 micromol/kg fumonisin B(1). The other fumonisin derivatives did not alter serum analytes, organ weights, or hepatic structure. These results suggest that, of the naturally occurring fumonisins, fumonisin B(1) is the principal hepatotoxic derivative in the B6C3F(1) mouse.

  14. Density Functional Calculation of the Electronic Structures of Some A5B6C7-TYPE Crystals

    NASA Astrophysics Data System (ADS)

    Akkus, Harun

    The electronic band structures of some A5B6C7-type ternary compounds, BiSeI, BiSI, BiSCl, BiSBr, BiSeBr and SbSeBr, are investigated using the density functional theory and pseudopotential theory under the generalized gradient approximation (GGA). The electronic band structures obtained show that these crystals, except for BiSeI, have an indirect band gap.

  15. Quality Assurance Grading Guidelines for Research and Development at DOE Facilities (DOE Order 5700.6C)

    SciTech Connect

    Powell, T.B.

    1992-01-01

    The quality assurance (QA) requirements for the U.S. Department of Energy (DOE) are established in DOE Order 5700.6C. This order is applicable for all DOE departmental elements, management, and maintenance and operating contractors and requires that documented Quality Assurance Programs (QAPs) are prepared at all levels; it has one attachment. The DOE Office of Energy Research (DOE-ER) has issued a standard to ensure implementation of the full intent of this order in the ER community.

  16. Efficiency of PBN to Trap 3-CAR in B6C3F1 Mouse Liver Slices: An EPR Study.

    DTIC Science & Technology

    1995-09-01

    AL/OE-TR-1995-0139 UNITED STATES AIR FORCE ARMSTRONG LABORATORY EFFICIENCY OF PBN TO TRAP 3-CAR IN B6C3F1 MOUSE LIVER SLICES: AN EPR STUDY...and Eckstein, JM. 1993 Comparative intestinal and testes toxicity of 4 aminothiols in irradiated and non-irradiated mice . Ann Clin and Lab Sei 23 (6...Air Force Armstrong Laboratory. Additional copies may be purchased from: National Technical Information Service 5285 Port Royal Road Springfield

  17. Prototropic μ-H(8,9) and μ-H(9,10) Tautomers Derived from the [nido-5,6-C2B8H11](-) Anion.

    PubMed

    Tok, Oleg L; Růžičková, Zdenka; Růžička, Aleš; Hnyk, Drahomír; Štíbr, Bohumil

    2016-10-17

    Reported is an unusual tautomeric behavior within the [nido-5,6-C2B8H11](-) (1a(-)) cage that has no precedence in the whole area of carborane chemistry. Isolated were two skeletal tautomers, anions [6-Ph-nido-5,6-C2B8H10-μ(8,9)](-) (2d(-)) and [5,6-Me2-nido-5,6-C2B8H9-μ(9,10)](-) (3b(-)), which differ in the positioning of the open-face hydrogen bridge. Their structures have been determined by X-ray diffraction analyses. The 3b(-)structure is stabilized by intermolecular interaction involving Et3NH(+) and B8-B9 and H8 atoms in the solid phase; however, its dissolution in CD3CN causes instant conversion to the more stable [5,6-Me2-nido-5,6-C2B8H9-μ(8,9)](-) (2b(-)) tautomer. The dynamic electron-correlation-based MP2/6-31G* computations suggest that the parent [nido-5,6-C2B8H11-μ(8,9)](-) (2a(-)) tautomer is 3.9 kcal·mol(-1) more stable than the [nido-5,6-C2B8H11-μ(9,10)](-) (3a(-)) counterpart and the μ(8,9) structure 2(-) is therefore the most stable tautomeric form in the solution, as was also demonstrated by multinuclear ((1)H, (11)B, and (13)C) NMR measurements on the whole series of C-substituted compounds.

  18. Structure-Function Analysis of Friedreich's Ataxia Mutants Reveals Determinants of Frataxin Binding and Activation of the Fe-S Assembly Complex

    SciTech Connect

    Bridwell-Rabb, Jennifer; Winn, Andrew M; Barondeau, David P

    2012-08-01

    Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease associated with the loss of function of the protein frataxin (FXN) that results from low FXN levels due to a GAA triplet repeat expansion or, occasionally, from missense mutations in the FXN gene. Here biochemical and structural properties of FXN variants, including three FRDA missense mutations (N146K, Q148R, and R165C) and three related mutants (N146A, Q148G, and Q153A), were determined in an effort to understand the structural basis for the loss of function. In vitro assays revealed that although the three FRDA missense mutations exhibited similar losses of cysteine desulfurase and Fe-S cluster assembly activities, the causes for these activation defects were distinct. The R165C variant exhibited a kcat/KM higher than that of native FXN but weak binding to the NFS1, ISD11, and ISCU2 (SDU) complex, whereas the Q148R variant exhibited the lowest kcat/KM of the six tested FXN variants and only a modest binding deficiency. The order of the FXN binding affinities for the SDU Fe-S assembly complex was as follows: FXN > Q148R > N146A > Q148G > N146K > Q153A > R165C. Four different classes of FXN variants were identified on the basis of their biochemical properties. Together, these structure-function studies reveal determinants for the binding and allosteric activation of the Fe-S assembly complex and provide insight into how FRDA missense mutations are functionally compromised.

  19. Lead isotopes in lichen transplants around a Cu smelter in Russia determined by MC-ICP-MS reveal transient records of multiple sources.

    PubMed

    Spiro, B; Weiss, D J; Purvis, O W; Mikhailova, I; Williamson, B J; Coles, B J; Udachin, V

    2004-12-15

    Transplants of the lichen Hypogymnia physodes, which is relatively tolerant to SO2 and heavy metals, were deployed for 3 months over a 60 km long SW-NE transect centered on a highly polluting Cu smelter and its adjoining town of Karabash, southern Urals, Russia. The abundance of 206Pb, 207Pb, 208Pb, and 204Pb were determined by MC-ICP-MS. The measurement of 204Pb revealed critical features, which would otherwise remain concealed: (i) The precise isotope ratios referenced to 204Pb allowed several different sources to be resolved even within the small area covered: (a) the obvious pollutant source of the Karabash Cu smelter; (b) two dispersed sources, likely to include soil with lower and different contributions of thorogenic and uranogenic lead; and (c) one anthropogenic source with higher contribution of 235U derived Pb. (ii) In part of the transect, the Pb isotope composition changed while the Pb concentrations remained the same. This indicates that the Pb content of the transplantation material from the background site was largely replaced and that the transplants provide a transient record reflecting a continuous accumulation and loss of environmental Pb, probably mainly in the form of extracellular particles. Overall, the method of lichen transplantation coupled with Pb isotope ratio determinations proved effective in assessing the usefulness of lichens in biomonitoring and in resolving different sources of atmospheric deposition.

  20. Human SAS-6 C-Terminus Nucleates and Promotes Microtubule Assembly in Vitro by Binding to Microtubules.

    PubMed

    Gupta, Hindol; Badarudeen, Binshad; George, Athira; Thomas, Geethu Emily; Gireesh, K K; Manna, Tapas K

    2015-10-20

    Centrioles are essential components of the animal centrosome and play crucial roles in the formation of cilia and flagella. They are cylindrical structures composed of nine triplet microtubules organized around a central cartwheel. Recent studies have identified spindle assembly abnormal protein SAS-6 as a critical component necessary for formation of the cartwheel. However, the molecular details of how the cartwheel participates in centriolar microtubule assembly have not been clearly understood. In this report, we show that the C-terminal tail (residues 470-657) of human SAS-6, HsSAS-6 C, the region that has been shown to extend toward the centriolar wall where the microtubule triplets are organized, nucleated and induced microtubule polymerization in vitro. The N-terminus (residues 1-166) of HsSAS-6, the domain known to be involved in formation of the central hub of the cartwheel, did not, however, exert any effect on microtubule polymerization. HsSAS-6 C bound to the microtubules and localized along the lengths of the microtubules in vitro. Microtubule pull-down and coimmunoprecipitation (Co-IP) experiments with S-phase synchronized HeLa cell lysates showed that the endogenous HsSAS-6 coprecipitated with the microtubules, and it mediated interaction with tubulin. Isothermal calorimetry titration and size exclusion chromatography showed that HsSAS-6 C bound to the αβ-tubulin dimer in vitro. The results demonstrate that HsSAS-6 possesses an intrinsic microtubule assembly promoting activity and further implicate that its outer exposed C-terminal tail may play critical roles in microtubule assembly and stabilizing microtubule attachment with the centriolar cartwheel.

  1. Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F sub 1 mice

    SciTech Connect

    Huff, J.E.; Haseman, J.K.; Eustis, S.; Maronpot, R.R. ); DeMarini, D.M. ); Peters, A.C.; Persing, R.L. ); Chrisp, C.E. ); Jacobs, A.C. )

    1989-07-01

    Toxicology and carcinogenesis studies of benzene were conducted in groups of 60 F344/N rats and 60 B6C3F{sub 1} mice of each sex for each of three exposure doses and vehicle controls. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations, on clinical pathologic findings and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F{sub 1} mice, and female B6C3F{sub 1} mice. Dose-related lymphocytopenia was observed for male and female F344/N rats and male and female B6C3F{sub 1} mice. These unequivocal observations show clearly that benzene is a trans-species, trans-sex, multisite potent carcinogen.

  2. Quantitation of TCE-Induced Radicals in Liver of B6C3Fl Mice In Vivo: An EPR Study

    DTIC Science & Technology

    1996-02-01

    PAGE 1 First derivative EPR spectrum of B6C3F1 mouse liver (a) after and (b) before lyophilization 8 2 GC/MS of PBN extract (a) Total ion current...of TCE-induced cancer in a number of animal species remains to be elucidated. The biological effects of TCE are of special interest to us because TCE...injection the mouse was killed and the liver was harvested. Figure 2A shows the total ion current gas chromatogram of the GC/MS analysis of.a non polar

  3. Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F{sub 1} mouse model

    SciTech Connect

    Desai, Varsha G.; Herman, Eugene H.; Moland, Carrie L.; Branham, William S.; Lewis, Sherry M.; Davis, Kelly J.; George, Nysia I.; Lee, Taewon; Kerr, Susan; Fuscoe, James C.

    2013-01-01

    Serum levels of cardiac troponins serve as biomarkers of myocardial injury. However, troponins are released into the serum only after damage to cardiac tissue has occurred. Here, we report development of a mouse model of doxorubicin (DOX)-induced chronic cardiotoxicity to aid in the identification of predictive biomarkers of early events of cardiac tissue injury. Male B6C3F{sub 1} mice were administered intravenous DOX at 3 mg/kg body weight, or an equivalent volume of saline, once a week for 4, 6, 8, 10, 12, and 14 weeks, resulting in cumulative DOX doses of 12, 18, 24, 30, 36, and 42 mg/kg, respectively. Mice were sacrificed a week following the last dose. A significant reduction in body weight gain was observed in mice following exposure to a weekly DOX dose for 1 week and longer compared to saline-treated controls. DOX treatment also resulted in declines in red blood cell count, hemoglobin level, and hematocrit compared to saline-treated controls after the 2nd weekly dose until the 8th and 9th doses, followed by a modest recovery. All DOX-treated mice had significant elevations in cardiac troponin T concentrations in plasma compared to saline-treated controls, indicating cardiac tissue injury. Also, a dose-related increase in the severity of cardiac lesions was seen in mice exposed to 24 mg/kg DOX and higher cumulative doses. Mice treated with cumulative DOX doses of 30 mg/kg and higher showed a significant decline in heart rate, suggesting drug-induced cardiac dysfunction. Altogether, these findings demonstrate the development of DOX-induced chronic cardiotoxicity in B6C3F{sub 1} mice. -- Highlights: ► 24 mg/kg was a cumulative cardiotoxic dose of doxorubicin in male B6C3F{sub 1} mice. ► Doxorubicin-induced hematological toxicity was in association with splenomegaly. ► Doxorubicin induced severe testicular toxicity in B6C3F{sub 1} male mice.

  4. Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential.

    PubMed

    Jeong, Jayoung; Han, Beom Seok; Cho, Wan-Seob; Choi, Mina; Ha, Chang-Su; Lee, Byoung-Seok; Kim, Yong-Bum; Son, Woo-Chan; Kim, Choong-Yong

    2010-09-01

    3-Monochloropropane-1, 2-diol (or 3-chloro-1,2-propanediol, 3-MCPD) is a well-known food processing contaminant found in a wide range of foods and ingredients. It has been classified as non-genotoxic carcinogen but its carcinogenic potential in the rodents has been controversial. The carcinogenicity to B6C3F1 mice by drinking water administration was assessed over a period of 104 weeks. Three groups, each comprising 50 male and 50 female mice received 3-MCPD at dosages of 30, 100 or 300 ppm up to Day 100 and 200 ppm onward (4.2, 14.3 and 33.0 mg/kg for males; 3.7, 12.2, and 31.0 mg/kg for females), were allocated. Survival was good, with at least 80% of males and 72% of females in each group surviving 104 weeks. Body weights and body weight gain were decreased in males and females receiving 200 ppm. Water and food consumptions of both sexes at 300/200 ppm were lowered. Emaciated or crouching position was observed for animals of both sexes exposed to 200 ppm. There were some differences in hematology and serum biochemistry compared with controls, although there was no histopathological evidence to support those changes. Histopathological examination did not reveal any neoplastic or non-neoplastic findings attributable to treatment with 3-MCPD. It is concluded that drinking water administration of 3-MCPD for 104 weeks revealed no evidence of carcinogenic potential.

  5. Magnetic Particle Spectroscopy Reveals Dynamic Changes in the Magnetic Behavior of Very Small Superparamagnetic Iron Oxide Nanoparticles During Cellular Uptake and Enables Determination of Cell-Labeling Efficacy.

    PubMed

    Poller, Wolfram C; Löwa, Norbert; Wiekhorst, Frank; Taupitz, Matthias; Wagner, Susanne; Möller, Konstantin; Baumann, Gert; Stangl, Verena; Trahms, Lutz; Ludwig, Antje

    2016-02-01

    In vivo tracking of nanoparticle-labeled cells by magnetic resonance imaging (MRI) crucially depends on accurate determination of cell-labeling efficacy prior to transplantation. Here, we analyzed the feasibility and accuracy of magnetic particle spectroscopy (MPS) for estimation of cell-labeling efficacy in living THP-1 cells incubated with very small superparamagnetic iron oxide nanoparticles (VSOP). Cell viability and proliferation capacity were not affected by the MPS measurement procedure. In VSOP samples without cell contact, MPS enabled highly accurate quantification. In contrast, MPS constantly overestimated the amount of cell associated and internalized VSOP. Analyses of the MPS spectrum shape expressed as harmonic ratio A₅/A₃ revealed distinct changes in the magnetic behavior of VSOP in response to cellular uptake. These changes were proportional to the deviation between MPS and actual iron amount, therefore allowing for adjusted iron quantification. Transmission electron microscopy provided visual evidence that changes in the magnetic properties correlated with cell surface interaction of VSOP as well as with alterations of particle structure and arrangement during the phagocytic process. Altogether, A₅/A₃-adjusted MPS enables highly accurate, cell-preserving VSOP quantification and furthermore provides information on the magnetic characteristics of internalized VSOP.

  6. A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics

    NASA Astrophysics Data System (ADS)

    Kueh, Hao Yuan; Zhu, Yanting; Shi, Jue

    2016-11-01

    Anti-mitotic drugs constitute a major class of cytotoxic chemotherapeutics used in the clinic, killing cancer cells by inducing prolonged mitotic arrest that activates intrinsic apoptosis. Anti-mitotics-induced apoptosis is known to involve degradation of anti-apoptotic Bcl-2 proteins during mitotic arrest; however, it remains unclear how this mechanism accounts for significant heterogeneity observed in the cell death responses both within and between cancer cell types. To unravel quantitative determinants underlying variability in anti-mitotic drug response, we constructed a single-cell dynamical Bcl-2 network model describing cell death control during mitotic arrest, and constrained the model using experimental data from four representative cancer cell lines. The modeling analysis revealed that, given a variable, slowly accumulating pro-apoptotic signal arising from anti-apoptotic protein degradation, generation of a switch-like apoptotic response requires formation of pro-apoptotic Bak complexes with hundreds of subunits, suggesting a crucial role for high-order cooperativity. Moreover, we found that cell-type variation in susceptibility to drug-induced mitotic death arises primarily from differential expression of the anti-apoptotic proteins Bcl-xL and Mcl-1 relative to Bak. The dependence of anti-mitotic drug response on Bcl-xL and Mcl-1 that we derived from the modeling analysis provides a quantitative measure to predict sensitivity of distinct cancer cells to anti-mitotic drug treatment.

  7. Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation.

    PubMed

    Støve, Svein Isungset; Magin, Robert S; Foyn, Håvard; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas

    2016-07-06

    N-Terminal acetylation is a common and important protein modification catalyzed by N-terminal acetyltransferases (NATs). Six human NATs (NatA-NatF) contain one catalytic subunit each, Naa10 to Naa60, respectively. In contrast to the ribosome-associated NatA to NatE, NatF/Naa60 specifically associates with Golgi membranes and acetylates transmembrane proteins. To gain insight into the molecular basis for the function of Naa60, we developed an Naa60 bisubstrate CoA-peptide conjugate inhibitor, determined its X-ray structure when bound to CoA and inhibitor, and carried out biochemical experiments. We show that Naa60 adapts an overall fold similar to that of the catalytic subunits of ribosome-associated NATs, but with the addition of two novel elongated loops that play important roles in substrate-specific binding. One of these loops mediates a dimer to monomer transition upon substrate-specific binding. Naa60 employs a catalytic mechanism most similar to Naa50. Collectively, these data reveal the molecular basis for Naa60-specific acetyltransferase activity with implications for its Golgi-specific functions.

  8. A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics

    PubMed Central

    Kueh, Hao Yuan; Zhu, Yanting; Shi, Jue

    2016-01-01

    Anti-mitotic drugs constitute a major class of cytotoxic chemotherapeutics used in the clinic, killing cancer cells by inducing prolonged mitotic arrest that activates intrinsic apoptosis. Anti-mitotics-induced apoptosis is known to involve degradation of anti-apoptotic Bcl-2 proteins during mitotic arrest; however, it remains unclear how this mechanism accounts for significant heterogeneity observed in the cell death responses both within and between cancer cell types. To unravel quantitative determinants underlying variability in anti-mitotic drug response, we constructed a single-cell dynamical Bcl-2 network model describing cell death control during mitotic arrest, and constrained the model using experimental data from four representative cancer cell lines. The modeling analysis revealed that, given a variable, slowly accumulating pro-apoptotic signal arising from anti-apoptotic protein degradation, generation of a switch-like apoptotic response requires formation of pro-apoptotic Bak complexes with hundreds of subunits, suggesting a crucial role for high-order cooperativity. Moreover, we found that cell-type variation in susceptibility to drug-induced mitotic death arises primarily from differential expression of the anti-apoptotic proteins Bcl-xL and Mcl-1 relative to Bak. The dependence of anti-mitotic drug response on Bcl-xL and Mcl-1 that we derived from the modeling analysis provides a quantitative measure to predict sensitivity of distinct cancer cells to anti-mitotic drug treatment. PMID:27811996

  9. Age-specific absolute and relative organ weight distributions for B6C3F1 mice.

    PubMed

    Marino, Dale J

    2012-01-01

    The B6C3F1 mouse is the standard mouse strain used in toxicology studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). While numerous reports have been published on growth, survival, and tumor incidence, no overall compilation of organ weight data is available. Importantly, organ weight change is an endpoint used by regulatory agencies to develop toxicity reference values (TRVs) for use in human health risk assessments. Furthermore, physiologically based pharmacokinetic (PBPK) models, which utilize relative organ weights, are increasingly being used to develop TRVs. Therefore, all available absolute and relative organ weight data for untreated control B6C3F1 mice were collected from NCI/NTP studies in order to develop age-specific distributions. Results show that organ weights were collected more frequently in NCI/NTP studies at 2-wk (60 studies), 3-mo (147 studies), and 15-mo (40 studies) intervals than at other intervals, and more frequently from feeding and inhalation than drinking water studies. Liver, right kidney, lung, heart, thymus, and brain weights were most frequently collected. From the collected data, the mean and standard deviation for absolute and relative organ weights were calculated. Results show age-related increases in absolute liver, right kidney, lung, and heart weights and relatively stable brain and right testis weights. The results suggest a general variability trend in absolute organ weights of brain < right testis < right kidney < heart < liver < lung < spleen < thymus. This report describes the results of this effort.

  10. Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice

    PubMed Central

    Thakur, Sheetal A.; Nyska, Abraham; White, Kimber L.; Smith, Matthew J.; Auttachoat, Wimolnut; Germolec, Dori R.

    2014-01-01

    Interstitial cystitis (IC) is a chronic disorder characterized by bladder discomfort and urinary urgency in the absence of identifiable infection. Despite the expanding use in treatment of IC and other chronic conditions, the effects of Elmiron® treatment on immune system remain unknown. Therefore, female B6C3F1/N mice were orally administered Elmiron® daily for 28-days at doses of 63, 125, 250, 500 or 1000 mg/kg to evaluate its immunomodulatory effects. Mice treated with Elmiron® had a significant increase in absolute numbers of splenic macrophages (63, 500 and 1000 mg/kg) and natural killer (NK) cells (250 and 1000 mg/kg). Elmiron® treatment did not affect the humoral immune response or T cell proliferative response. However, innate immune responses such as phagocytosis by liver macrophages (1000 mg/kg) and NK cell activity were enhanced (500 and 1000 mg/kg). Further analysis using a disease resistance model showed that Elmiron® -treated mice demonstrated significantly increased anti-tumor activity against B16F10 melanoma cells at the 500 and 1000 mg/kg doses. Collectively, we conclude that Elmiron® administration stimulates the immune system, increasing numbers of specific cell populations and enhancing macrophage phagocytosis and NK cell activity in female B6C3F1/N mice. This augmentation may have largely contributed to the reduced number of B16F10 melanoma tumors. PMID:24657363

  11. Sarafotoxin S6c is a relatively weak displacer of specifically bound /sup 125/I-endothelin

    SciTech Connect

    Nayler, W.G.; Gu, X.H.; Casley, D.J.

    1989-05-30

    Sarafotoxin S6a, S6b and S6c are chemically related vasoconstrictor polypeptides obtained from the venom of the snake, Atractaspis engaddensis. Each contains twenty one amino acid residues, two intrachain cysteine linkages and a long hydrophobic tail. Structurally these polypeptides resemble endothelin. Binding studies with /sup 125/I-endothelin showed that /sup 125/I-endothelin bound to rat ventricular membranes is totally displaceable by sarafotoxin S6b and endothelin, with IC50 values of 0.21 and 0.16 nM, respectively. Sarafotoxin S6c, which differs from sarafotoxin S6b in containing threonine instead of serine at residue 2, arginine instead of lysine at residue 4, and glutamic acid instead of lysine at residue 9, only weakly displaced bound /sup 125/I-endothelin (IC50, 854 nM). These results indicate that the ability of the sarafotoxins to interact with the endothelin binding site is not solely dependent on the long hydrophobic tail or the cysteine linkages.

  12. Effect of the Gas6 c.834+7G>A polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients.

    PubMed

    Losonczy, Gergely; Vajas, Attila; Takács, Lili; Dzsudzsák, Erika; Fekete, Agnes; Márhoffer, Eva; Kardos, László; Ajzner, Eva; Hurtado, Begoña; de Frutos, Pablo Garcia; Berta, András; Balogh, István

    2012-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26-0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30-393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98-12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry

  13. Effect of the Gas6 c.834+7G>A Polymorphism and the Interaction of Known Risk Factors on AMD Pathogenesis in Hungarian Patients

    PubMed Central

    Losonczy, Gergely; Vajas, Attila; Takács, Lili; Dzsudzsák, Erika; Fekete, Ágnes; Márhoffer, Éva; Kardos, László; Ajzner, Éva; Hurtado, Begoña; de Frutos, Pablo Garcia

    2012-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of

  14. CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F, MOUSE

    EPA Science Inventory

    CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO THE MALE F344/N RAT AND B6C3F1 MOUSE.

    Bromodichloromethane (BDCM) has been shown to produce kidney and large bowel tumors in both male and female F344/N rats, kidney tumors in male B6C3F 1 mice and ...

  15. Comprehensive Identification of Long Non-coding RNAs in Purified Cell Types from the Brain Reveals Functional LncRNA in OPC Fate Determination

    PubMed Central

    Dong, Xiaomin; Chen, Kenian; Cuevas-Diaz Duran, Raquel; You, Yanan; Sloan, Steven A.; Zhang, Ye; Zong, Shan; Cao, Qilin; Barres, Ben A.; Wu, Jia Qian

    2015-01-01

    Long non-coding RNAs (lncRNAs) (> 200 bp) play crucial roles in transcriptional regulation during numerous biological processes. However, it is challenging to comprehensively identify lncRNAs, because they are often expressed at low levels and with more cell-type specificity than are protein-coding genes. In the present study, we performed ab initio transcriptome reconstruction using eight purified cell populations from mouse cortex and detected more than 5000 lncRNAs. Predicting the functions of lncRNAs using cell-type specific data revealed their potential functional roles in Central Nervous System (CNS) development. We performed motif searches in ENCODE DNase I digital footprint data and Mouse ENCODE promoters to infer transcription factor (TF) occupancy. By integrating TF binding and cell-type specific transcriptomic data, we constructed a novel framework that is useful for systematically identifying lncRNAs that are potentially essential for brain cell fate determination. Based on this integrative analysis, we identified lncRNAs that are regulated during Oligodendrocyte Precursor Cell (OPC) differentiation from Neural Stem Cells (NSCs) and that are likely to be involved in oligodendrogenesis. The top candidate, lnc-OPC, shows highly specific expression in OPCs and remarkable sequence conservation among placental mammals. Interestingly, lnc-OPC is significantly up-regulated in glial progenitors from experimental autoimmune encephalomyelitis (EAE) mouse models compared to wild-type mice. OLIG2-binding sites in the upstream regulatory region of lnc-OPC were identified by ChIP (chromatin immunoprecipitation)-Sequencing and validated by luciferase assays. Loss-of-function experiments confirmed that lnc-OPC plays a functional role in OPC genesis. Overall, our results substantiated the role of lncRNA in OPC fate determination and provided an unprecedented data source for future functional investigations in CNS cell types. We present our datasets and analysis results

  16. Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection

    PubMed Central

    Wilde, Aimee D.; Snyder, Daniel J.; Putnam, Nicole E.; Valentino, Michael D.; Hammer, Neal D.; Lonergan, Zachery R.; Hinger, Scott A.; Aysanoa, Esar E.; Blanchard, Catlyn; Dunman, Paul M.; Wasserman, Gregory A.; Chen, John; Shopsin, Bo; Gilmore, Michael S.; Skaar, Eric P.; Cassat, James E.

    2015-01-01

    Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survival during invasive infection, we performed a transposon sequencing (TnSeq) analysis of S. aureus during experimental osteomyelitis. TnSeq identified 65 genes essential for staphylococcal survival in infected bone and an additional 148 mutants with compromised fitness in vivo. Among the loci essential for in vivo survival was SrrAB, a staphylococcal two-component system previously reported to coordinate hypoxic and nitrosative stress responses in vitro. Healthy bone is intrinsically hypoxic, and intravital oxygen monitoring revealed further decreases in skeletal oxygen concentrations upon S. aureus infection. The fitness of an srrAB mutant during osteomyelitis was significantly increased by depletion of neutrophils, suggesting that neutrophils impose hypoxic and/or nitrosative stresses on invading bacteria. To more globally evaluate staphylococcal responses to changing oxygenation, we examined quorum sensing and virulence factor production in staphylococci grown under aerobic or hypoxic conditions. Hypoxic growth resulted in a profound increase in quorum sensing-dependent toxin production, and a concomitant increase in cytotoxicity toward mammalian cells. Moreover, aerobic growth limited quorum sensing and cytotoxicity in an SrrAB-dependent manner, suggesting a mechanism by which S. aureus modulates quorum sensing and toxin production in response to environmental oxygenation. Collectively, our results demonstrate that bacterial hypoxic responses are key determinants of the staphylococcal-host interaction. PMID:26684646

  17. Local Effect of Enhancer of Zeste-Like Reveals Cooperation of Epigenetic and cis-Acting Determinants for Zygotic Genome Rearrangements

    PubMed Central

    Denby Wilkes, Cyril; Matelot, Mélody; Vervoort, Michel; Sperling, Linda; Duharcourt, Sandra

    2014-01-01

    In the ciliate Paramecium tetraurelia, differentiation of the somatic nucleus from the zygotic nucleus is characterized by massive and reproducible deletion of transposable elements and of 45,000 short, dispersed, single-copy sequences. A specific class of small RNAs produced by the germline during meiosis, the scnRNAs, are involved in the epigenetic regulation of DNA deletion but the underlying mechanisms are poorly understood. Here, we show that trimethylation of histone H3 (H3K27me3 and H3K9me3) displays a dynamic nuclear localization that is altered when the endonuclease required for DNA elimination is depleted. We identified the putative histone methyltransferase Ezl1 necessary for H3K27me3 and H3K9me3 establishment and show that it is required for correct genome rearrangements. Genome-wide analyses show that scnRNA-mediated H3 trimethylation is necessary for the elimination of long, repeated germline DNA, while single copy sequences display differential sensitivity to depletion of proteins involved in the scnRNA pathway, Ezl1- a putative histone methyltransferase and Dcl5- a protein required for iesRNA biogenesis. Our study reveals cis-acting determinants, such as DNA length, also contribute to the definition of germline sequences to delete. We further show that precise excision of single copy DNA elements, as short as 26 bp, requires Ezl1, suggesting that development specific H3K27me3 and H3K9me3 ensure specific demarcation of very short germline sequences from the adjacent somatic sequences. PMID:25254958

  18. Large-scale phosphotyrosine proteomic profiling of rat renal collecting duct epithelium reveals predominance of proteins involved in cell polarity determination.

    PubMed

    Zhao, Boyang; Knepper, Mark A; Chou, Chung-Lin; Pisitkun, Trairak

    2012-01-01

    Although extensive phosphoproteomic information is available for renal epithelial cells, previous emphasis has been on phosphorylation of serines and threonines with little focus on tyrosine phosphorylation. Here we have carried out large-scale identification of phosphotyrosine sites in pervanadate-treated native inner medullary collecting ducts of rat, with a view towards identification of physiological processes in epithelial cells that are potentially regulated by tyrosine phosphorylation. The method combined antibody-based affinity purification of tyrosine phosphorylated peptides coupled with immobilized metal ion chromatography to enrich tyrosine phosphopeptides, which were identified by LC-MS/MS. A total of 418 unique tyrosine phosphorylation sites in 273 proteins were identified. A large fraction of these sites have not been previously reported on standard phosphoproteomic databases. All results are accessible via an online database: http://helixweb.nih.gov/ESBL/Database/iPY/. Analysis of surrounding sequences revealed four overrepresented motifs: [D/E]xxY*, Y*xxP, DY*, and Y*E, where the asterisk symbol indicates the site of phosphorylation. These motifs plus contextual information, integrated using the NetworKIN tool, suggest that the protein tyrosine kinases involved include members of the insulin- and ephrin-receptor kinase families. Analysis of the gene ontology (GO) terms and KEGG pathways whose protein elements are overrepresented in our data set point to structures involved in epithelial cell-cell and cell-matrix interactions ("adherens junction," "tight junction," and "focal adhesion") and to components of the actin cytoskeleton as major sites of tyrosine phosphorylation in these cells. In general, these findings mesh well with evidence that tyrosine phosphorylation plays a key role in epithelial polarity determination.

  19. Observation of the widetilde{A} - widetilde{X} Electronic Transition of C_6-C_{10} Peroxy Radicals

    NASA Astrophysics Data System (ADS)

    Kline, Neal D.; Miller, Terry A.

    2013-06-01

    The widetilde{A} - widetilde{X} electronic transition of straight chain C_6-C_{10} peroxy radicals and of the isooctyl peroxy radical have been observed and analyzed. These larger hydrocarbons are significant constituents of gasoline with heptane (octane rating of 0) and isooctane (2,2,4 trimethylpentane; octane rating of 100) being the two standards on which the octane rating scale is based. Spectra were obtained by abstraction of hydrogen atoms from the hydrocarbons using chlorine atoms. The origin and -OO stretch regions of the straight chain peroxy radicals are easily identifiable. It is relatively easy to uniquely identify hexyl peroxy, but differentiation among the spectra of the larger straight chain peroxy radicals has proven difficult. However, isooctyl peroxy is easily distinguished and the observation of the tertiary peroxy radical along with the primary and/or secondary peroxy radical(s) is discussed.

  20. Do vehicular emissions dominate the source of C6-C8 aromatics in the megacity Shanghai of eastern China?

    PubMed

    Wang, Hongli; Wang, Qian; Chen, Jianmin; Chen, Changhong; Huang, Cheng; Qiao, Liping; Lou, Shengrong; Lu, Jun

    2015-01-01

    The characteristic ratios of volatile organic compounds (VOCs) to i-pentane, the indicator of vehicular emissions, were employed to apportion the vehicular and non-vehicular contributions to reactive species in urban Shanghai. Two kinds of tunnel experiments, one tunnel with more than 90% light duty gasoline vehicles and the other with more than 60% light duty diesel vehicles, were carried out to study the characteristic ratios of vehicle-related emissions from December 2009 to January 2010. Based on the experiments, the characteristic ratios of C6-C8 aromatics to i-pentane of vehicular emissions were 0.53 ± 0.08 (benzene), 0.70 ± 0.12 (toluene), 0.41 ± 0.09 (m,p-xylenes), 0.16 ± 0.04 (o-xylene), 0.023 ± 0.011 (styrene), and 0.15 ± 0.02 (ethylbenzene), respectively. The source apportionment results showed that around 23.3% of C6-C8 aromatics in urban Shanghai were from vehicular emissions, which meant that the non-vehicular emissions had more importance. These findings suggested that emission control of non-vehicular sources, i.e. industrial emissions, should also receive attention in addition to the control of vehicle-related emissions in Shanghai. The chemical removal of VOCs during the transport from emissions to the receptor site had a large impact on the apportionment results. Generally, the overestimation of vehicular contributions would occur when the VOC reaction rate constant with OH radicals (kOH) was larger than that of the vehicular indicator, while for species with smaller kOH than the vehicular indicator, the vehicular contribution would be underestimated by the method of characteristic ratios.

  1. Carcinogenicity of malachite green chloride and leucomalachite green in B6C3F1 mice and F344 rats.

    PubMed

    Culp, Sandra J; Mellick, Paul W; Trotter, Ronald W; Greenlees, Kevin J; Kodell, Ralph L; Beland, Frederick A

    2006-08-01

    Malachite green is a triphenylmethane dye used in the fish industry as an anti-fungal agent. Leucomalachite green is formed by the metabolic reduction of malachite green and persists in the tissues of exposed fish. In this study, we examined the carcinogenicity of malachite green chloride and leucomalachite green. Female F344 rats (48 per group) were fed diets containing 0, 100, 300, or 600 ppm malachite green chloride for 104 weeks, at which time the extent of tumorigenesis was assessed. Additional groups of 48 female and 48 male F344 rats were fed diets containing 0, 91, 272, or 543 ppm leucomalachite green for 104 weeks. Groups of 48 female B6C3F1 mice were fed diets containing 0, 100, 225, or 450 ppm malachite green chloride or 0, 91, 204, or 408 ppm leucomalachite green for 104 weeks. For each of the exposures, food consumption in the treatment groups was similar to the controls. Rats fed malachite green chloride or leucomalachite green had dose-dependent reductions in body weight; in mice, there were no consistent effects upon body weights with either compound. Female rats exposed to malachite green chloride had increased incidences of thyroid gland follicular cell adenoma or carcinoma and hepatocellular adenoma, and a dose-related increasing trend in mammary gland carcinoma. Female rats fed malachite green chloride and female and male rats fed leucomalachite green had a dose-related decreasing trend in the incidence of mononuclear cell leukemia. In male rats fed leucomalachite green there was a decreasing trend in pituitary gland adenoma and an increasing trend in interstitial cell adenoma of the testis. There were no treatment-related neoplasms in female B6C3F1 mice fed malachite green chloride. Female mice fed leucomalachite green had a dose-related increasing trend in the incidence of hepatocellular adenoma or carcinoma, with the incidence being significant in the highest dose group.

  2. The cooling capabilities of C2F6/C3F8 saturated fluorocarbon blends for the ATLAS silicon tracker

    NASA Astrophysics Data System (ADS)

    Bates, R.; Battistin, M.; Berry, S.; Bitadze, A.; Bonneau, P.; Bousson, N.; Boyd, G.; Botelho-Direito, J.; Crespo-Lopez, O.; DiGirolamo, B.; Doubek, M.; Giugni, D.; Hallewell, G.; Lombard, D.; Katunin, S.; McMahon, S.; Nagai, K.; Robinson, D.; Rossi, C.; Rozanov, A.; Vacek, V.; Zwalinski, L.

    2015-03-01

    We investigate and address the performance limitations of the ATLAS silicon tracker fluorocarbon evaporative cooling system operation in the cooling circuits of the barrel silicon microstrip (SCT) sub-detector. In these circuits the minimum achievable evaporation temperatures with C3F8 were higher than the original specification, and were thought to allow an insufficient safety margin against thermal runaway in detector modules subject to a radiation dose initially foreseen for 10 years operation at LHC. We have investigated the cooling capabilities of blends of C3F8 with molar admixtures of up to 25% C2F6, since the addition of the more volatile C2F6 component was expected to allow a lower evaporation temperature for the same evaporation pressure.A custom built recirculator allowed the in-situ preparation of C2F6/C3F8 blends. These were circulated through a representative mechanical and thermal setup reproducing an as-installed ATLAS SCT barrel tracker cooling circuit. Blend molar compositions were verified to a precision of 3.10-3 in a custom ultrasonic instrument.Thermal measurements in a range of C2F6/C3F8 blends were compared with measurements in pure C3F8. These indicated that a blend with 25% C2F6 would allow a reduction in evaporation temperature of around 9oC to below -15oC, even at the highest module power dissipations envisioned after 10 years operation at LHC. Such a reduction would allow more than a factor two in safety margin against temperature dependant leakage power induced thermal runaway.Furthermore, a blend containing up to 25% C2F6 could be circulated without changes to the on-detector elements of the existing ATLAS inner detector evaporative cooling system.

  3. Allelotyping of butadiene-induced lung and mammary adenocarcinomas of B6C3F1 mice: frequent losses of heterozygosity in regions homologous to human tumor-suppressor genes.

    PubMed Central

    Wiseman, R W; Cochran, C; Dietrich, W; Lander, E S; Söderkvist, P

    1994-01-01

    To identify the potential involvement of tumor-suppressor gene inactivation during neoplastic development in B6C3F1 mice, genetic losses were determined from allelotypes of butadiene-induced lung and mammary adenocarcinomas. By using length polymorphisms in restriction fragments and simple sequence repeats, or "microsatellites," markers on each autosome were analyzed for allele losses in tumor DNAs. Losses of heterozygosity on chromosome 11 were observed at several loci surrounding the p53 tumor-suppressor gene (Trp53) in 12 of 17 mammary tumors and 2 of 8 lung tumors. Although most of these alterations appeared to result from nondisjunction, at least two examples of somatic recombination or deletion were also observed. Southern analysis revealed a homozygous deletion of the remaining Trp53 allele of one of these mammary tumors. Losses of heterozygosity were also detected at the Rb-1 tumor-suppressor gene in 7 of 17 mammary tumors and 1 lung tumor. Finally, frequent allele losses were observed on chromosome 4 in lung tumors. Analysis of nine chromosome 4 loci defined an interstitial deletion containing the Ifa gene cluster in one of the lung tumors. A tumor-suppressor gene was previously mapped to this region of chromosome 4 in studies with somatic cell hybrids. In addition, homozygous deletions have been reported in a homologous region of human chromosome 9p for acute lymphocytic leukemias, glioblastomas, melanomas, and lung carcinomas. These findings suggest that the inactivation of tumor-suppressor genes including Trp53, Rb-1, and an unidentified gene on chromosome 4 plays a significant role during carcinogenesis in mice. Images PMID:8170984

  4. Differential Transcriptomic Analysis of Spontaneous Lung Tumors in B6C3F1 Mice: Comparison to Human Non–Small Cell Lung Cancer

    PubMed Central

    Pandiri, Arun R.; Sills, Robert C.; Ziglioli, Vincent; Ton, Thai-Vu T.; Hong, Hue–Hua L.; Lahousse, Stephanie A.; Gerrish, Kevin E.; Auerbach, Scott S.; Shockley, Keith R.; Bushel, Pierre R.; Peddada, Shyamal D.; Hoenerhoff, Mark J.

    2016-01-01

    Lung cancer is the leading cause of cancer-related death in people and is mainly due to environmental factors such as smoking and radon. The National Toxicology Program (NTP) tests various chemicals and mixtures for their carcinogenic hazard potential. In the NTP chronic bioassay using B6C3F1 mice, the incidence of lung tumors in treated and control animals is second only to the liver tumors. In order to study the molecular mechanisms of chemically induced lung tumors, an understanding of the genetic changes that occur in spontaneous lung (SL) tumors from untreated control animals is needed. The authors have evaluated the differential transcriptomic changes within SL tumors compared to normal lungs from untreated age-matched animals. Within SL tumors, several canonical pathways associated with cancer (eukaryotic initiation factor 2 signaling, RhoA signaling, PTEN signaling, and mammalian target of rapamycin signaling), metabolism (Inositol phosphate metabolism, mitochondrial dysfunction, and purine and pyramidine metabolism), and immune responses (FcγR-mediated phagocytosis, clathrin-mediated endocytosis, interleukin 8 signaling, and CXCR4 signaling) were altered. Meta-analysis of murine SL tumors and human non–small cell lung cancer transcriptomic data sets revealed a high concordance. These data provide important information on the differential transcriptomic changes in murine SL tumors that will be critical to our understanding of chemically induced lung tumors and will aid in hazard analysis in the NTP 2-year carcinogenicity bioassays. PMID:22688403

  5. Quercetin-6-C-β-D-glucopyranoside, natural analog of quercetin exhibits anti-prostate cancer activity by inhibiting Akt-mTOR pathway via aryl hydrocarbon receptor.

    PubMed

    Hamidullah; Kumar, Rajeev; Saini, Karan Singh; Kumar, Amit; Kumar, Sudhir; Ramakrishna, E; Maurya, Rakesh; Konwar, Rituraj; Chattopadhyay, Naibedya

    2015-12-01

    Pre-clinical studies suggest mitigating effect of dietary flavonoid quercetin against cancer and other diseases. However, quercetin suffers from poor metabolic stability, which appears to offset its pharmacological efficacy. Recently, we isolated quercetin-6-C-β-D-glucopyranoside (QCG) from Ulmus wallichiana planchon that has greater stability profile over quercetin. In the present study, the cytotoxic and apoptotic effects of QCG on prostate cancer cells were assessed. QCG inhibited prostate cancer cell proliferation by arresting cells at G0/G1 phase of cell cycle and induces apoptosis as evident from cytochrome c release, cleavage of caspase 3 and poly (ADP-ribose) polymerase. Mechanistic studies revealed that QCG inhibited reactive oxygen species (ROS) generation and Akt/mTOR cell survival pathways. Aryl hydrocarbon receptor (AhR) was a critical mediator of QCG action as knockdown of AhR attenuated QCG-induced cell cycle arrest, apoptosis and inhibition of Akt/mTOR pathway in prostate cancer cells. Taken together, our results suggest that QCG exhibits anti-cancer activity against prostate cancer cells via AhR-mediated down regulation of Akt/mTOR pathway in PC-3 cells.

  6. Liver toxicity and carcinogenicity in F344/N rats and B6C3F1 mice exposed to Kava Kava.

    PubMed

    Behl, Mamta; Nyska, Abraham; Chhabra, Rajendra S; Travlos, Gregory S; Fomby, Laurene M; Sparrow, Barney R; Hejtmancik, Milton R; Chan, Po C

    2011-11-01

    Kava Kava is an herbal supplement used as an alternative to antianxiety drugs. Although some reports suggest an association of Kava Kava with hepatotoxicity , it continues to be used in the United States due to lack of toxicity characterization. In these studies F344/N rats and B6C3F1 mice were administered Kava Kava extract orally by gavage in corn oil for two weeks, thirteen weeks or two years. Results from prechronic studies administered Kava Kava at 0.125 to 2g/kg body weight revealed dose-related increases in liver weights and incidences of hepatocellular hypertrophy. In the chronic studies, there were dose-related increases in the incidences of hepatocellular hypertrophy in rats and mice administered Kava Kava for up to 1g/kg body weight. This was accompanied by significant increases in incidences of centrilobular fatty change. There was no treatment- related increase in carcinogenic activity in the livers of male or female rats in the chronic studies. Male mice showed a significant dose-related increase in the incidence of hepatoblastomas. In female mice, there was a significant increase in the combined incidence of hepatocellular adenoma and carcinoma in the low and mid dose groups but not in the high dose group. These findings were accompanied by several nonneoplastic hepatic lesions.

  7. NTP Toxicology and Carcinogenesis Studies of Isobutene (CAS No. 115-11-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1998-12-01

    Isobutene is produced during the fractionation of refinery gases or through the catalytic cracking of methyl-t-butyl ether. Isobutene is primarily used to produce diisobutylene, trimers, butyl rubber, and other polymers. In addition, it is used in the production of isooctane, high-octane aviation gasoline, methyl-t-butyl ether, and copolymer resins with butadiene and acrylonitrile. Isobutene was selected for evaluation because of the potential for human exposure due to its large production volume and the lack of adequate data on its carcinogenic potential. The toxicity and carcinogenicity of isobutene were determined in male and female F344/N rats and B6C3F1 mice exposed to isobutene (greater than 98% pure) by inhalation for 14 weeks or 2 years. The mutagenicity of isobutene was assessed in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed by inhalation for 14 weeks. 14-WEEK STUDIES: Groups of 10 male and 10 female F344/N rats and B6C3F1 mice were exposed to isobutene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm 6 hours per day, 5 days per week, for 14 weeks. Concentrations greater than 8,000 ppm isobutene were not used because of the danger of explosion. All rats and mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the chamber controls. No exposure-related gross lesions were observed in male or female rats or mice at necropsy. Microscopically, minimal hypertrophy of goblet cells lining the nasopharyngeal duct in the most caudal nose section was observed in some rats in each exposed group of males and females. 2-YEAR STUDIES: Based on the lack of significant exposure-related toxicologic effects in the 14-week rat and mouse studies, 8,000 ppm was selected as the highest exposure concentration in the 2-year studies. Concentrations of 0, 500, 2,000, and 8,000 ppm were selected for rats and mice with the

  8. Toxicity and carcinogenicity studies of Caramel Colour IV in F344 rats and B6C3F1 mice.

    PubMed

    MacKenzie, K M; Boysen, B G; Field, W E; Petsel, S R; Chappel, C I; Emerson, J L; Stanley, J

    1992-05-01

    Caramel Colour IV, a type of caramel colour used in the manufacture of cola soft drinks, was evaluated for subchronic and chronic toxicity in rats, and carcinogenicity in Fischer-344 (F344) rats and B6C3F1 mice. In each of the studies, Caramel Colour IV was mixed with demineralized water and the solutions given to the animals ad lib. in the drinking fluid. The concentrations of Caramel Colour IV in the drinking fluid were adjusted periodically to achieve the desired caramel colour intake per kg body weight. In the range-finding studies, groups of 30 rats/sex were given Caramel Colour IV at levels of 0, 15, 20, 25 or 30 g/kg for 13 wk, and groups of 10 male rats were given levels of 0, 2.5, 5, 10 or 15 g/kg for 6 wk followed, for some dose groups, by a 2-wk withdrawal period, and then re-initiation of dosing for another 2 wk. In the rat chronic toxicity study, levels of Caramel Colour IV of 0, 2.5, 5, 7.5 or 10 g/kg were given to groups of 25 rats/sex for 12 months. The test groups in the rat and mouse carcinogenicity studies were composed of 50 animals/sex and each species was given the caramel colour at levels of 0, 0, 2.5, 5 or 10 g/kg for 24 months. In each of the studies, treated animals tended to have dose-related lower water consumption than controls. This was attributed to poor palatability of the drinking fluid, and was generally associated with decreased food consumption and body weights. Rats given caramel colour often had soft or liquid malodorous faeces although there were no treatment-related ante-mortem observations in mice. Blood biochemical changes in the rat (i.e. reduced blood urea nitrogen, alkaline phosphatase and total serum protein) appeared to be related to dietary influences and were not considered toxicologically significant. There were no treatment-related alterations in haematological variables or treatment-related differences in survival or in the incidence of benign or malignant tumours among treated and control groups and no

  9. Ly6C(hi) Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis.

    PubMed

    Möhle, Luisa; Mattei, Daniele; Heimesaat, Markus M; Bereswill, Stefan; Fischer, André; Alutis, Marie; French, Timothy; Hambardzumyan, Dolores; Matzinger, Polly; Dunay, Ildiko R; Wolf, Susanne A

    2016-05-31

    Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6C(hi) monocytes in the brain than antibiotic-treated mice. Elimination of Ly6C(hi) monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6C(hi) monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6C(hi) monocytes.

  10. Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures

    PubMed Central

    Phillips, Tracie D.; Richardson, Molly; Lisa Cheng, Yi-Shing; He, Lingyu; McDonald, Thomas J.; Cizmas, Leslie H.; Safe, Stephen H.; Donnelly, Kirby C.; Wang, Fen; Moorthy, Bhagavatula; Zhou, Guo-Dong

    2014-01-01

    The genotoxicity of a complex mixture [neutral fraction (NF)] from a wood preserving waste and reconstituted mixture (RM) mimicking the NF with seven major polycyclic aromatic hydrocarbons (PAHs) and benzo(a)pyrene (BaP) was investigated by determining DNA adducts and tumor incidence in male B6C3F1 mice exposed to 3 different doses of the chemical mixtures. The peak values of DNA adducts were observed after 24 h and the highest levels of PAH-DNA adducts were exhibited in mice administered NF+BaP, and the highest tumor incidence and mortality were also observed in this group. DNA adduct levels after 1, 7, or 21 d were significantly correlated with animal mortality and incidence of total tumors including liver, lung, and forestomach. However, only hepatic DNA adducts after 7 d significantly correlated with liver tumor incidence. Most proteins involved in DNA repair including ATM, pATR, Chk1, pChk1, DNA PKcs, XRCC1, FANCD2, Ku80, Mre11 and Brca2 were significantly lower in liver tumor tissue compared to non-tumor tissue. Expression of proteins involved in apoptosis and cell cycle regulation were also significantly different in tumor vs non-tumor tissues and it is possible that PAH-induced changes in these gene products are important for tumor development and growth. PMID:24888377

  11. The Pressure Distribution over the Horizontal and Vertical Tail Surfaces of the F6C-4 Pursuit Airplane in Violent Maneuvers

    NASA Technical Reports Server (NTRS)

    Rhode, R V

    1929-01-01

    This investigation of the pressure distribution on the tail surfaces of a pursuit airplane in violent maneuvers was conducted for the purpose of determining the maximum loads likely to be encountered on these surfaces in flight. The information is a part of that needed for a revision of existing loading specifications to bring these into closer agreement with the actual flight conditions. A standard F6C-4 airplane was used and the pressure distribution over the right horizontal and complete vertical tail surfaces was recorded throughout violent maneuvers. The results show that the existing loading specifications do not conform satisfactorily to the loadings existent in critical conditions, and in some cases were exceeded by the loads obtained. An acceleration of 10.5 G. Was recorded in one maneuver in which the pilot suffered severely; it is therefore indicated that the limits of the physical resistance of the pilot to violent maneuvers are being approached. Navy specifications for the structural design of tail surfaces are included as an appendix. (author)

  12. Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

    PubMed Central

    Tsuboi, Masaya; Watanabe, Manabu; Nibe, Kazumi; Yoshimi, Natsuko; Kato, Akihisa; Sakaguchi, Masahiro; Yamato, Osamu; Tanaka, Miyuu; Kuwamura, Mitsuru; Kushida, Kazuya; Harada, Tomoyuki; Chambers, James Kenn; Sugano, Sumio; Uchida, Kazuyuki; Nakayama, Hiroyuki

    2017-01-01

    Whole exome sequencing (WES) has become a common tool for identifying genetic causes of human inherited disorders, and it has also recently been applied to canine genome research. We conducted WES analysis of neuroaxonal dystrophy (NAD), a neurodegenerative disease that sporadically occurs worldwide in Papillon dogs. The disease is considered an autosomal recessive monogenic disease, which is histopathologically characterized by severe axonal swelling, known as “spheroids,” throughout the nervous system. By sequencing all eleven DNA samples from one NAD-affected Papillon dog and her parents, two unrelated NAD-affected Papillon dogs, and six unaffected control Papillon dogs, we identified 10 candidate mutations. Among them, three candidates were determined to be “deleterious” by in silico pathogenesis evaluation. By subsequent massive screening by TaqMan genotyping analysis, only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, suggesting that it may be a causal mutation of canine NAD. As a human homologue of this gene is a causative gene for infantile neuroaxonal dystrophy, this canine phenotype may serve as a good animal model for human disease. The results of this study also indicate that WES analysis is a powerful tool for exploring canine hereditary diseases, especially in rare monogenic hereditary diseases. PMID:28107443

  13. The interleukin 6 c.-174 CC genotype is a predictor for new cardiovascular events in patients with coronary heart disease within three years follow-up.

    PubMed

    Reichert, Stefan; Schlitt, Axel; Benten, Ann-Christin; Hofmann, Britt; Schaller, Hans-Günter; Schulz, Susanne

    2016-07-01

    The main aim of this study was to evaluate putative associations between the interleukin (IL)-6 c.-174G>C polymorphism (rs 1800795) and the cardiovascular outcome (combined endpoint: myocardial infarction, stroke/TIA, cardiac death, death according to stroke) among patients with coronary heart disease (CHD) within three years follow-up. Overall 942 in-patients with CHD were included. The drop-out rate was 4.9%. The IL-6 polymorphism was determined with PCR-SSP. Kaplan-Meier plots with Log Rank test and Cox regression were used as statistically procedures. The IL-6 CC genotype was associated with a higher incidence of the combined endpoint (25.0% versus 13.5%, p<0.001) and an increased Hazard Ratio (HR 2.165, 95% CI 1.516-3.092, p<0.001) adjusted for established cofactors for CHD. This result suggests that the IL-6 -174 polymorphism is a putative independent risk indicator for new cardiovascular events among patients with CHD.

  14. Subchronic toxicity study of 3-monochloropropane-1,2-diol administered by drinking water to B6C3F1 mice.

    PubMed

    Cho, Wan-Seob; Han, Beom Seok; Lee, Hakyung; Kim, Cheulkyu; Nam, Ki Taek; Park, Kidae; Choi, Mina; Kim, Sung Jun; Kim, Seung Hee; Jeong, Jayoung; Jang, Dong Deuk

    2008-05-01

    3-Monochloropropane-1,2-diol (3-MCPD) is a food processing contaminant in a wide range of foods and ingredients and is a suspected cause of cancer. In this study, the 13-week toxicity of 3-MCPD was examined in B6C3F1 mice (10/sex/group) administered 3-MCPD doses of 0, 5, 25, 100, 200 and 400 ppm dissolved in their drinking water over a 13-week period. All the mice survived to the end of study. The mean body weight gains in the males and females given 400 ppm were significantly lower than those of the controls. The relative kidney weights of the males and females given 200 and 400 ppm were significantly higher than those of the controls without any corresponding histopathological changes. The sperm motility was lower in the 400 ppm group than the control, and there was a significant increase in the incidence of germinal epithelium degeneration in the 200 and 400 ppm groups. A delayed total estrus cycle length was observed in the 400 ppm group without any histopathological changes. Based on these results, the target organ was determined to be kidney, testis, and ovary. The no-observed-adverse-effect level (NOAEL) was found to be 100 ppm (18.05 mg/kg/day for males and 15.02 mg/kg/day for females).

  15. Nasal dosimetry of inspired naphthalene vapor in the male and female B6C3F1 mouse.

    PubMed

    Morris, John B

    2013-07-05

    Naphthalene vapor is a nasal cytotoxicant in the rat and mouse but is a nasal carcinogen in only the rat. Inhalation dosimetry is a critical aspect of the inhalation toxicology of inspired vapors and may contribute to the species differences in the nasal response. To define the nasal dosimetry of naphthalene in the B6C3F1 male and female mouse, uptake of naphthalene vapor was measured in the surgically isolated upper respiratory tract (URT) at inspiratory flow rates of 25 or 50 ml/min. Uptake was measured at multiple concentrations (0.5, 3, 10, 30 ppm) in controls and mice treated with the cytochrome P450 inhibitor 5-phenyl-1-pentyne. In both sexes, URT uptake efficiency was strongly concentration dependent averaging 90% at 0.5 ppm compared to 50% at 30 ppm (25 ml/min flow rate), indicating saturable processes were involved. Both uptake efficiency and the concentration dependence of uptake were significantly diminished by 5-phenyl-1-pentyne indicating inspired naphthalene vapor is extensively metabolized in the mouse nose with saturation of metabolism occurring at the higher concentrations. A hybrid computational fluid dynamic physiologically based pharmacokinetic model was developed for nasal dosimetry. This model accurately predicted the observed URT uptake efficiencies. Overall, the high URT uptake efficiency of naphthalene in the mouse nose indicates the absence of a tumorigenic response is not attributable to low delivered dose rates in this species.

  16. Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1(low) Monocytes.

    PubMed

    Saja, Maha F; Baudino, Lucie; Jackson, William D; Cook, H Terence; Malik, Talat H; Fossati-Jimack, Liliane; Ruseva, Marieta; Pickering, Matthew C; Woollard, Kevin J; Botto, Marina

    2015-09-22

    Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. However, their response to hyperlipidemia remains poorly understood. Here, we report that in the presence of elevated levels of triglyceride-rich lipoproteins, induced by administration of poloxamer 407, the blood numbers of non-classical Ly6C/Gr1(low) monocytes drop, while the number of bone marrow progenitors remains similar. We observed an increased crawling and retention of the Gr1(low) monocytes at the endothelial interface and a marked accumulation of CD68(+) macrophages in several organs. Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1(low) monocyte depletion involved a pertussis-toxin-sensitive receptor axis. Collectively, these findings demonstrate that a triglyceride-rich environment can alter blood monocyte distribution, promoting the extravasation of Gr1(low) cells. The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.

  17. Reduced Il17a expression distinguishes a Ly6c(lo)MHCII(hi) macrophage population promoting wound healing.

    PubMed

    Rodero, Mathieu P; Hodgson, Samantha S; Hollier, Brett; Combadiere, Christophe; Khosrotehrani, Kiarash

    2013-03-01

    Macrophages are the main components of inflammation during skin wound healing. They are critical in wound closure and in excessive inflammation, resulting in defective healing observed in chronic wounds. Given the heterogeneity of macrophage phenotypes and functions, we here hypothesized that different subpopulations of macrophages would have different and sometimes opposing effects on wound healing. Using multimarker flow cytometry and RNA expression array analyses on macrophage subpopulations from wound granulation tissue, we identified a Ly6c(lo)MHCII(hi) "noninflammatory" subset that increased both in absolute number and proportion during normal wound healing and was missing in Ob/Ob and MYD88-/- models of delayed healing. We also identified IL17 as the main cytokine distinguishing this population from proinflammatory macrophages and demonstrated that inhibition of IL17 by blocking Ab or in IL17A-/- mice accelerated normal and delayed healing. These findings dissect the complexity of the role and activity of the macrophages during wound inflammation and may contribute to the development of therapeutic approaches to restore healing in chronic wounds.

  18. PowerPlex® Fusion 6C System: evaluation study for analysis of casework and database samples

    PubMed Central

    Cisana, Selena; Cerri, Nicoletta; Bosetti, Alessandro; Verzeletti, Andrea; Cortellini, Venusia

    2017-01-01

    Aim To report on the successful analysis of amplicons obtained with PowerPlex® Fusion 6C System, a highly robust 27-plex genotyping kit developed for human identification laboratories, on the Applied Biosystems® 3500 Genetic Analyzer. Method We performed characterization and evaluation studies following the Scientific Working Group on DNA Analysis Methods (SWGDAM) validation guidelines, examining several critical areas of kit performance. We report the results of sensitivity, robustness, heterozygous peak height ratio, precision, concordance, caseworks, and mixture interpretations. We tested sensitivity, using serial dilutions of control DNA. Results The minimum amount of input DNA resulting in a full profile was 125 pg. Inhibition, inducted by urea, showed a progressively fragmentation of DNA and a full profile was obtained until 1M of inhibitor factor. To test the profile quality, casework samples were extracted with different extraction methods: Chelex®100, QIAmp DNA Micro Kit and Phenol-Chloroform extraction. The results demonstrated that extraction chemistries do not have affect on amplification performance. Concordance check was performed by typing some casework samples and comparing the typing results with those obtained with other available kits. Thus, concordance was expected and supported by the data. Conclusion Reliable DNA typing results can be obtained using this new kit, demonstrating its effectiveness and utility in forensic analysis. PMID:28252872

  19. Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

    PubMed Central

    Iribarne, Maria; Nishiwaki, Yuko; Nakamura, Shohei; Araragi, Masato; Oguri, Eri; Masai, Ichiro

    2017-01-01

    Genetic mutations in aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) cause photoreceptor degeneration associated with Leber congenital amaurosis 4 (LCA4) in human patients. Here we report retinal phenotypes of a zebrafish aipl1 mutant, gold rush (gosh). In zebrafish, there are two aipl1 genes, aipl1a and aipl1b, which are expressed mainly in rods and cones, respectively. The gosh mutant gene encodes cone-specific aipl1, aipl1b. Cone photoreceptors undergo progressive degeneration in the gosh mutant, indicating that aipl1b is required for cone survival. Furthermore, the cone-specific subunit of cGMP phosphodiesterase 6 (Pde6c) is markedly decreased in the gosh mutant, and the gosh mutation genetically interacts with zebrafish pde6c mutation eclipse (els). These data suggest that Aipl1 is required for Pde6c stability and function. In addition to Pde6c, we found that zebrafish cone-specific guanylate cyclase, zGc3, is also decreased in the gosh and els mutants. Furthermore, zGc3 knockdown embryos showed a marked reduction in Pde6c. These observations illustrate the interdependence of cGMP metabolism regulators between Aipl1, Pde6c, and Gc3 in photoreceptors. PMID:28378769

  20. Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver.

    PubMed

    Jiang, Yan; Chen, Jiahong; Tong, Jian; Chen, Tao

    2014-01-01

    Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.

  1. Silicon etch using SF{sub 6}/C{sub 4}F{sub 8}/Ar gas mixtures

    SciTech Connect

    Bates, Robert L.; Stephan Thamban, P. L.; Goeckner, Matthew J.; Overzet, Lawrence J.

    2014-07-01

    While plasmas using mixtures of SF{sub 6}, C{sub 4}F{sub 8}, and Ar are widely used in deep silicon etching, very few studies have linked the discharge parameters to etching results. The authors form such linkages in this report. The authors measured the optical emission intensities of lines from Ar, F, S, SF{sub x}, CF{sub 2}, C{sub 2}, C{sub 3}, and CS as a function of the percentage C{sub 4}F{sub 8} in the gas flow, the total gas flow rate, and the bias power. In addition, the ion current density and electron temperature were measured using a floating Langmuir probe. For comparison, trenches were etched of various widths and the trench profiles (etch depth, undercut) were measured. The addition of C{sub 4}F{sub 8} to an SF{sub 6}/Ar plasma acts to reduce the availability of F as well as increase the deposition of passivation film. Sulfur combines with carbon in the plasma efficiently to create a large optical emission of CS and suppress optical emissions from C{sub 2} and C{sub 3}. At low fractional flows of C{sub 4}F{sub 8}, the etch process appears to be controlled by the ion flux more so than by the F density. At large C{sub 4}F{sub 8} fractional flows, the etch process appears to be controlled more by the F density than by the ion flux or deposition rate of passivation film. CF{sub 2} and C{sub 2} do not appear to cause deposition from the plasma, but CS and other carbon containing molecules as well as ions do.

  2. Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice.

    PubMed

    Dieter, M P

    1994-11-01

    Toxicity and potential carcinogenicity studies of boric acid were investigated in mice to verify in a second rodent species that this was a noncarcinogenic chemical. Earlier chronic studies in rats indicated boric acid was not a carcinogen. The chemical is nominated for testing because over 200 tons are produced annually, there are multiple uses for the product, and there is potential for widespread human exposure, both orally and dermally. Both sexes of B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. Mortality, clinical signs of toxicity, estimates of food consumption, body weight gain, and histopathologic examination of selected tissues constituted the variables measured. In the 14-day study mortality was proportional to dose and time of exposure in both sexes, occurring in dose groups as low as 2.5% and as early as 7 days of exposure. Body weights were depressed more than 10% below controls in the higher dose groups of both sexes. Mortality in the 13-week study was confined to the two highest dose groups in male mice and to the 2%-dose group in females. Body weight depression from 8 to 23% below those of controls occurred in the 0.50% and higher dose groups of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice.

    PubMed Central

    Dieter, M P

    1994-01-01

    Toxicity and potential carcinogenicity studies of boric acid were investigated in mice to verify in a second rodent species that this was a noncarcinogenic chemical. Earlier chronic studies in rats indicated boric acid was not a carcinogen. The chemical is nominated for testing because over 200 tons are produced annually, there are multiple uses for the product, and there is potential for widespread human exposure, both orally and dermally. Both sexes of B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. Mortality, clinical signs of toxicity, estimates of food consumption, body weight gain, and histopathologic examination of selected tissues constituted the variables measured. In the 14-day study mortality was proportional to dose and time of exposure in both sexes, occurring in dose groups as low as 2.5% and as early as 7 days of exposure. Body weights were depressed more than 10% below controls in the higher dose groups of both sexes. Mortality in the 13-week study was confined to the two highest dose groups in male mice and to the 2%-dose group in females. Body weight depression from 8 to 23% below those of controls occurred in the 0.50% and higher dose groups of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7889889

  4. Dose-, route-, and sex-dependent urinary excretion of phenol metabolites in B6C3F, mice

    SciTech Connect

    Kenyon, E.M.; Seeley, M.E.; Janszen, D.; Medinsky, M.A.

    1995-07-01

    Phenol is the major oxidized metabolite of benzene, a known human leukemogen and ubiquitous environmental pollutant. Unlike benzene, phenol does not induce tumors in mice following oral exposure; benzene also exhibits sex-related differences in genotoxicity to bone marrow cells that are not observed following phenol administration. We studied the urinary excretion of phenol metabolites in mice as a means to further investigate the metabolic basis for differences in benzene- and phenol-induced toxicity. Male and female B6C3F, mice (n = 3/group) were exposed to 15, 40, 100, or 225 {mu}mol [{sup 14}C]phenol/kg by iv tail vein injection (6 {mu}Ci/mouse). First-pass intestinal metabolism of phenol was evaluated by comparison of urinary excretion of phenol metabolites following iv administration with additional groups of male mice that received the same dose levels by oral gavage. Mice were placed in glass metabolism cages, and urine was collected over dry ice for 48 h. Urinary metabolites were separated by high-pressure liquid chromatography (HPLC) and quantified by liquid scintillation spectrometry. Urinary excretion of conjugated metabolites of phenol was dose-dependent in both male and female mice administered phenol by iv injection or gavage. The major urinary metabolites of phenol were phenol sulfate (PS), phenol glucuronide (PG), and hydroquinone glucoronide (HQG). Sulfation was the dominant pathway at all dose levels, but decreased as a percent of the excreted dose with a concomitant increase in glucorodination as the dose level increased. Male mice consistently excreted a higher proportion of phenol as the oxidized conjugated metabolite, HQG, compared to female mice, suggesting that male mice oxidize phenol to hydroquinone more rapidly than female mice. 31 refs., 6 figs., 2 tabs.

  5. Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 1. Hydrochlorothiazide.

    PubMed

    Bucher, J R; Huff, J; Haseman, J K; Eustis, S L; Elwell, M R; Davis, W E; Meierhenry, E F

    1990-10-01

    Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15-day, 13-week and 2-year studies. No rats died during the 15-day or 13-week studies at dietary concentrations of up to 50,000 ppm. Deaths of male mice in the top dose group in the 13-week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical-related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2-year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non-neoplastic lesions in mice were associated with hydrochlorothiazide. In high-dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.

  6. Crystal structure, NMR study, dielectric relaxation and AC conductivity of a new compound [Cd3(SCN)2Br6(C2H9N2)2]n

    NASA Astrophysics Data System (ADS)

    Saidi, K.; Kamoun, S.; Ayedi, H. Ferid; Arous, M.

    2013-11-01

    The crystal structure, the 13C NMR spectroscopy and the complex impedance have been carried out on [Cd3(SCN)2Br6(C2H9N2)2]n. Crystal structure shows a 2D polymeric network built up of two crystallographically independent cadmium atoms with two different octahedral coordinations. This compound exhibits a phase transition at (T=355±2 K) which has been characterized by differential scanning calorimetry (DSC), X-rays powder diffraction, AC conductivity and dielectric measurements. Examination of 13C CP/MAS line shapes shows indirect spin-spin coupling (14N and 13C) with a dipolar coupling constant of 1339 Hz. The AC conductivity of this compound has been carried out in the temperature range 325-376 K and the frequency range from 10-2 Hz to 10 MHz. The impedance data were well fitted to two equivalent electrical circuits. The results of the modulus study reveal the presence of two distinct relaxation processes. One, at low frequency side, is thermally activated due to the ionic conduction of the crystal and the other, at higher frequency side, gradually disappears when temperature reaches 355 K which is attributed to the localized dipoles in the crystal. Moreover, the temperature dependence of DC-conductivity in both phases follows the Arrhenius law and the frequency dependence of σ(ω,T) follows Jonscher's universal law. The near values of activation energies obtained from the conductivity data and impedance confirm that the transport is through the ion hopping mechanism.

  7. Investigation of the formation of N-nitrosodiethanolamine in B6C3F1 mice following topical administration of triethanolamine.

    PubMed

    Saghir, Shakil A; Brzak, Kathy A; Markham, Dan A; Bartels, Michael J; Stott, William T

    2005-10-01

    To determine potential nitrosation of triethanolamine (TEA) to N-nitrosodiethanolamine (NDELA) at different physiological conditions of the GI tract, in vitro NDELA formation was examined in aqueous reaction mixtures at several pHs (2-10) adjusted with acetic, sulphuric or hydrochloric acids or in cultures of mouse cecal microflora incubated. In vivo NDELA formation was also determined in blood, ingesta, and urine of female B6C3F1 mice after repeated dermal, most relevant human route, or single oral exposure to 1000 mg/kg TEA in the presence of high oral dosages of NaNO(2). Appropriate diethanolamine (DEA) controls were included to account for this impurity in the TEA used. Samples were analyzed for NDELA using GC/MS. The highest degree of nitrosation of TEA to NDELA ( approximately 3%) was observed in the in vitro cultures at pH 4 and acetic acid with lower amounts obtained using sulphuric acid ( approximately 1.3%) and hydrochloric acid ( approximately 1.2%). At pH 7, <1% of the TEA was nitrosated to NDELA and at pH 2 (HCl) or pH 10 (NaOH) no NDELA was found above the limit of detection. In incubated cultures containing cecal microflora and nutrient broth, only 0.68% of TEA was nitrosated to NDELA. No NDELA was formed in rats repeatedly dermally dosed with TEA at the limits of detection in blood (0.001 microg/ml, ppm), ingesta (0.006 microg/ml, ppm), and urine (0.47 microg/ml, ppm). Levels of NDELA measured in blood and ingesta after a single oral dose of TEA and NaNO(2) were less than those in DEA controls. These findings in toto confirm the lack of any significant formation of NDELA from TEA in vivo.

  8. Toxicity of furfuryl alcohol to F344 rats and B6C3F1 mice exposed by inhalation.

    PubMed

    Irwin, R D; Chou, B J; Mellick, P W; Miller, R A; Mahler, J; Roycroft, J

    1997-01-01

    Groups of F344 rats and B6C3F1 mice were exposed to furfuryl alcohol vapor for 6 hours per day, 5 days per week for 14 days (0, 16, 31, 63, 125, 250 ppm) or 13 weeks (0, 2, 4, 8, 16, 32 ppm). Reduced survival was observed in the 14-day study at 250 ppm. Final mean body weights of rats and mice exposed to 125 ppm and of female mice exposed to 63 ppm were lower than controls at the end of the 14-day study; there were no significant differences in mean body weight among chemical-exposed and control groups in the 13-week study. Exposure to furfuryl alcohol had no toxicologically significant effect on organ weights in either rats or mice, and did not cause any adverse changes in hematology or serum chemistry parameters evaluated in rates in the 13-week study. Microscopic lesions associated with exposure to furfuryl alcohol were present in the nose of both rats and mice at all exposure concentrations in both the 14-day and 13-week studies. Lesions observed in the 14-day study consisted of inflammation of the nasal turbinates accompanied by necrosis and squamous metaplasia of the respiratory epithelium and necrosis and degeneration of the olfactory epithelium. Similar lesions were observed in both rats and mice in the 13-week study. In addition, squamous metaplasia and goblet cell hyperplasia of the respiratory epithelium, squamous metaplasia of the transitional epithelium and degeneration, hyperplasia and some respiratory metaplasia of the olfactory epithelium were also observed in rats in the 13-week study, and hyaline droplets in the respiratory epithelium and chronic inflammation and respiratory metaplasia in the olfactory epithelium were observed in mice in the 13-week study. In general the nasal passages of mice appeared less sensitive than those of rats at the concentrations used in the 13-week study; a no-observable-effect level was not achieved in either the 14-day or the 13-week study.

  9. New examples of ternary rare-earth metal boride carbides containing finite boron carbon chains: The crystal and electronic structure of RE15B6C20 (RE=Pr, Nd)

    NASA Astrophysics Data System (ADS)

    Babizhetskyy, Volodymyr; Mattausch, Hansjürgen; Simon, Arndt; Hiebl, Kurt; Ben Yahia, Mouna; Gautier, Régis; Halet, Jean-François

    2008-08-01

    The ternary rare-earth metal boride carbides RE15B6C20 (RE=Pr, Nd) were synthesized by co-melting the elements. They exist above 1270 K. Their crystal structures were determined from single-crystal X-ray diffraction data. Both crystallize in the space group P1¯, Z=1, a=8.3431(8) Å, b=9.2492(9) Å, c=8.3581(8) Å, α=84.72(1)°, β=89.68(1)°, γ =84.23(1)° (R1=0.041 (wR2=0.10) for 3291 reflections with Io>2σ(Io)) for Pr15B6C20, and a=8.284(1) Å, b=9.228(1) Å, c=8.309(1) Å, α=84.74(1)°, β=89.68(1)°, γ=84.17(2)° (R1=0.033 (wR2=0.049) for 2970 reflections with Io>2σ(Io)) for Nd15B6C20. Their structure consists of a three-dimensional framework of rare-earth metal atoms resulting from the stacking of slightly corrugated and distorted square nets, leading to cavities filled with unprecedented B2C4 finite chains, disordered C3 entities and isolated carbon atoms, respectively. Structural and theoretical analyses suggest the ionic formulation (RE3+)15([B2C4]6-)3([C3]4-)2(C4-)2·11ē. Accordingly, density functional theory calculations indicate that the compounds are metallic. Both structural arguments as well as energy calculations on different boron vs. carbon distributions in the B2C4 chains support the presence of a CBCCBC unit. Pr15B6C18 exhibits antiferromagnetic order at TN=7.9 K, followed by a meta-magnetic transition above a critical external field B>0.03 T. On the other hand, Nd15B6C18 is a ferromagnet below TC≈40 K.

  10. Comparative phosphoproteomic analysis of mammalian glomeruli reveals conserved podocin C-terminal phosphorylation as a determinant of slit diaphragm complex architecture.

    PubMed

    Rinschen, Markus M; Pahmeyer, Caroline; Pisitkun, Trairak; Schnell, Nicole; Wu, Xiongwu; Maaß, Martina; Bartram, Malte P; Lamkemeyer, Tobias; Schermer, Bernhard; Benzing, Thomas; Brinkkoetter, Paul T

    2015-04-01

    Glomerular biology is dependent on tightly controlled signal transduction networks that control phosphorylation of signaling proteins such as cytoskeletal regulators or slit diaphragm proteins of kidney podocytes. Cross-species comparison of phosphorylation events is a powerful mean to functionally prioritize and identify physiologically meaningful phosphorylation sites. Here, we present the result of phosphoproteomic analyses of cow and rat glomeruli to allow cross-species comparisons. We discovered several phosphorylation sites with potentially high biological relevance, e.g. tyrosine phosphorylation of the cytoskeletal regulator synaptopodin and the slit diaphragm protein neph-1 (Kirrel). Moreover, cross-species comparisons revealed conserved phosphorylation of the slit diaphragm protein nephrin on an acidic cluster at the intracellular terminus and conserved podocin phosphorylation on the very carboxyl terminus of the protein. We studied a highly conserved podocin phosphorylation site in greater detail and show that phosphorylation regulates affinity of the interaction with nephrin and CD2AP. Taken together, these results suggest that species comparisons of phosphoproteomic data may reveal regulatory principles in glomerular biology. All MS data have been deposited in the ProteomeXchange with identifier PXD001005 (http://proteomecentral.proteomexchange.org/dataset/PXD001005).

  11. Structure-function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination.

    PubMed

    Zhao, Liang; Ng, Ee Ting; Davidson, Tara-Lynne; Longmuss, Enya; Urschitz, Johann; Elston, Marlee; Moisyadi, Stefan; Bowles, Josephine; Koopman, Peter

    2014-08-12

    The mammalian sex-determining factor SRY comprises a conserved high-mobility group (HMG) box DNA-binding domain and poorly conserved regions outside the HMG box. Mouse Sry is unusual in that it includes a C-terminal polyglutamine (polyQ) tract that is absent in nonrodent SRY proteins, and yet, paradoxically, is essential for male sex determination. To dissect the molecular functions of this domain, we generated a series of Sry mutants, and studied their biochemical properties in cell lines and transgenic mouse embryos. Sry protein lacking the polyQ domain was unstable, due to proteasomal degradation. Replacing this domain with irrelevant sequences stabilized the protein but failed to restore Sry's ability to up-regulate its key target gene SRY-box 9 (Sox9) and its sex-determining function in vivo. These functions were restored only when a VP16 transactivation domain was substituted. We conclude that the polyQ domain has important roles in protein stabilization and transcriptional activation, both of which are essential for male sex determination in mice. Our data disprove the hypothesis that the conserved HMG box domain is the only functional domain of Sry, and highlight an evolutionary paradox whereby mouse Sry has evolved a novel bifunctional module to activate Sox9 directly, whereas SRY proteins in other taxa, including humans, seem to lack this ability, presumably making them dependent on partner proteins(s) to provide this function.

  12. Analysis of Large Seeds from Three Different Medicago truncatula Ecotypes Reveals a Potential Role of Hormonal Balance in Final Size Determination of Legume Grains

    PubMed Central

    Bandyopadhyay, Kaustav; Uluçay, Orhan; Şakiroğlu, Muhammet; Udvardi, Michael K.; Verdier, Jerome

    2016-01-01

    Legume seeds are important as protein and oil source for human diet. Understanding how their final seed size is determined is crucial to improve crop yield. In this study, we analyzed seed development of three accessions of the model legume, Medicago truncatula, displaying contrasted seed size. By comparing two large seed accessions to the reference accession A17, we described mechanisms associated with large seed size determination and potential factors modulating the final seed size. We observed that early events during embryogenesis had a major impact on final seed size and a delayed heart stage embryo development resulted to large seeds. We also observed that the difference in seed growth rate was mainly due to a difference in embryo cell number, implicating a role of cell division rate. Large seed accessions could be explained by an extended period of cell division due to a longer embryogenesis phase. According to our observations and recent reports, we observed that auxin (IAA) and abscisic acid (ABA) ratio could be a key determinant of cell division regulation at the end of embryogenesis. Overall, our study highlights that timing of events occurring during early seed development play decisive role for final seed size determination. PMID:27618017

  13. Effects of Environmentally Relevant Levels of Perfluorooctane Sulfonate on Clinical Parameters and Immunological Functions in B6C3F1 Mice

    PubMed Central

    Fair, Patricia A.; Driscoll, Erin; Mollenhauer, Meagan A. M.; Bradshaw, Sarah G.; Yun, Se Hun; Kannan, Kurunthachalam; Bossart, Gregory D.; Keil, Deborah E.; Peden-Adams, Margie M.

    2012-01-01

    In the first part of a series of studies to account for perfluoroocatane sulfonate (PFOS)-induced sheep red blood cell (SRBC)-specific IgM antibody suppression in mice, a survey of clinical and immunotoxicological endpoints were examined. Adult female B6C3F1 mice were exposed orally for 28 days to a total administered dose of 0, 0.1, 0.5, 1, or 5 mg PFOS/kg. Uterus wet weight was significantly decreased compared to control at the 5 mg/kg dose. No indication of wasting syndrome, malnutrition, alteration of thyroid homeostasis, or signs of overt toxicity were observed. Numbers of splenic CD19+/CD21−, CD19+/CD21+, B220+/CD40+, CD4+/CD154−, CD4+/CD154+, and MHC-II+ cells were not altered. Additionally, ex vivo IL-4, IL-5, and IL-6 production by in vitro anti-CD3- or phorbol myristate acetate-stimulated CD4+ T-cells were not affected. Ex vivo IL-6 production by B-cells was significantly increased by in vitro stimulation with either anti-CD40 or lipopolysaccharide. Increased IL-6 production by B-cells was the most sensitive endpoint assessed resulting in alterations at the lowest dose tested (0.1 mg/kg TAD) following anti-CD40 stimulation. Further studies are required to characterize effects on inflammatory markers such as IL-6 at environmentally relevant concentrations of PFOS and to determine the key events associated with PFOS-induced IgM suppression to address potential human health risks. PMID:21261439

  14. Subchronic 10 day immunotoxicity of polydimethylsiloxane (silicone) fluid, gel and elastomer and polyurethane disks in female B6C3F1 mice.

    PubMed

    Bradley, S G; Munson, A E; McCay, J A; Brown, R D; Musgrove, D L; Wilson, S; Stern, M; Luster, M I; White, K L

    1994-01-01

    Millions of people have been exposed to silicones because of the widespread use in consumer products such as cosmetics and toiletries, food products, household products and paints. Silicones have wide use in medical practice, including lubricants in tubing and syringes, and as implantable devices. The most prevalent silicone in medical use is polydimethylsiloxane. This study was undertaken to determine the subchronic immunotoxicologic potential of the principal constituents of breast implants: silicone fluid, silicone gel and silicone elastomer. An alternative covering for devices containing silicone gels, polyurethane, was also included in the study. Silicone fluid and gel were injected subcutaneously into female B6C3F1 mice (1 ml/mouse) and 6 mm disks of silicone elastomer or polyurethane were implanted subcutaneously. There were no treatment-related deaths or overt signs of toxicity. None of the tested materials had notable effects on body or organ weights, erythrocytes or leukocytes in the blood, blood chemistries such as alanine aminotransferase, urea nitrogen, glucose, albumin or total protein. The cellularity of the bone marrow and responses to CSF-GM and CSF-M were normal. The tested silicones did not alter the distribution of B cells and T cells in the spleen, but polyurethane perturbed the distribution of CD4+CD8+ and CD4-CD8- T cells. The antibody response to sheep erythrocytes was not markedly altered, nor were proliferative responses to concanavalin A, phytohemagglutinin, lipopolysaccharide or allogeneic cells. Reticuloendothelial function was normal, but polyurethane evoked an enhanced phagocytosis of Covaspheres by adherent peritoneal cells. Natural killer cell activity and serum complement were not altered. All silicone materials afforded modest protection to a challenge with Listeria monocytogenes that killed 40 to 58% of control mice. Host resistance to Streptococcus pneumoniae or the B16F10 tumor was not affected by any of the treatments. There

  15. CCL2, but not its receptor, is essential to restrict immune privileged central nervous system-invasion of Japanese encephalitis virus via regulating accumulation of CD11b(+) Ly-6C(hi) monocytes.

    PubMed

    Kim, Jin Hyoung; Patil, Ajit Mahadev; Choi, Jin Young; Kim, Seong Bum; Uyangaa, Erdenebileg; Hossain, Ferdaus Mohd Altaf; Park, Sang-Youel; Lee, John Hwa; Kim, Koanhoi; Eo, Seong Kug

    2016-10-01

    Japanese encephalitis virus (JEV) is a re-emerging zoonotic flavivirus that poses an increasing threat to global health and welfare due to rapid changes in climate and demography. Although the CCR2-CCL2 axis plays an important role in trafficking CD11b(+) Ly-6C(hi) monocytes to regulate immunopathological diseases, little is known about their role in monocyte trafficking during viral encephalitis caused by JEV infection. Here, we explored the role of CCR2 and its ligand CCL2 in JE caused by JEV infection using CCR2- and CCL2-ablated murine models. Somewhat surprisingly, the ablation of CCR2 and CCL2 resulted in starkly contrasting susceptibility to JE. CCR2 ablation induced enhanced resistance to JE, whereas CCL2 ablation highly increased susceptibility to JE. This contrasting regulation of JE progression by CCR2 and CCL2 was coupled to central nervous system (CNS) infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. There was also enhanced expression of CC and CXC chemokines in the CNS of CCL2-ablated mice, which appeared to induce CNS infiltration of these cell populations. However, our data revealed that contrasting regulation of JE in CCR2- and CCL2-ablated mice was unlikely to be mediated by innate natural killer and adaptive T-cell responses. Furthermore, CCL2 produced by haematopoietic stem cell-derived leucocytes played a dominant role in CNS accumulation of Ly-6C(hi) monocytes in infected bone marrow chimeric models, thereby exacerbating JE progression. Collectively, our data indicate that CCL2 plays an essential role in conferring protection against JE caused by JEV infection. In addition, blockage of CCR2, but not CCL2, will aid in the development of strategies for prophylactics and therapeutics of JE.

  16. Proteomic profiling of Pseudomonas aeruginosa AES-1R, PAO1 and PA14 reveals potential virulence determinants associated with a transmissible cystic fibrosis-associated strain

    PubMed Central

    2012-01-01

    Background Pseudomonas aeruginosa is an opportunistic pathogen that is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). While most CF patients are thought to acquire P. aeruginosa from the environment, person-person transmissible strains have been identified in CF clinics worldwide. The molecular basis for transmissibility and colonization of the CF lung remains poorly understood. Results A dual proteomics approach consisting of gel-based and gel-free comparisons were undertaken to analyse protein profiles in a transmissible, early (acute) isolate of the Australian epidemic strain 1 (AES-1R), the virulent burns/wound isolate PA14, and the poorly virulent, laboratory-associated strain PAO1. Over 1700 P. aeruginosa proteins were confidently identified. AES-1R protein profiles revealed elevated abundance of proteins associated with virulence and siderophore biosynthesis and acquisition, antibiotic resistance and lipopolysaccharide and fatty acid biosynthesis. The most abundant protein in AES-1R was confirmed as a previously hypothetical protein with sequence similarity to carbohydrate-binding proteins and database search revealed this gene is only found in the CF-associated strain PA2192. The link with CF infection may suggest that transmissible strains have acquired an ability to rapidly interact with host mucosal glycoproteins. Conclusions Our data suggest that AES-1R expresses higher levels of proteins, such as those involved in antibiotic resistance, iron acquisition and virulence that may provide a competitive advantage during early infection in the CF lung. Identification of novel proteins associated with transmissibility and acute infection may aid in deciphering new strategies for intervention to limit P. aeruginosa infections in CF patients. PMID:22264352

  17. Materials Data on CdH6C(BrN)3 (SG:15) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-02-04

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  18. Materials Data on Cs4Re6C4S9N4 (SG:2) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-05-24

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  19. Materials Data on RbH6C2S2NO4 (SG:14) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-04-22

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  20. Materials Data on FeAg3H6(C3N4)2 (SG:9) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-02-10

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  1. Materials Data on ZnH6C2(SO3)2 (SG:9) by Materials Project

    SciTech Connect

    Kristin Persson

    2016-03-28

    Computed materials data using density functional theory calculations. These calculations determine the electronic structure of bulk materials by solving approximations to the Schrodinger equation. For more information, see https://materialsproject.org/docs/calculations

  2. Identification of a human ABCC10 orthologue in Catharanthus roseus reveals a U12-type intron determinant for the N-terminal domain feature.

    PubMed

    El-Guizani, Taissir; Guibert, Clotilde; Triki, Saida; St-Pierre, Benoit; Ducos, Eric

    2014-04-01

    ABC (ATP-binding cassette) transporters are members of a large superfamily of proteins that utilize ATP hydrolysis to translocate a wide range of substrates across biological membranes. In general, members of C subfamily (ABCC) are structurally characterized by an additional (N-terminal) transmembrane domain (TMD0). Phylogenetic analysis of plant ABCCs separates their protein sequences into three distinct clusters: I and II are plant specific whereas cluster III contains both human and plant ABCCs. Screening of the Plant Medicinal Genomics Resource database allowed us to identify 16 ABCCs partial sequences in Catharanthus roseus; two of which belong to the unique CrABCC1 transcript that we identified in cluster III. Genomic organization of CrABCC1 TMD0 coding sequence displays an AT-AC U12-type intron that is conserved in higher plant orthologues. We showed that CrABCC1, like its human orthologue ABCC10, produces alternative transcripts that encode protein sequences with a truncated form of TMD0 without the first transmembrane span (TM1). Subcellular localization of CrABCC1 TMD0 variants using yellow fluorescent protein fusions reveals that the TM1 is required for a correct routing of the TMD0 to the tonoplast. Finally, the specific repartition of CrABCC1 orthologues in some species suggests that this gene was lost several times during evolution and that its physiological function may, rely on a common feature of multicellular eukaryotes.

  3. Comparative Transcriptomic Analysis Reveals That Ethylene/H2O2-Mediated Hypersensitive Response and Programmed Cell Death Determine the Compatible Interaction of Sand Pear and Alternaria alternata

    PubMed Central

    Wang, Hong; Lin, Jing; Chang, Youhong; Jiang, Cai-Zhong

    2017-01-01

    A major restriction on sand pear (Pyrus pyrifolia) production is black spot disease caused by the necrotrophic fungus Alternaria alternata. However, the pear response mechanism to A. alternata is unknown at the molecular level. Here, host responses of a resistant cultivar Cuiguan (CG) and a susceptible cultivar Sucui1 (SC1) to A. alternata infection were investigated. We found that the primary necrotic lesion formed at 1 dpi and the expansion of lesions was aggressive in SC1. Data from transcriptomic profiles using RNA-Seq technology identified a large number of differentially expressed genes (DEGs) between CG and SC1 in the early phase of A. alternata infection. K-mean cluster and Mapman analysis revealed that genes involved in ethylene (ET) biosynthesis and ET signaling pathway, such as ACS, ACOs, and ERFs, and in hypersensitive response (HR) and programmed cell death (PCD) were significantly enriched and up-regulated in the susceptible cultivar SC1. Conversely, genes involved in response to hydrogen peroxide and superoxide were differentially up-regulated in the resistant cultivar CG after inoculation with the fungus. Furthermore, ET levels were highly accumulated in SC1, but not in CG. Higher activities of detoxifying enzymes such as catalases were detected in CG. Our results demonstrate that the ET-/H2O2-mediated PCD and detoxifying processes play a vital role in the interaction of pear and A. alternata. PMID:28261248

  4. Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion

    PubMed Central

    Tenor, Jennifer L.; Oehlers, Stefan H.; Yang, Jialu L.

    2015-01-01

    ABSTRACT The human fungal pathogen Cryptococcus neoformans is capable of infecting a broad range of hosts, from invertebrates like amoebas and nematodes to standard vertebrate models such as mice and rabbits. Here we have taken advantage of a zebrafish model to investigate host-pathogen interactions of Cryptococcus with the zebrafish innate immune system, which shares a highly conserved framework with that of mammals. Through live-imaging observations and genetic knockdown, we establish that macrophages are the primary immune cells responsible for responding to and containing acute cryptococcal infections. By interrogating survival and cryptococcal burden following infection with a panel of Cryptococcus mutants, we find that virulence factors initially identified as important in causing disease in mice are also necessary for pathogenesis in zebrafish larvae. Live imaging of the cranial blood vessels of infected larvae reveals that C. neoformans is able to penetrate the zebrafish brain following intravenous infection. By studying a C. neoformans FNX1 gene mutant, we find that blood-brain barrier invasion is dependent on a known cryptococcal invasion-promoting pathway previously identified in a murine model of central nervous system invasion. The zebrafish-C. neoformans platform provides a visually and genetically accessible vertebrate model system for cryptococcal pathogenesis with many of the advantages of small invertebrates. This model is well suited for higher-throughput screening of mutants, mechanistic dissection of cryptococcal pathogenesis in live animals, and use in the evaluation of therapeutic agents. PMID:26419880

  5. Intrinsic Determinants of Aβ12–24 pH-Dependent Self-Assembly Revealed by Combined Computational and Experimental Studies

    PubMed Central

    Xu, Weixin; Zhang, Ce; Derreumaux, Philippe; Gräslund, Astrid; Morozova-Roche, Ludmilla; Mu, Yuguang

    2011-01-01

    The propensity of amyloid- (A) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment A and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of A dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, -sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in A amyloid formation; it is highly prompted in the order of pH 5.02.98.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of -sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases. PMID:21957446

  6. Restriction Site-Associated DNA Sequencing (RAD-seq) Reveals an Extraordinary Number of Transitions among Gecko Sex-Determining Systems.

    PubMed

    Gamble, Tony; Coryell, Jessi; Ezaz, Tariq; Lynch, Joshua; Scantlebury, Daniel P; Zarkower, David

    2015-05-01

    Sex chromosomes have evolved many times in animals and studying these replicate evolutionary "experiments" can help broaden our understanding of the general forces driving the origin and evolution of sex chromosomes. However this plan of study has been hindered by the inability to identify the sex chromosome systems in the large number of species with cryptic, homomorphic sex chromosomes. Restriction site-associated DNA sequencing (RAD-seq) is a critical enabling technology that can identify the sex chromosome systems in many species where traditional cytogenetic methods have failed. Using newly generated RAD-seq data from 12 gecko species, along with data from the literature, we reinterpret the evolution of sex-determining systems in lizards and snakes and test the hypothesis that sex chromosomes can routinely act as evolutionary traps. We uncovered between 17 and 25 transitions among gecko sex-determining systems. This is approximately one-half to two-thirds of the total number of transitions observed among all lizards and snakes. We find support for the hypothesis that sex chromosome systems can readily become trap-like and show that adding even a small number of species from understudied clades can greatly enhance hypothesis testing in a model-based phylogenetic framework. RAD-seq will undoubtedly prove useful in evaluating other species for male or female heterogamety, particularly the majority of fish, amphibian, and reptile species that lack visibly heteromorphic sex chromosomes, and will significantly accelerate the pace of biological discovery.

  7. Structure of Yeast OSBP-Related Protein Osh1 Reveals Key Determinants for Lipid Transport and Protein Targeting at the Nucleus-Vacuole Junction.

    PubMed

    Manik, Mohammad Kawsar; Yang, Huiseon; Tong, Junsen; Im, Young Jun

    2017-03-10

    Yeast Osh1 belongs to the oxysterol-binding protein (OSBP) family of proteins and contains multiple targeting modules optimized for lipid transport at the nucleus-vacuole junction (NVJ). The key determinants for NVJ targeting and the role of Osh1 at NVJs have remained elusive because of unknown lipid specificities. In this study, we determined the structures of the ankyrin repeat domain (ANK), and OSBP-related domain (ORD) of Osh1, in complex with Nvj1 and ergosterol, respectively. The Osh1 ANK forms a unique bi-lobed structure that recognizes a cytosolic helical segment of Nvj1. We discovered that Osh1 ORD binds ergosterol and phosphatidylinositol 4-phosphate PI(4)P in a competitive manner, suggesting counter-transport function of the two lipids. Ergosterol is bound to the hydrophobic pocket in a head-down orientation, and the structure of the PI(4)P-binding site in Osh1 is well conserved. Our results suggest that Osh1 performs non-vesicular transport of ergosterol and PI(4)P at the NVJ.

  8. Analysis of integrated multiple 'omics' datasets reveals the mechanisms of initiation and determination in the formation of tuberous roots in Rehmannia glutinosa.

    PubMed

    Li, Mingjie; Yang, Yanhui; Li, Xinyu; Gu, Li; Wang, Fengji; Feng, Fajie; Tian, Yunhe; Wang, Fengqing; Wang, Xiaoran; Lin, Wenxiong; Chen, Xinjian; Zhang, Zhongyi

    2015-09-01

    All tuberous roots in Rehmannia glutinosa originate from the expansion of fibrous roots (FRs), but not all FRs can successfully transform into tuberous roots. This study identified differentially expressed genes and proteins associated with the expansion of FRs, by comparing the tuberous root at expansion stages (initiated tuberous root, ITRs) and FRs at the seedling stage (initiated FRs, IFRs). The role of miRNAs in the expansion of FRs was also explored using the sRNA transcriptome and degradome to identify miRNAs and their target genes that were differentially expressed between ITRs and FRs at the mature stage (unexpanded FRs, UFRs, which are unable to expand into ITRs). A total of 6032 genes and 450 proteins were differentially expressed between ITRs and IFRs. Integrated analyses of these data revealed several genes and proteins involved in light signalling, hormone response, and signal transduction that might participate in the induction of tuberous root formation. Several genes related to cell division and cell wall metabolism were involved in initiating the expansion of IFRs. Of 135 miRNAs differentially expressed between ITRs and UFRs, there were 27 miRNAs whose targets were specifically identified in the degradome. Analysis of target genes showed that several miRNAs specifically expressed in UFRs were involved in the degradation of key genes required for the formation of tuberous roots. As far as could be ascertained, this is the first time that the miRNAs that control the transition of FRs to tuberous roots in R. glutinosa have been identified. This comprehensive analysis of 'omics' data sheds new light on the mechanisms involved in the regulation of tuberous roots formation.

  9. Combined Crystal Structure of a Type I Cohesin: MUTATION AND AFFINITY BINDING STUDIES REVEAL STRUCTURAL DETERMINANTS OF COHESIN-DOCKERIN SPECIFICITIES.

    PubMed

    Cameron, Kate; Weinstein, Jonathan Y; Zhivin, Olga; Bule, Pedro; Fleishman, Sarel J; Alves, Victor D; Gilbert, Harry J; Ferreira, Luís M A; Fontes, Carlos M G A; Bayer, Edward A; Najmudin, Shabir

    2015-06-26

    Cohesin-dockerin interactions orchestrate the assembly of one of nature's most elaborate multienzyme complexes, the cellulosome. Cellulosomes are produced exclusively by anaerobic microbes and mediate highly efficient hydrolysis of plant structural polysaccharides, such as cellulose and hemicellulose. In the canonical model of cellulosome assembly, type I dockerin modules of the enzymes bind to reiterated type I cohesin modules of a primary scaffoldin. Each type I dockerin contains two highly conserved cohesin-binding sites, which confer quaternary flexibility to the multienzyme complex. The scaffoldin also bears a type II dockerin that anchors the entire complex to the cell surface by binding type II cohesins of anchoring scaffoldins. In Bacteroides cellulosolvens, however, the organization of the cohesin-dockerin types is reversed, whereby type II cohesin-dockerin pairs integrate the enzymes into the primary scaffoldin, and type I modules mediate cellulosome attachment to an anchoring scaffoldin. Here, we report the crystal structure of a type I cohesin from B. cellulosolvens anchoring scaffoldin ScaB to 1.84-Å resolution. The structure resembles other type I cohesins, and the putative dockerin-binding site, centered at β-strands 3, 5, and 6, is likely to be conserved in other B. cellulosolvens type I cohesins. Combined computational modeling, mutagenesis, and affinity-based binding studies revealed similar hydrogen-bonding networks between putative Ser/Asp recognition residues in the dockerin at positions 11/12 and 45/46, suggesting that a dual-binding mode is not exclusive to the integration of enzymes into primary cellulosomes but can also characterize polycellulosome assembly and cell-surface attachment. This general approach may provide valuable structural information of the cohesin-dockerin interface, in lieu of a definitive crystal structure.

  10. Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A>G Variant Is Determinant of Increased Atorvastatin Response

    PubMed Central

    Rodrigues, Alice C.; Perin, Paula M. S.; Purim, Sheila G.; Silbiger, Vivian N.; Genvigir, Fabiana D. V.; Willrich, Maria Alice V.; Arazi, Simone S.; Luchessi, Andre D.; Hirata, Mario H.; Bernik, Marcia M. S.; Dorea, Egidio L.; Santos, Carla; Faludi, Andre A.; Bertolami, Marcelo C.; Salas, Antonio; Freire, Ana; Lareu, Maria V.; Phillips, Christopher; Porras-Hurtado, Liliana; Fondevila, Manuel; Carracedo, Angel; Hirata, Rosario D. C.

    2011-01-01

    Aims The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. Material and Methods One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot® and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (−71T>C) gene polymorphisms were identified by TaqMan® Real-time PCR. Results Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3–8.0, p < 0.05). Conclusion SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy. PMID:22016628

  11. Lung Deposition and Clearance of Inhaled Vanadium Pentoxide in Chronically Exposed F344 Rats and B6C3F1 Mice

    SciTech Connect

    Dill, Jeffrey A.; Lee, Kyeonghee M.; Mellinger, Kathleen H.; Bates, Derrick J.; Burka, Leo T.; Roycroft, Joseph H.

    2004-01-01

    Female F344 rats and B6C3F1 mice were exposed to vanadium pentoxide (V{sub 2}O{sub 5}) at concentrations of 0, 0.5, 1, or 2 mg/m{sup 3} (rats) and 0, 1, 2, or 4 mg/m{sup 3} (mice) for 6 h/day, 5 days/week (for up to 18 months), by whole-body inhalation. Lung weights and lung burdens of vanadium were determined for exposed animals after 1, 5, and 12 days and after 1, 2, 6, 12, and 18 months of V{sub 2}O{sub 5} exposure. Blood vanadium concentrations were determined at 1, 2, 6, 12, and 18 months for all animals including controls. A model that assumed a first-order deposition rate and a first-order elimination rate for vanadium was employed to fit the lung burden data. Comparisons between exposed groups indicated a progressive increase in lung weight with exposure concentration and time on exposure for both species. The vanadium lung burdens appeared to reach steady state in the lowest exposure groups (0.5 and 1 mg/m{sup 3} for rats and mice, respectively) but showed a decline in the higher exposure groups. This deposition pattern was similar between rats and mice but the maximum lung burdens were observed at different times (1 or 2 months in mice vs. 6 months in rats). The vanadium deposition rate decreased faster in mice, while the elimination half-lives of vanadium lung burdens were about six- to nine-fold shorter in mice than in rats at 1 and 2 mg/m{sup 3}. Thus, the retention of vanadium in the lungs at 18 months was lower in mice ({approx}2% retained) compared with rats (13-15% retained) at the common exposure concentrations of 1 and 2 mg/m{sup 3}. The lung burden data were approximately proportional to the exposure concentration in both species, likely due to concomitant decreases in deposition and elimination to a similar extent with increasing exposure. The area under the lung burden versus time curves and the area under the blood concentration (control-normalized) versus time curves were also proportional to exposure concentration. The progression of

  12. Core phenomenology. TEC report on CRBRP PRA Phase II, Task 6C. Final draft report, Revision 1

    SciTech Connect

    1984-04-04

    As part of the determination of the risk potential associated with core-damage accident sequences for the CRBRP, a review of the core-damage phenomenology is necessary. How core damage proceeds, its effects on the primary system boundary, and the timing and energetic potential associated with core damage are important to determining the challenge to containment and the ultimate release of fission products to the environment. This chapter addresses the phenomenology related to the core-damage processes and by the use of a core-response event tree, estimates are made of the probability that certain core-response scenarios are followed.

  13. CARCINOGENICITY OF BROMODICHLOROMETHANE ADMINISTERED IN DRINKING WATER TO MALE F344/N RATS AND B6C3F1 MICE

    EPA Science Inventory

    A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F1 mice. Mouse: Target concentrations of BDCM (dissolved in deionized water containing 0.25% emulphor) were 0.05, ...

  14. THE INDUCTION OF HEPATOCELLULAR NEOPLASIA BY TRICHLOROACETIC ACID ADMINISTERED IN THE DRINKING WATER OF THE MALE B6C3F1 MOUSE

    EPA Science Inventory

    Summary What is the study? The study is a chronic bioassay (2 years) of trichloroacetic acid, a drinking water disinfection by-product, in the male B6C3F1 mouse.
    What is the impact to the field and the Agency?
    The impact of this study will derive from the use of...

  15. EFFECT OF TRICHLOROETHYLENE ON DNA METHYLATION AND EXPRESSION OF EARLY-INTERMEDIATE PROTOONCOGENES IN THE LIVER OF B6C3F1 MICE. (R825384)

    EPA Science Inventory

    Trichloroethylene (TCE) is a multimedia environmental pollution that is carcinogenic in mouse liver. The ability of TCE to modulate DNA methylation and the expression of immediate-early protooncogenes was evaluated. Female B6C3F1 mice were administered 1000 mg/kg TCE by gavage 5 ...

  16. EVALUATION OF THE IMMUNOMODULATORY EFFECTS OF THE DISINFECTION BYPRODUCT, SODIUM CHLORITE, IN FEMALE B6C3F1 MICE: A DRINKING WATER STUDY

    EPA Science Inventory

    Evaluation of the Immunomodulatory Effects of the Disinfection By-product, Sodium chlorite, in Female B6C3f1 mice: A Drinking Water Study.

    Niel A. Karrow, Tal, L. Guo, J. Ann McCay, Greg W. Johnson, Ronnetta D. Brown, Debrorah L. Musgrove, Dori R. Germolec, Robert W. Lueb...

  17. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.

    PubMed

    Li, Qing; Wojciechowski, Robert; Simpson, Claire L; Hysi, Pirro G; Verhoeven, Virginie J M; Ikram, Mohammad Kamran; Höhn, René; Vitart, Veronique; Hewitt, Alex W; Oexle, Konrad; Mäkelä, Kari-Matti; MacGregor, Stuart; Pirastu, Mario; Fan, Qiao; Cheng, Ching-Yu; St Pourcain, Beaté; McMahon, George; Kemp, John P; Northstone, Kate; Rahi, Jugnoo S; Cumberland, Phillippa M; Martin, Nicholas G; Sanfilippo, Paul G; Lu, Yi; Wang, Ya Xing; Hayward, Caroline; Polašek, Ozren; Campbell, Harry; Bencic, Goran; Wright, Alan F; Wedenoja, Juho; Zeller, Tanja; Schillert, Arne; Mirshahi, Alireza; Lackner, Karl; Yip, Shea Ping; Yap, Maurice K H; Ried, Janina S; Gieger, Christian; Murgia, Federico; Wilson, James F; Fleck, Brian; Yazar, Seyhan; Vingerling, Johannes R; Hofman, Albert; Uitterlinden, André; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart; Oostra, Ben A; Zhou, Xin; Teo, Yik-Ying; Tai, E Shyong; Vithana, Eranga; Barathi, Veluchamy; Zheng, Yingfeng; Siantar, Rosalynn Grace; Neelam, Kumari; Shin, Youchan; Lam, Janice; Yonova-Doing, Ekaterina; Venturini, Cristina; Hosseini, S Mohsen; Wong, Hoi-Suen; Lehtimäki, Terho; Kähönen, Mika; Raitakari, Olli; Timpson, Nicholas J; Evans, David M; Khor, Chiea-Chuen; Aung, Tin; Young, Terri L; Mitchell, Paul; Klein, Barbara; van Duijn, Cornelia M; Meitinger, Thomas; Jonas, Jost B; Baird, Paul N; Mackey, David A; Wong, Tien Yin; Saw, Seang-Mei; Pärssinen, Olavi; Stambolian, Dwight; Hammond, Christopher J; Klaver, Caroline C W; Williams, Cathy; Paterson, Andrew D; Bailey-Wilson, Joan E; Guggenheim, Jeremy A

    2015-02-01

    To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

  18. Multispectral airborne imagery in the field reveals genetic determinisms of morphological and transpiration traits of an apple tree hybrid population in response to water deficit

    PubMed Central

    Virlet, Nicolas; Costes, Evelyne; Martinez, Sébastien; Kelner, Jean-Jacques; Regnard, Jean-Luc

    2015-01-01

    Genetic studies of response to water deficit in adult trees are limited by low throughput of the usual phenotyping methods in the field. Here, we aimed at overcoming this bottleneck, applying a new methodology using airborne multispectral imagery and in planta measurements to compare a high number of individuals. An apple tree population, grafted on the same rootstock, was submitted to contrasting summer water regimes over two years. Aerial images acquired in visible, near- and thermal-infrared at three dates each year allowed calculation of vegetation and water stress indices. Tree vigour and fruit production were also assessed. Linear mixed models were built accounting for date and year effects on several variables and including the differential response of genotypes between control and drought conditions. Broad-sense heritability of most variables was high and 18 quantitative trait loci (QTLs) independent of the dates were detected on nine linkage groups of the consensus apple genetic map. For vegetation and stress indices, QTLs were related to the means, the intra-crown heterogeneity, and differences induced by water regimes. Most QTLs explained 15−20% of variance. Airborne multispectral imaging proved relevant to acquire simultaneous information on a whole tree population and to decipher genetic determinisms involved in response to water deficit. PMID:26208644

  19. Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer.

    PubMed

    Ryu, Je-Kyung; Kim, Soo Jin; Rah, Sang-Hyun; Kang, Ji In; Jung, Hi Eun; Lee, Dongsun; Lee, Heung Kyu; Lee, Jie-Oh; Park, Beom Seok; Yoon, Tae-Young; Kim, Ho Min

    2017-01-17

    Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, binds Toll-like receptor 4 (TLR4)-MD2 complex and activates innate immune responses. LPS transfer to TLR4-MD2 is catalyzed by both LPS binding protein (LBP) and CD14. To define the sequential molecular interactions underlying this transfer, we reconstituted in vitro the entire LPS transfer process from LPS micelles to TLR4-MD2. Using electron microscopy and single-molecule approaches, we characterized the dynamic intermediate complexes for LPS transfer: LBP-LPS micelles, CD14-LBP-LPS micelle, and CD14-LPS-TLR4-MD2 complex. A single LBP molecule bound longitudinally to LPS micelles catalyzed multi-rounds of LPS transfer to CD14s that rapidly dissociated from LPB-LPS complex upon LPS transfer via electrostatic interactions. Subsequently, the single LPS molecule bound to CD14 was transferred to TLR4-MD2 in a TLR4-dependent manner. The definition of the structural determinants of the LPS transfer cascade to TLR4 may enable the development of targeted therapeutics for intervention in LPS-induced sepsis.

  20. Determination of the microscopic equilibrium dissociation constants for risedronate and its analogues reveals two distinct roles for the nitrogen atom in nitrogen-containing bisphosphonate drugs.

    PubMed

    Hounslow, Andrea M; Carran, John; Brown, Richard J; Rejman, Dominik; Blackburn, G Michael; Watts, Donald J

    2008-07-24

    Microscopic equilibrium dissociation constants, k as, were determined for four nitrogen-containing bisphosphonates (N-BP): risedronate and its analogues 2-(2-aminophenyl)-1-hydroxyethylidene-1,1-bisphosphonate, NE 11807, and NE 97220. The proportion of each and of analogues 2-(3'-( N-ethyl)pyridinium)-ethylidenebisphosphonate and 2-(3-piperinidyl)-1-hydroxyethylidene-1,1-bisphosphonate, having a positively charged nitrogen and three negative charges on the bisphosphonate group ("carbocation analogue") at pH 7.5, was calculated. When set in order of increasing potency at inhibiting farnesyl diphosphate (FDP) synthase (their intracellular target), the N-BPs are also ranked in order of decreasing mole fraction of carbocation analogue. However, only a weak correlation exists between potency for inhibiting FDP synthase and potency for inhibiting Dictyostelium discoideum growth. It is concluded that, although high potency for inhibiting FDP synthase is favored when the nitrogen atom in a N-BP is uncharged, N-BPs having a positively charged nitrogen can still be potent inhibitors of Dictyostelium growth owing to favorable interaction with a second, unidentified target.

  1. Multispectral airborne imagery in the field reveals genetic determinisms of morphological and transpiration traits of an apple tree hybrid population in response to water deficit.

    PubMed

    Virlet, Nicolas; Costes, Evelyne; Martinez, Sébastien; Kelner, Jean-Jacques; Regnard, Jean-Luc

    2015-09-01

    Genetic studies of response to water deficit in adult trees are limited by low throughput of the usual phenotyping methods in the field. Here, we aimed at overcoming this bottleneck, applying a new methodology using airborne multispectral imagery and in planta measurements to compare a high number of individuals.An apple tree population, grafted on the same rootstock, was submitted to contrasting summer water regimes over two years. Aerial images acquired in visible, near- and thermal-infrared at three dates each year allowed calculation of vegetation and water stress indices. Tree vigour and fruit production were also assessed. Linear mixed models were built accounting for date and year effects on several variables and including the differential response of genotypes between control and drought conditions.Broad-sense heritability of most variables was high and 18 quantitative trait loci (QTLs) independent of the dates were detected on nine linkage groups of the consensus apple genetic map. For vegetation and stress indices, QTLs were related to the means, the intra-crown heterogeneity, and differences induced by water regimes. Most QTLs explained 15-20% of variance.Airborne multispectral imaging proved relevant to acquire simultaneous information on a whole tree population and to decipher genetic determinisms involved in response to water deficit.

  2. CD11c(hi) Dendritic Cells Regulate Ly-6C(hi) Monocyte Differentiation to Preserve Immune-privileged CNS in Lethal Neuroinflammation.

    PubMed

    Kim, Jin Hyoung; Choi, Jin Young; Kim, Seong Bum; Uyangaa, Erdenebelig; Patil, Ajit Mahadev; Han, Young Woo; Park, Sang-Youel; Lee, John Hwa; Kim, Koanhoi; Eo, Seong Kug

    2015-12-02

    Although the roles of dendritic cells (DCs) in adaptive defense have been defined well, the contribution of DCs to T cell-independent innate defense and subsequent neuroimmunopathology in immune-privileged CNS upon infection with neurotropic viruses has not been completely defined. Notably, DC roles in regulating innate CD11b(+)Ly-6C(hi) monocyte functions during neuroinflammation have not yet been addressed. Using selective ablation of CD11c(hi)PDCA-1(int/lo) DCs without alteration in CD11c(int)PDCA-1(hi) plasmacytoid DC number, we found that CD11c(hi) DCs are essential to control neuroinflammation caused by infection with neurotropic Japanese encephalitis virus, through early and increased infiltration of CD11b(+)Ly-6C(hi) monocytes and higher expression of CC chemokines. More interestingly, selective CD11c(hi) DC ablation provided altered differentiation and function of infiltrated CD11b(+)Ly-6C(hi) monocytes in the CNS through Flt3-L and GM-CSF, which was closely associated with severely enhanced neuroinflammation. Furthermore, CD11b(+)Ly-6C(hi) monocytes generated in CD11c(hi) DC-ablated environment had a deleterious rather than protective role during neuroinflammation, and were more quickly recruited into inflamed CNS, depending on CCR2, thereby exacerbating neuroinflammation via enhanced supply of virus from the periphery. Therefore, our data demonstrate that CD11c(hi) DCs provide a critical and unexpected role to preserve the immune-privileged CNS in lethal neuroinflammation via regulating the differentiation, function, and trafficking of CD11b(+)Ly-6C(hi) monocytes.

  3. Aspirin revealed

    NASA Astrophysics Data System (ADS)

    Lacey, D.; Hu, X. K.; Loboda, A. V.; Mosey, N. J.; Lipson, R. H.

    2007-03-01

    Experiments are described where the experimental conditions have been optimized to detect aspirin by MALDI mass spectrometry. Although protonated aspirin was not observed by MALDI, sodium and potassium aspirin adducts could be found. Significantly better signals could be obtained by using Rb and Cs salts as cationization sources. Quantum calculations were carried out to determine the structure and energetics of the Li, K, Rb, and Cs alkali--aspirin adducts.

  4. Genetic Analysis Reveals a Hierarchy of Interactions between Polycystin-Encoding Genes and Genes Controlling Cilia Function during Left-Right Determination

    PubMed Central

    Grimes, Daniel T.; Keynton, Jennifer L.; Buenavista, Maria T.; Jin, Xingjian; Patel, Saloni H.; Kyosuke, Shinohara; Williams, Debbie J.; Hamada, Hiroshi; Hussain, Rohanah; Nauli, Surya M.; Norris, Dominic P.

    2016-01-01

    During mammalian development, left-right (L-R) asymmetry is established by a cilia-driven leftward fluid flow within a midline embryonic cavity called the node. This ‘nodal flow’ is detected by peripherally-located crown cells that each assemble a primary cilium which contain the putative Ca2+ channel PKD2. The interaction of flow and crown cell cilia promotes left side-specific expression of Nodal in the lateral plate mesoderm (LPM). Whilst the PKD2-interacting protein PKD1L1 has also been implicated in L-R patterning, the underlying mechanism by which flow is detected and the genetic relationship between Polycystin function and asymmetric gene expression remains unknown. Here, we characterize a Pkd1l1 mutant line in which Nodal is activated bilaterally, suggesting that PKD1L1 is not required for LPM Nodal pathway activation per se, but rather to restrict Nodal to the left side downstream of nodal flow. Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor of Pkd2. This study therefore provides a genetic pathway for the early stages of L-R determination. Moreover, using a system in which cultured cells are supplied artificial flow, we demonstrate that PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation. Finally, we show that an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function; as such, destabilizing the domain causes L-R defects in the mouse. Our demonstration that PKD1L1 protein can mediate a response to flow coheres with a mechanosensation model of flow sensation in which the force of fluid flow drives asymmetric gene expression in the embryo. PMID:27272319

  5. Molecular determinants of substrate specificity revealed by the structure of Clostridium thermocellum arabinofuranosidase 43A from glycosyl hydrolase family 43 subfamily 16.

    PubMed

    Goyal, Arun; Ahmed, Shadab; Sharma, Kedar; Gupta, Vikas; Bule, Pedro; Alves, Victor D; Fontes, Carlos M G A; Najmudin, Shabir

    2016-12-01

    The recent division of the large glycoside hydrolase family 43 (GH43) into subfamilies offers a renewed opportunity to develop structure-function studies aimed at clarifying the molecular determinants of substrate specificity in carbohydrate-degrading enzymes. α-L-Arabinofuranosidases (EC 3.2.1.55) remove arabinose side chains from heteropolysaccharides such as xylan and arabinan. However, there is some evidence suggesting that arabinofuranosidases are substrate-specific, being unable to display a debranching activity on different polysaccharides. Here, the structure of Clostridium thermocellum arabinofuranosidase 43A (CtAbf43A), which has been shown to act in the removal of arabinose side chains from arabinoxylan but not from pectic arabinan, is reported. CtAbf43A belongs to GH43 subfamily 16, the members of which have a restricted capacity to attack xylans. The crystal structure of CtAbf43A comprises a five-bladed β-propeller fold typical of GH43 enzymes. CtAbf43A displays a highly compact architecture compatible with its high thermostability. Analysis of CtAbf43A along with the other member of GH43 subfamily 16 with known structure, the Bacillus subtilis arabinofuranosidase BsAXH-m2,3, suggests that the specificity of subfamily 16 for arabinoxylan is conferred by a long surface substrate-binding cleft that is complementary to the xylan backbone. The lack of a curved-shaped carbohydrate-interacting platform precludes GH43 subfamily 16 enzymes from interacting with the nonlinear arabinan scaffold and therefore from deconstructing this polysaccharide.

  6. Genetic manipulation of a transcription-regulating sequence of porcine reproductive and respiratory syndrome virus reveals key nucleotides determining its activity.

    PubMed

    Zheng, Haihong; Zhang, Keyu; Zhu, Xing-Quan; Liu, Changlong; Lu, Jiaqi; Gao, Fei; Zhou, Yan; Zheng, Hao; Lin, Tao; Li, Liwei; Tong, Guangzhi; Wei, Zuzhang; Yuan, Shishan

    2014-08-01

    The factors that determine the transcription-regulating sequence (TRS) activity of porcine reproductive and respiratory syndrome virus (PRRSV) remain largely unclear. In this study, the effect of mutagenesis of conserved C nucleotides at positions 5 and 6 in the leader TRS (TRS-L) and/or canonical body TRS7 (TRS-B7) on the synthesis of subgenomic (sg) mRNA and virus infectivity was investigated in the context of a type 2 PRRSV infectious cDNA clone. The results showed that a double C mutation in the leader TRS completely abolished sg mRNAs synthesis and virus infectivity, but a single C mutation did not. A single C or double C mutation in TRS-B7.1 or/and TRS-B7.2 impaired or abolished the corresponding sg mRNA synthesis. Introduction of identical mutations in the leader and body TRSs partially restored sg mRNA7.1 and/or sg mRNA7.2 transcription, indicating that the base-pairing interaction between sense TRS-L and cTRS-B is a crucial factor influencing sg mRNA synthesis. Analysis of the mRNA leader-body junctions of mutants provided evidence for a mechanism of discontinuous minus-strand transcription. This study also showed that mutational inactivation of TRS-B7.1 or TRS-B7.2 did not affect the production of infectious progeny virus, and the sg mRNA formed from each of them could express N protein. However, TRS-B7.1 plays more important roles than TRS-B7.2 in maintaining the growth characteristic of type 2 PRRSV. These results provide more insight into the molecular mechanism of genome expression and subgenomic mRNA transcription of PRRSV.

  7. Diversity and Determinants of the Three-dimensional Anatomical Axis of the Heart as Revealed Using Multidetector-row Computed Tomography.

    PubMed

    Mori, Shumpei; Anderson, Robert H; Tahara, Natsuko; Izawa, Yu; Toba, Takayoshi; Fujiwara, Sei; Shimoyama, Shinsuke; Watanabe, Yoshiaki; Nishii, Tatsuya; Kono, Atsushi K; Hirata, Ken-Ichi

    2017-02-08

    The location of the heart within the thorax varies significantly between individuals. The resultant diversity of the anatomical cardiac long axis, however, and its determinants, have yet to be systematically investigated. We enrolled 100 consecutive patients undergoing coronary arterial computed tomographic angiography, decomposing the vector of the anatomical cardiac long axis by projecting it to horizontal, frontal, and sagittal planes. The projected vectors on each plane were then converted into three rotation angles using coordinate transformation. We then measured the extent of aortic wedging, using the vertical distance between the inferior margins of the non-adjacent aortic sinus and the epicardium. We took the aortic root rotation angle to be zero when an "en face" view of the right coronary aortic sinus was obtained in the frontal view, defining leftward rotation to be positive. The mean horizontal, frontal, and sagittal rotation angles were 48.7° ± 9.5°, 52.3° ± 12.0°, and 34.0° ± 11.2°, respectively. The mean extent of aortic wedging, and the aortic root rotation angle, were 42.7 ± 9.8 mm, and 5.3° ± 16.4°. Horizontal rotation of the anatomical axis was associated with leftward and ventral rotation, and vice versa. Multivariate analysis showed aortic root rotation to be associated with horizontal cardiac rotation, while aortic wedging is associated with frontal and sagittal cardiac rotation. We have quantified the marked individual variation observed in the anatomical axis of the living heart, identifying the different mechanisms involved in producing the marked three-dimensional diversity of the living heart. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc.

  8. Transcriptome and Proteome Analyses of TNFAIP8 Knockdown Cancer Cells Reveal New Insights into Molecular Determinants of Cell Survival and Tumor Progression.

    PubMed

    Day, Timothy F; Mewani, Rajshree R; Starr, Joshua; Li, Xin; Chakravarty, Debyani; Ressom, Habtom; Zou, Xiaojun; Eidelman, Ofer; Pollard, Harvey B; Srivastava, Meera; Kasid, Usha N

    2017-01-01

    Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is the first discovered oncogenic and an anti-apoptotic member of a conserved TNFAIP8 or TIPE family of proteins. TNFAIP8 mRNA is induced by NF-kB, and overexpression of TNFAIP8 has been correlated with poor prognosis in many cancers. Downregulation of TNFAIP8 expression has been associated with decreased pulmonary colonization of human tumor cells, and enhanced sensitivities of tumor xenografts to radiation and docetaxel. Here we have investigated the effects of depletion of TNFAIP8 on the mRNA, microRNA and protein expression profiles in prostate and breast cancers and melanoma. Depending on the tumor cell type, knockdown of TNFAIP8 was found to be associated with increased mRNA expression of several antiproliferative and apoptotic genes (e.g., IL-24, FAT3, LPHN2, EPHA3) and fatty acid oxidation gene ACADL, and decreased mRNA levels of oncogenes (e.g., NFAT5, MALAT1, MET, FOXA1, KRAS, S100P, OSTF1) and glutamate transporter gene SLC1A1. TNFAIP8 knockdown cells also exhibited decreased expression of multiple onco-proteins (e.g., PIK3CA, SRC, EGFR, IL5, ABL1, GAP43), and increased expression of the orphan nuclear receptor NR4A1 and alpha 1 adaptin subunit of the adaptor-related protein complex 2 AP2 critical to clathrin-mediated endocytosis. TNFAIP8-centric molecules were found to be predominately implicated in the hypoxia-inducible factor-1α (HIF-1α) signaling pathway, and cancer and development signaling networks. Thus TNFAIP8 seems to regulate the cell survival and cancer progression processes in a multifaceted manner. Future validation of the molecules identified in this study is likely to lead to new subset of molecules and functional determinants of cancer cell survival and progression.

  9. Genetic Analysis Reveals a Hierarchy of Interactions between Polycystin-Encoding Genes and Genes Controlling Cilia Function during Left-Right Determination.

    PubMed

    Grimes, Daniel T; Keynton, Jennifer L; Buenavista, Maria T; Jin, Xingjian; Patel, Saloni H; Kyosuke, Shinohara; Vibert, Jennifer; Williams, Debbie J; Hamada, Hiroshi; Hussain, Rohanah; Nauli, Surya M; Norris, Dominic P

    2016-06-01

    During mammalian development, left-right (L-R) asymmetry is established by a cilia-driven leftward fluid flow within a midline embryonic cavity called the node. This 'nodal flow' is detected by peripherally-located crown cells that each assemble a primary cilium which contain the putative Ca2+ channel PKD2. The interaction of flow and crown cell cilia promotes left side-specific expression of Nodal in the lateral plate mesoderm (LPM). Whilst the PKD2-interacting protein PKD1L1 has also been implicated in L-R patterning, the underlying mechanism by which flow is detected and the genetic relationship between Polycystin function and asymmetric gene expression remains unknown. Here, we characterize a Pkd1l1 mutant line in which Nodal is activated bilaterally, suggesting that PKD1L1 is not required for LPM Nodal pathway activation per se, but rather to restrict Nodal to the left side downstream of nodal flow. Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor of Pkd2. This study therefore provides a genetic pathway for the early stages of L-R determination. Moreover, using a system in which cultured cells are supplied artificial flow, we demonstrate that PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation. Finally, we show that an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function; as such, destabilizing the domain causes L-R defects in the mouse. Our demonstration that PKD1L1 protein can mediate a response to flow coheres with a mechanosensation model of flow sensation in which the force of fluid flow drives asymmetric gene expression in the embryo.

  10. Determination of the melon chloroplast and mitochondrial genome sequences reveals that the largest reported mitochondrial genome in plants contains a significant amount of DNA having a nuclear origin

    PubMed Central

    2011-01-01

    Background The melon belongs to the Cucurbitaceae family, whose economic importance among vegetable crops is second only to Solanaceae. The melon has a small genome size (454 Mb), which makes it suitable for molecular and genetic studies. Despite similar nuclear and chloroplast genome sizes, cucurbits show great variation when their mitochondrial genomes are compared. The melon possesses the largest plant mitochondrial genome, as much as eight times larger than that of other cucurbits. Results The nucleotide sequences of the melon chloroplast and mitochondrial genomes were determined. The chloroplast genome (156,017 bp) included 132 genes, with 98 single-copy genes dispersed between the small (SSC) and large (LSC) single-copy regions and 17 duplicated genes in the inverted repeat regions (IRa and IRb). A comparison of the cucumber and melon chloroplast genomes showed differences in only approximately 5% of nucleotides, mainly due to short indels and SNPs. Additionally, 2.74 Mb of mitochondrial sequence, accounting for 95% of the estimated mitochondrial genome size, were assembled into five scaffolds and four additional unscaffolded contigs. An 84% of the mitochondrial genome is contained in a single scaffold. The gene-coding region accounted for 1.7% (45,926 bp) of the total sequence, including 51 protein-coding genes, 4 conserved ORFs, 3 rRNA genes and 24 tRNA genes. Despite the differences observed in the mitochondrial genome sizes of cucurbit species, Citrullus lanatus (379 kb), Cucurbita pepo (983 kb) and Cucumis melo (2,740 kb) share 120 kb of sequence, including the predicted protein-coding regions. Nevertheless, melon contained a high number of repetitive sequences and a high content of DNA of nuclear origin, which represented 42% and 47% of the total sequence, respectively. Conclusions Whereas the size and gene organisation of chloroplast genomes are similar among the cucurbit species, mitochondrial genomes show a wide variety of sizes, with a non

  11. Examination of immune parameters and host-resistance mechanisms in B6C3F1 mice following adult exposure to 2,3,7,8-tetrachlorodibenzo-'p'-dioxin

    SciTech Connect

    House, R.V.; Lauer, L.D.; Murray, M.J.; Thomas, P.T.; Ehrlich, J.P.

    1990-01-01

    Adult female B6C3F1 mice were given a single IP dose of 0, 0.1, 1.0, or 10.0 micrograms/kg TCDD and examined for immune function and host resistance seven to ten days later. Exposure to TCDD resulted in a significant dose-related decrease in induction of both IgM and IgG antibody-forming cells. The suppression was noted for both T-dependent and T-independent antigens. TCDD at a dosage of 10 micrograms/kg was shown to suppress production of viral hemagglutinin. In contrast, TCDD exposure had no significant effect on natural killer cell function, production of interferon, or various parameters of macrophage function. Host resistance assessment revealed a significant increase in susceptibility to fatal infection with influenza virus, but no significant alteration in susceptibility to infection with the bacterium Listeria monocytogenes.

  12. Gene expression profiling in male B6C3F1 mouse livers exposed to kava identifies--changes in drug metabolizing genes and potential mechanisms linked to kava toxicity.

    PubMed

    Guo, Lei; Shi, Qiang; Dial, Stacey; Xia, Qingsu; Mei, Nan; Li, Quan-zhen; Chan, Po-Chuen; Fu, Peter

    2010-02-01

    The association of kava products with liver-related health risks has prompted regulatory action in many countries. We used a genome-wide gene expression approach to generate global gene expression profiles from the livers of male B6C3F1 mice administered kava extract by gavage for 14 weeks, and identified the differentially expressed drug metabolizing genes in response to kava treatments. Analyses of gene functions and pathways reveal that the levels of significant numbers of genes involving drug metabolism were changed and that the pathways involving xenobiotics metabolism, Nrf2-mediated oxidative stress response, mitochondrial functions and others, were altered. Our results indicate that kava extract can significantly modulate drug metabolizing enzymes, potentially leading to herb-drug interactions and hepatotoxicity.

  13. Revealing Rembrandt

    PubMed Central

    Parker, Andrew J.

    2014-01-01

    The power and significance of artwork in shaping human cognition is self-evident. The starting point for our empirical investigations is the view that the task of neuroscience is to integrate itself with other forms of knowledge, rather than to seek to supplant them. In our recent work, we examined a particular aspect of the appreciation of artwork using present-day functional magnetic resonance imaging (fMRI). Our results emphasized the continuity between viewing artwork and other human cognitive activities. We also showed that appreciation of a particular aspect of artwork, namely authenticity, depends upon the co-ordinated activity between the brain regions involved in multiple decision making and those responsible for processing visual information. The findings about brain function probably have no specific consequences for understanding how people respond to the art of Rembrandt in comparison with their response to other artworks. However, the use of images of Rembrandt's portraits, his most intimate and personal works, clearly had a significant impact upon our viewers, even though they have been spatially confined to the interior of an MRI scanner at the time of viewing. Neuroscientific studies of humans viewing artwork have the capacity to reveal the diversity of human cognitive responses that may be induced by external advice or context as people view artwork in a variety of frameworks and settings. PMID:24795552

  14. A conceptual framework for using DOE 5700. 6C and the other DOE orders as an integrated management system; the Fermilab experience

    SciTech Connect

    Bodnarczuk, M.

    1992-06-01

    In this paper, I describe a conceptual framework that uses DOE Order 5700.6C and more than 140 other DOE Orders as an integrated management system -- but I describe it within the context of the broader sociological and cultural issues of doing research at DOE funded facilities. The conceptual framework has two components. The first involves an interpretation of the 10 criteria of DOE 5700.6C that is tailored for a research environment. The second component involves using the 10 criteria as functional categories that orchestrate and integrate the other DOE Orders into a total management system. The Fermilab approach aims at reducing (or eliminating) the redundancy and overlap within the DOE Orders system at the contractor level.

  15. A conceptual framework for using DOE 5700.6C and the other DOE orders as an integrated management system; the Fermilab experience

    SciTech Connect

    Bodnarczuk, M.

    1992-06-01

    In this paper, I describe a conceptual framework that uses DOE Order 5700.6C and more than 140 other DOE Orders as an integrated management system -- but I describe it within the context of the broader sociological and cultural issues of doing research at DOE funded facilities. The conceptual framework has two components. The first involves an interpretation of the 10 criteria of DOE 5700.6C that is tailored for a research environment. The second component involves using the 10 criteria as functional categories that orchestrate and integrate the other DOE Orders into a total management system. The Fermilab approach aims at reducing (or eliminating) the redundancy and overlap within the DOE Orders system at the contractor level.

  16. Data on IL-6 c.-174 G>C genotype and allele frequencies in patients with coronary heart disease in dependence of cardiovascular outcome.

    PubMed

    Reichert, Stefan; Schlitt, Axel; Benten, Ann-Christin; Hofmann, Britt; Schaller, Hans-Günter; Schulz, Susanne

    2016-09-01

    In this data article we present data on the distribution of alleles and genotypes of the interleukin (IL)-6 c.-174 G>C polymorphism (rs 1800795) in patients with coronary heart disease (CHD) in dependence of the incidence of new cardiovascular events (combined endpoint: myocardial infarction, stroke/TIA, cardiac death, death according to stroke) within three years follow-up. Moreover, we investigated putative associations between individual expression of IL-6 genotypes and IL-6 serum level. This investigation is a subanalysis of the article entitled "The Interleukin 6 c.-174 CC genotype is a predictor for new cardiovascular events in patients with coronary heart disease within three years follow-up" (ClinicalTrials.gov identifier: NCT01045070) (Reichert et al., 2016) [1].

  17. Nqrs Data for C8H9KO6 [C8H5KO4·2(H2O)] (Subst. No. 1092)

    NASA Astrophysics Data System (ADS)

    Chihara, H.; Nakamura, N.

    This document is part of Subvolume A `Substances Containing Ag … C10H15' of Volume 48 `Nuclear Quadrupole Resonance Spectroscopy Data' of Landolt-Börnstein - Group III `Condensed Matter'. It contains an extract of Section `3.2 Data tables' of the Chapter `3 Nuclear quadrupole resonance data' providing the NQRS data for C8H9KO6 [C8H5KO4·2(H2O)] (Subst. No. 1092)

  18. Quantitation of Free Radicals in B6C3F1 Mouse Liver Slices on Exposure to Four Chemical Carcinogens: An EPR-Spin Trapping Study

    DTIC Science & Technology

    1996-03-01

    AL/OE-TR-1996-0083 UNITED STATES AIR FORCE ARMSTRONG LABORATORY QUANTITÄTEN OF FREE RADICALS IN B6C3F1 MOUSE LIVER SLICES ON EXPOSURE TO FOUR...AFB, OH 45433 Janusz Byczkowski MANTECH GEO-CENTERS JOINTVENTURE P.O. BOX 31009 DAYTON, OH 45437 Alasdair Carmichael ARMED FORCES RADIOBIOLOGY...request copies of this report from the Air Force Armstrong Laboratory. Additional copies may be purchased from: National Technical Information Service

  19. Evidence of CCR2-independent transmigration of Ly6C(hi) monocytes into the brain after permanent cerebral ischemia in mice.

    PubMed

    Chu, Hannah X; Kim, Hyun Ah; Lee, Seyoung; Broughton, Brad R S; Drummond, Grant R; Sobey, Christopher G

    2016-04-15

    Previously we showed that INCB3344, a CCR2 antagonist, inhibits transmigration of Ly6C(hi) monocytes into the brain after ischemia-reperfusion. Here we tested the effect of CCR2 inhibition during permanent cerebral ischemia. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (30 or 100mg/kg IP) 1h before middle cerebral artery occlusion and at 2 and 6h after the initiation of ischemia. After 24h, we assessed functional outcome, infarct volume and quantified immune cells in blood and brain. The increase in circulating bone marrow-derived Ly6C(hi) monocytes, but not the infiltration of those cells into the brain, was blocked by the CCR2 antagonist. INCB3344 had no effect on either neurological deficit or infarct volume. Our data confirm that cerebral ischemia triggers a CCR2-dependent increase in circulating Ly6C(hi) monocytes, but suggest that in the absence of reperfusion these cells may transmigrate into the ischemic brain in a CCR2-independent manner.

  20. Thalidomide enhances both primary and secondary host resistances to Listeria monocytogenes infection by a neutrophil-related mechanism in female B6C3F1 mice

    SciTech Connect

    Guo, Tai L. . E-mail: tlguo@hsc.vcu.edu; Chi, Rui P.; Karrow, Niel A.; Zhang, Ling X.; Pruett, Stephen B.; Germolec, Dori R.; White, Kimber L.

    2005-12-15

    Previously, we have reported that thalidomide can modulate the immune responses in female B6C3F1 mice. Furthermore, thalidomide immunomodulation increased primary host resistance to intravenously infected Listeria monocytogenes. The present study was intended to evaluate the mechanisms underlying the enhanced host resistance to L. monocytogenes by focusing on the neutrophils. Female B6C3F1 mice were treated intraperitoneally with thalidomide (100 mg/kg) for 15 days. Exposure to thalidomide increased the numbers of neutrophils in the spleens and livers of L. monocytogenes-infected mice when compared to the L. monocytogenes-infected control mice. Additionally, the percentage of neutrophils was also significantly increased after Thd treatment in L. monocytogenes-infected mice. Further studies using antibodies to deplete corresponding cells indicated that thalidomide-mediated increase in primary host resistance (both the moribundity and colony counts in the liver and spleen) to L. monocytogenes infection was due to its effect on neutrophils but not CD8{sup +} T cells or NK cells. Finally, Thd exposure also increased host resistance to secondary host resistance to L. monocytogenes infection, and depletion of neutrophils abolished the protective effect. In conclusion, thalidomide enhanced host resistance to both primary and secondary L. monocytogenes infections by a neutrophil-related mechanism in female B6C3F1 mice.

  1. Hepatic DNA adducts and production of mutagenic urine in 2,6-dinitrotoluene-treated B6C3F1 male mice.

    PubMed

    George, S E; Kohan, M J; Warren, S H

    1996-04-19

    The hepatocarcinogen 2,6-dinitrotoluene (2,6-DNT) is an intermediate in the chemical synthesis of 2,4,6-trinitrotoluene and polyurethane products and can contaminate the waste stream emitted by these industries. In this study, the production of mutagenic urine metabolites and the formation of hepatic DNA adducts is examined in the B6C3F1 male mouse. Animals were administered 50 mg/kg 2,6-DNT by gavage for 3 consecutive days. No body or liver weight effects were observed in treated animals. Following sacrifice, the livers were excised and DNA isolated for examination of 2,6-DNT-derived DNA adducts. During 2,6-DNT treatment, urine was collected, concentrated, and tested for mutagenicity in the Salmonella reversion bioassay. Mutagenic urine metabolites (469+/-53 revertants/ml urine) were excreted from B6C3F1 mice treated with 2,6-DNT and were comparable to results obtained for CD-1 mice and Fischer 344 rats. Two distinct hepatic DNA adducts (0.8+/-0.1 and 0.6+/-0.1 RAL/10(8) nucleotides) were detected in B6C3F1 mice by (32)P-postlabeling and thin layer chromatography which differed from the four adducts observed in hepatic DNA from 2,6-DNT-treated Fischer 344 rats.

  2. Caldicellulosiruptor Core and Pangenomes Reveal Determinants for

    SciTech Connect

    Blumer-Schuette, Sara E.; Giannone, Richard J; Zurawski, Jeffrey V; Ozdemir, Inci; Ma, Qin; Yin, Yanbin; Xu, Ying; Kataeva, Irena; Poole, Farris; Adams, Michael W. W.; Hamilton-Brehm, Scott; Elkins, James G; Larimer, Frank W; Land, Miriam L; Hauser, Loren John; Cottingham, Robert W; Hettich, Robert {Bob} L; Kelly, Robert M

    2012-01-01

    Extremely thermophilic bacteria of the genus Caldicellulosiruptor utilize carbohydrate components of plant cell walls, including cellulose and hemicellulose, facilitated by a diverse set of glycoside hydrolases (GHs). From a biofuel perspective, this capability is crucial for deconstruction of plant biomass into fermentable sugars. While all species from the genus grow on xylan and acidpretreated switchgrass, growth on crystalline cellulose is variable. The basis for this variability was examined using microbiological, genomic, and proteomic analyses of eight globally diverse Caldicellulosiruptor species. The open Caldicellulosiruptor pangenome (4,009 open reading frames [ORFs]) encodes 106 GHs, representing 43 GH families, but only 26 GHs from 17 families are included in the core (noncellulosic) genome (1,543 ORFs). Differentiating the strongly cellulolytic Caldicellulosiruptor species from the others is a specific genomic locus that encodes multidomain cellulases from GH families 9 and 48, which are associated with cellulose-binding modules. This locus also encodes a novel adhesin associated with type IV pili, which was identified in the exoproteome bound to crystalline cellulose. Taking into account the core genomes, pangenomes, and individual genomes, the ancestral Caldicellulosiruptor was likely cellulolytic and evolved, in some cases, into species that lost the ability to degrade crystalline cellulose while maintaining the capacity to hydrolyze amorphous cellulose and hemicellulose.

  3. Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

    PubMed Central

    Filser, Johannes Georg; Erbach, Eva; Faller, Thomas; Kreuzer, Paul Erich; Li, Qiang

    2013-01-01

    The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET. PMID:24068676

  4. Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans.

    PubMed

    Filser, Johannes Georg; Kessler, Winfried; Artati, Anna; Erbach, Eva; Faller, Thomas; Kreuzer, Paul Erich; Li, Qiang; Lichtmannegger, Josef; Numtip, Wanwiwa; Klein, Dominik; Pütz, Christian; Semder, Brigitte; Csanády, György András

    2013-12-01

    The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.

  5. Expansion of CD11b(+)Ly6G (+)Ly6C (int) cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions.

    PubMed

    Spallanzani, Raúl Germán; Dalotto-Moreno, Tomás; Raffo Iraolagoitia, Ximena Lucía; Ziblat, Andrea; Domaica, Carolina Inés; Avila, Damián Ezequiel; Rossi, Lucas Ezequiel; Fuertes, Mercedes Beatriz; Battistone, María Agustina; Rabinovich, Gabriel Adrián; Salatino, Mariana; Zwirner, Norberto Walter

    2013-12-01

    The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b(+)Gr-1(+), mostly CD11b(+)Ly6G(+)Ly6C(int) and CD11b(+)Ly6G(-)Ly6C(high) cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b(+)Ly6G(+)Ly6C(int) cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b(+)Ly6G(+)Ly6C(int) cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b(+)Gr-1(+) cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b(+)Gr-1(+) cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b(+)Ly6G(+)Ly6C(int) cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence.

  6. A novel technique for measurement of thermal rate constants and temperature dependences of dissociative recombination: CO2+, CF3+, N2O+, C7H8+, C7H7+, C6H6+, C6H5+, C5H6+, C4H4+, and C3H3+

    NASA Astrophysics Data System (ADS)

    Fournier, Joseph A.; Shuman, Nicholas S.; Melko, Joshua J.; Ard, Shaun G.; Viggiano, Albert A.

    2013-04-01

    A novel technique using a flowing afterglow-Langmuir probe apparatus for measurement of temperature dependences of rate constants for dissociative recombination (DR) is presented. Low (˜1011 cm-3) concentrations of a neutral precursor are added to a noble gas/electron afterglow plasma thermalized at 300-500 K. Charge exchange yields one or many cation species, each of which may undergo DR. Relative ion concentrations are monitored at a fixed reaction time while the initial plasma density is varied between 109 and 1010 cm-3. Modeling of the decrease in concentration of each cation relative to the non-recombining noble gas cation yields the rate constant for DR. The technique is applied to several species (O2+, CO2+, CF3+, N2O+) with previously determined 300 K values, showing excellent agreement. The measurements of those species are extended to 500 K, with good agreement to literature values where they exist. Measurements are also made for a range of CnHm+ (C7H7+, C7H8+, C5H6+, C4H4+, C6H5+, C3H3+, and C6H6+) derived from benzene and toluene neutral precursors. CnHm+ DR rate constants vary from 8-12 × 10-7 cm3 s-1 at 300 K with temperature dependences of approximately T-0.7. Where prior measurements exist these results are in agreement, with the exception of C3H3+ where the present results disagree with a previously reported flat temperature dependence.

  7. A novel technique for measurement of thermal rate constants and temperature dependences of dissociative recombination: CO2(+), CF3(+), N2O(+), C7H8(+), C7H7(+), C6H6(+), C6H5(+), C5H6(+), C4H4(+), and C3H3(+).

    PubMed

    Fournier, Joseph A; Shuman, Nicholas S; Melko, Joshua J; Ard, Shaun G; Viggiano, Albert A

    2013-04-21

    A novel technique using a flowing afterglow-Langmuir probe apparatus for measurement of temperature dependences of rate constants for dissociative recombination (DR) is presented. Low (~10(11) cm(-3)) concentrations of a neutral precursor are added to a noble gas∕electron afterglow plasma thermalized at 300-500 K. Charge exchange yields one or many cation species, each of which may undergo DR. Relative ion concentrations are monitored at a fixed reaction time while the initial plasma density is varied between 10(9) and 10(10) cm(-3). Modeling of the decrease in concentration of each cation relative to the non-recombining noble gas cation yields the rate constant for DR. The technique is applied to several species (O2(+), CO2(+), CF3(+), N2O(+)) with previously determined 300 K values, showing excellent agreement. The measurements of those species are extended to 500 K, with good agreement to literature values where they exist. Measurements are also made for a range of CnHm(+) (C7H7(+), C7H8(+), C5H6(+), C4H4(+), C6H5(+), C3H3(+), and C6H6(+)) derived from benzene and toluene neutral precursors. CnHm(+) DR rate constants vary from 8-12 × 10(-7) cm(3) s(-1) at 300 K with temperature dependences of approximately T(-0.7). Where prior measurements exist these results are in agreement, with the exception of C3H3(+) where the present results disagree with a previously reported flat temperature dependence.

  8. Toxicology and Carcinogenesis Studies of Furfuryl Alcohol (CAS No. 98-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1999-02-01

    Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day

  9. Toxicology and NTP Carcinogenesis Studies of a Polybrominated Biphenyl Mixture (Firemaster FF-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1983-06-01

    (0.1 mg/kg), and a dose-related increase in the serum levels of cholesterol in both male and female rats. Serum levels of GGTP were increased only in female mice given 10.0 mg/kg of PBB. There was a 5- to 6-fold increase in the activity of serum glutamic pyruvic transaminase (SGPT) in male and female mice in the 10.0 mg/kg groups. Serum enzyme activity of alkaline phosphate (AP) was also increased in mice given the highest dose of PBB. There was a significant dose-related increase in the serum levels of cholesterol in female mice, and the highest dose group was significantly greater than the control female mice. Serum glucose was significantly decreased in female mice administered 10.0 mg/kg of PBB. To determine the carcinogenic potential of PBB, rats and mice dosed for 6 months were observed without exposure to PBB for an additional 23 or 24 months, respectively (lifetime observation). The dosing (0.3 mg/kg or higher dose levels) shortened the survival time in male rats, whereas no such effect was observed in dosed females. There was also evidence of shortened survival time in the 10.0 mg/kg PBB-dosed mice. A significantly higher incidence of atypical hepatocellular foci, neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas was observed in dosed rats. The incidence of hepatocellular carcinoma was increased in both male and female mice (highest dose level) compared with control male and female mice. The incidence of hepatic neoplasms appeared to be dose dependent in rats and mice. Liver tumors were observed primarily in those groups of animals to which PBB was given in doses sufficient to induce readily observable hepatic toxicity. Under the conditions of these studies, polybrominated biphenyl mixture (Firemaster FF-1) was carcinogenic for Fisher 344/N rats and B6C3F1 mice of each sex, inducing neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas in rats and hepatocellular carcinomas in mice. Other toxicities included porphyrogenic

  10. Group 2 metal salts of pyromellitic acid: [Mg(H2O)6](C10H4O8) and [Ba(C10H4O8)(H2O)5].

    PubMed

    Dale, Sophie H; Elsegood, Mark R J; Kainth, Sarita

    2003-12-01

    Structural determinations of the magnesium(II) and barium(II) salts of pyromellitic acid (benzene-1,2,4,5-tetracarboxylic acid) are presented. Hexaaquamagnesium(II) benzene-1,2,4,5-tetracarboxylate(2-), [Mg(H(2)O)(6)](C(10)H(4)O(8)), (I), and pentaaqua[benzene-1,2,4,5-tetracarboxylato(2-)]barium(II), [Ba(C(10)H(4)O(8))(H(2)O)(5)], (II), are both centrosymmetric and both possess a 1:1 metal-ligand ratio, but the two structures are found to differ in that the magnesium salt contains a hexaaqua cation and possesses only hydrogen-bonding interactions between cations and anions, while the barium salt exhibits coordination of the carboxylate ligand to the nine-coordinate metal centre. In (I), both ions sit on a 2/m site symmetry, and in (II), the cation and anion are located on m and i site symmetries, respectively.

  11. Infrared band intensities and global warming potentials of CF4, C2F6, C3F8, C4F10, C5F12, and C6F14

    NASA Astrophysics Data System (ADS)

    Roehl, C. M.; Boglu, D.; Brühl, C.; Moortgat, G. K.

    1995-04-01

    IR band intensities have been measured for the species: CF4, C2F6, C3F8, C4F10, C5F12, and C6F14 via Fourier transform spectroscopy and compared to previous literature values if available. Relative radiative forcing calculations have been performed using these data in order to determine the global warming potential of the particular species. The relative forcing (compared to CFC11, per volume) increases with molecular weight in the above series from 0.47 to 2.1, the GWP for a time horizon of 100 yrs from 1.1 to 4.7. This corresponds to a GWP on CO2 basis per mass of about 5000.

  12. Discovery of a high-z protocluster with tunable filters: the case of 6C0140+326 at z= 4.4

    NASA Astrophysics Data System (ADS)

    Kuiper, E.; Hatch, N. A.; Venemans, B. P.; Miley, G. K.; Röttgering, H. J. A.; Kurk, J. D.; Overzier, R. A.; Pentericci, L.; Bland-Hawthorn, J.; Cepa, J.

    2011-10-01

    We present the first results obtained using a tunable narrow-band filter in the search for high-z protoclusters. Using the recently commissioned red tunable filter on the Gran Telescopio Canarias, we have searched for Lyα emitters in a 75 arcmin2 field centred on the z= 4.413 radio galaxy 6C0140+326. With three different wavelength tunings, we find a total of 27 unique candidate Lyα emitters. The availability of three different wavelength tunings allows us to make estimates of the redshifts for each of the objects. It also allows us to separate a possible protocluster from a structure in the immediate foreground. This division shows that the foreground region contains significantly fewer Lyα emitters. Also, the spatial distribution of the objects in the protocluster field deviates from a random distribution at the 2.5σ level. The observed redshift distribution of the emitters is different from the expected distribution of a blank field at the ˜3σ level, with the Lyα emitters concentrated near the radio galaxy at z > 4.38. The 6C0140+326 field is denser by a factor of 9 ± 5 than a blank field, and the number density of Lyα emitters close to the radio galaxy is similar to that of the z˜ 4.1 protocluster around TN J1338-1942. We thus conclude that there is an overdensity of Lyα emitters around the radio galaxy 6C0140+326. This is one of few known overdensities at such a high redshift.

  13. Relative Apoptosis-inducing Potential of Homeopa-thic Condurango 6C and 30C in H460 Lung Cancer Cells In vitro

    PubMed Central

    Sikdar, Sourav; Kumar Saha, Santu; Rahman Khuda-Bukhsh, Anisur

    2014-01-01

    Objectives: In homeopathy, it is claimed that more homeopathically-diluted potencies render more protective/curative effects against any disease condition. Potentized forms of Condurango are used successfully to treat digestive problems, as well as esophageal and stomach cancers. However, the comparative efficacies of Condurango 6C and 30C, one diluted below and one above Avogadro’s limit (lacking original drug molecule), respectively, have not been critically analyzed for their cell-killing (apoptosis) efficacy against lung cancer cells in vitro, and signalling cascades have not been studied. Hence, the present study was undertaken. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT) assays were conducted on H460-non-small-cell lung cancer (NSCLC) cells by using a succussed ethyl alcohol vehicle (placebo) as a control. Studies on cellular morphology, cell cycle regulation, generation of reactive oxygen species (ROS), changes in mitochondrial membrane potential (MMP), and DNA-damage were made, and expressions of related signaling markers were studied. The observations were done in a “blinded” manner. Results: Both Condurango 6C and 30C induced apoptosis via cell cycle arrest at subG0/G1 and altered expressions of certain apoptotic markers significantly in H460 cells. The drugs induced oxidative stress through ROS elevation and MMP depolarization at 18-24 hours. These events presumably activated a caspase-3-mediated signalling cascade, as evidenced by reverse transcriptase- polymerase chain reaction (RT-PCR), western blot and immunofluorescence studies at a late phase (48 hours) in which cells were pushed towards apoptosis. Conclusion: Condurango 30C had greater apoptotic effect than Condurango 6C as claimed in the homeopathic doctrine. PMID:25780691

  14. Volumetric Properties of the Mixture Benzene C6H6 + C7H8O Methyl phenyl ether (VMSD1412, LB4561_V)

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C7H8O Methyl phenyl ether (VMSD1412, LB4561_V)' providing data by calculation of isentropic compressibility from low-pressure density and thermodynamic speed of sound data at variable mole fraction and constant temperature, in the single-phase region(s).

  15. Volumetric Properties of the Mixture Benzene C6H6 + C10H7Cl 1-Chloronaphthalene (VMSD1511, LB4811_V)

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C10H7Cl 1-Chloronaphthalene (VMSD1511, LB4811_V)' providing data from direct measurement of low-pressure thermodynamic speed of sound at variable mole fraction and constant temperature, in the single-phase region(s).

  16. Volumetric Properties of the Mixture Benzene C6H6 + C7H8O Methyl phenyl ether (VMSD1511, LB4555_V)

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C7H8O Methyl phenyl ether (VMSD1511, LB4555_V)' providing data from direct measurement of low-pressure thermodynamic speed of sound at variable mole fraction and constant temperature, in the single-phase region(s).

  17. Volumetric Properties of the Mixture Benzene C6H6 + C6H10O Cyclohexanone (VMSD1111, LB4819_V0029

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C6H10O Cyclohexanone (VMSD1111, LB4819_V)' providing data from direct low-pressure measurement of mass density at variable mole fraction and constant temperature, in the single-phase region(s).

  18. Volumetric Properties of the Mixture Benzene C6H6 + C6H10O Cyclohexanone (VMSD1511, LB4829_V)

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C6H10O Cyclohexanone (VMSD1511, LB4829_V)' providing data from direct measurement of low-pressure thermodynamic speed of sound at variable mole fraction and constant temperature, in the single-phase region(s).

  19. Volumetric Properties of the Mixture Benzene C6H6 + C6H10O Cyclohexanone (VMSD1212, LB4824_V)

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C6H10O Cyclohexanone (VMSD1212, LB4824_V)' providing data by calculation of molar excess volume from low-pressure density measurements at variable mole fraction and constant temperature.

  20. Total electron-scattering cross sections for CHF3, C2F6, C3F8, and c-C4F8

    NASA Astrophysics Data System (ADS)

    Sanabia, Jason E.; Cooper, Gregory D.; Tossell, John A.; Moore, John H.

    1998-01-01

    The total electron-scattering cross section has been measured for 0-20 eV electrons incident upon CHF3, C2F6, C3F8, and cyclo-C4F8. The cross sections all have a broad maximum for electron energies near 9 eV, with more or less sharper peaks attributed to temporary-negative ion resonances at lower energies. For the linear molecules a resonance in the 3-6 eV range is associated with electron capture into the lowest unoccupied orbital. The shape of the cross section for the cyclic compound implies a stable ground-state negative ion.

  1. Toxicology and Carcinogenesis Studies of Mercuric Chloride (CAS No. 7487-94-7) in F344 Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1993-02-01

    Mercuric chloride is an inorganic compound that has been used in agriculture as a fungicide, in medicine as a topical antiseptic and disinfectant, and in chemistry as an intermediate in the production of other mercury compounds. The widespread use of mercury has resulted in increased levels of mercury in rivers and lakes. Mercuric chloride was evaluated in toxicity and carcinogenicity studies because of its extensive use and its occurrence as an environmental pollutant, and because of the lack of adequate long-term rodent studies. Toxicology and carcinogenesis studies were conducted by administering mercuric chloride (greater than 99% pure) in deionized water by gavage to groups of F344 rats or B6C3F1 mice for 16 days, 6 months, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537), in mouse lymphoma L5178Y cells, in Chinese hamster ovary cells, and in Drosophila melanogaster. 16-DAY STUDIES: Groups of five rats of each sex received 0, 1.25, 2.5, 5, 10, or 20 mg mercuric chloride/kg body weight and groups of five mice of each sex received 0, 5, 10, 20, 40, or 80 mg/kg in deionized water by gavage for 12 dose days. Two male rats in the 20 mg/kg group died in the first week, as did all male and four female mice from the 80 mg/kg group and one male mouse from the 40 mg/kg group. The final mean body weight of male rats receiving 20 mg/kg was 10% lower than that of the controls; the final mean body weight of 20 mg/kg females was 9% lower than that of the controls. Final mean body weights and body weight gains of dosed mice were similar to those of the controls. Absolute and relative kidney weights of male rats receiving 2.5 mg/kg or greater doses and of female rats administered 5 mg/kg or more were significantly greater than those of the controls. Absolute kidney weights of mice were significantly increased in all male dose groups and in the 40 mg/kg female dose group; relative kidney weights of dosed

  2. Structural Determination of Functional Domains in Early B-cell Factor (EBF) Family of Transcription Factors Reveals Similarities to Rel DNA-binding Proteins and a Novel Dimerization Motif*

    PubMed Central

    Siponen, Marina I.; Wisniewska, Magdalena; Lehtiö, Lari; Johansson, Ida; Svensson, Linda; Raszewski, Grzegorz; Nilsson, Lennart; Sigvardsson, Mikael; Berglund, Helena

    2010-01-01

    The early B-cell factor (EBF) transcription factors are central regulators of development in several organs and tissues. This protein family shows low sequence similarity to other protein families, which is why structural information for the functional domains of these proteins is crucial to understand their biochemical features. We have used a modular approach to determine the crystal structures of the structured domains in the EBF family. The DNA binding domain reveals a striking resemblance to the DNA binding domains of the Rel homology superfamily of transcription factors but contains a unique zinc binding structure, termed zinc knuckle. Further the EBF proteins contain an IPT/TIG domain and an atypical helix-loop-helix domain with a novel type of dimerization motif. The data presented here provide insights into unique structural features of the EBF proteins and open possibilities for detailed molecular investigations of this important transcription factor family. PMID:20592035

  3. Analysis of a pair of END+ and END− viruses derived from the same bovine viral diarrhea virus stock reveals the amino acid determinants in Npro responsible for inhibition of type I interferon production

    PubMed Central

    KOZASA, Takashi; ABE, Yuri; MITSUHASHI, Kazuya; TAMURA, Tomokazu; AOKI, Hiroshi; ISHIMARU, Masatoshi; NAKAMURA, Shigeyuki; OKAMATSU, Masatoshi; KIDA, Hiroshi; SAKODA, Yoshihiro

    2014-01-01

    The Exaltation of Newcastle disease virus (END) phenomenon is induced by the inhibition of type I interferon in pestivirus-infected cells in vitro, via proteasomal degradation of cellular interferon regulatory factor (IRF)-3 with the property of the viral autoprotease protein Npro. Reportedly, the amino acid residues in the zinc-binding TRASH motif of Npro determine the difference in characteristics between END-phenomenon-positive (END+) and END-phenomenon-negative (END−) classical swine fever viruses (CSFVs). However, the basic mechanism underlying this function in bovine viral diarrhea virus (BVDV) has not been elucidated from the genomic differences between END+ and END− viruses using reverse genetics till date. In the present study, comparison of complete genome sequences of a pair of END+ and END− viruses isolated from the same virus stock revealed that there were only four amino acid substitutions (D136G, I2623V, D3148G and D3502Y) between two viruses. Based on these differences, viruses with and without mutations at these positions were generated using reverse genetics. The END assay, measurements of induced type I interferon and IRF-3 detection in cells infected with these viruses revealed that the aspartic acid at position 136 in the zinc-binding TRASH motif of Npro was required to inhibit the production of type I interferon via the degradation of cellular IRF-3, consistently with CSFV. PMID:25648277

  4. Analysis of a pair of END+ and END- viruses derived from the same bovine viral diarrhea virus stock reveals the amino acid determinants in Npro responsible for inhibition of type I interferon production.

    PubMed

    Kozasa, Takashi; Abe, Yuri; Mitsuhashi, Kazuya; Tamura, Tomokazu; Aoki, Hiroshi; Ishimaru, Masatoshi; Nakamura, Shigeyuki; Okamatsu, Masatoshi; Kida, Hiroshi; Sakoda, Yoshihiro

    2015-05-01

    The Exaltation of Newcastle disease virus (END) phenomenon is induced by the inhibition of type I interferon in pestivirus-infected cells in vitro, via proteasomal degradation of cellular interferon regulatory factor (IRF)-3 with the property of the viral autoprotease protein N(pro). Reportedly, the amino acid residues in the zinc-binding TRASH motif of N(pro) determine the difference in characteristics between END-phenomenon-positive (END(+)) and END-phenomenon-negative (END(-)) classical swine fever viruses (CSFVs). However, the basic mechanism underlying this function in bovine viral diarrhea virus (BVDV) has not been elucidated from the genomic differences between END(+) and END(-) viruses using reverse genetics till date. In the present study, comparison of complete genome sequences of a pair of END(+) and END(-) viruses isolated from the same virus stock revealed that there were only four amino acid substitutions (D136G, I2623V, D3148G and D3502Y) between two viruses. Based on these differences, viruses with and without mutations at these positions were generated using reverse genetics. The END assay, measurements of induced type I interferon and IRF-3 detection in cells infected with these viruses revealed that the aspartic acid at position 136 in the zinc-binding TRASH motif of N(pro) was required to inhibit the production of type I interferon via the degradation of cellular IRF-3, consistently with CSFV.

  5. Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water.

    PubMed

    Cullen, John M; Ward, Jerrold M; Thompson, Chad M

    2016-02-01

    Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response.

  6. Salivaricin D, a Novel Intrinsically Trypsin-Resistant Lantibiotic from Streptococcus salivarius 5M6c Isolated from a Healthy Infant

    PubMed Central

    Birri, Dagim Jirata; Brede, Dag Anders

    2012-01-01

    In this work, we purified and characterized a newly identified lantibiotic (salivaricin D) from Streptococcus salivarius 5M6c. Salivaricin D is a 34-amino-acid-residue peptide (3,467.55 Da); the locus of the gene encoding this peptide is a 16.5-kb DNA segment which contains genes encoding the precursor of two lantibiotics, two modification enzymes (dehydratase and cyclase), an ABC transporter, a serine-like protease, immunity proteins (lipoprotein and ABC transporters), a response regulator, and a sensor histidine kinase. The immunity gene (salI) was heterologously expressed in a sensitive indicator and provided significant protection against salivaricin D, confirming its immunity function. Salivaricin D is a naturally trypsin-resistant lantibiotic that is similar to nisin-like lantibiotics. It is a relatively broad-spectrum bacteriocin that inhibits members of many genera of Gram-positive bacteria, including the important human pathogens Streptococcus pyogenes and Streptococcus pneumoniae. Thus, Streptococcus salivarius 5M6c may be a potential biological agent for the control of oronasopharynx-colonizing streptococcal pathogens or may be used as a probiotic bacterium. PMID:22101034

  7. A comparative study on dynamic stiffness in typical finite element model and multi-body model of C6-C7 cervical spine segment.

    PubMed

    Wang, Yawei; Wang, Lizhen; Du, Chengfei; Mo, Zhongjun; Fan, Yubo

    2016-06-01

    In contrast to numerous researches on static or quasi-static stiffness of cervical spine segments, very few investigations on their dynamic stiffness were published. Currently, scale factors and estimated coefficients were usually used in multi-body models for including viscoelastic properties and damping effects, meanwhile viscoelastic properties of some tissues were unavailable for establishing finite element models. Because dynamic stiffness of cervical spine segments in these models were difficult to validate because of lacking in experimental data, we tried to gain some insights on current modeling methods through studying dynamic stiffness differences between these models. A finite element model and a multi-body model of C6-C7 segment were developed through using available material data and typical modeling technologies. These two models were validated with quasi-static response data of the C6-C7 cervical spine segment. Dynamic stiffness differences were investigated through controlling motions of C6 vertebrae at different rates and then comparing their reaction forces or moments. Validation results showed that both the finite element model and the multi-body model could generate reasonable responses under quasi-static loads, but the finite element segment model exhibited more nonlinear characters. Dynamic response investigations indicated that dynamic stiffness of this finite element model might be underestimated because of the absence of dynamic stiffen effect and damping effects of annulus fibrous, while representation of these effects also need to be improved in current multi-body model. Copyright © 2015 John Wiley & Sons, Ltd.

  8. Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water

    PubMed Central

    Cullen, John M.; Ward, Jerrold M.

    2015-01-01

    Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. PMID:26538584

  9. Magnetic Field-Induced Precipitation Behaviors of Alloy Carbides M2C, M3C, and M6C in a Molybdenum-Containing Steel

    NASA Astrophysics Data System (ADS)

    Hou, T. P.; Li, Y.; Zhang, Y. D.; Wu, K. M.

    2014-05-01

    The effect of a 12-T high magnetic field on alloy carbide precipitation in an Fe-C-Mo alloy during tempering at an intermediate temperature was investigated. Thin foils and carbon extraction replicas of the treated specimens were examined by transmission electron microscopy (TEM). The results show that the applied high field effectively promoted the precipitation of (Fe,Mo)6C alloy carbide. The concentration of Fe atom in Fe6- x Mo x C carbide is increased whereas that of Mo atom decreased when the high magnetic field was applied. However, the high magnetic field almost had no detectable influence on the atom concentration in (Fe,Mo)2C and (Fe,Mo)3C carbides. First principle calculations have been performed to calculate the magnetic moment per iron atom of the carbides to explore the origin of the effect of the magnetic field. The influence of the high magnetic field on the precipitation behaviors of alloy carbides was closely related to the magnetic moment of (Fe,Mo)2C, (Fe,Mo)3C, and (Fe,Mo)6C. The magnetic field promotes the formation of the carbides with high total magnetic moment. The effect of the high magnetic field on the substitutional solute atom (Fe and Mo) concentration change in the three alloy carbides was attributed to their magnetization differences per Fe atom.

  10. MIF Promotes Classical Activation and Conversion of Inflammatory Ly6C(high) Monocytes into TipDCs during Murine Toxoplasmosis.

    PubMed

    Ruiz-Rosado, Juan de Dios; Olguín, Jonadab E; Juárez-Avelar, Imelda; Saavedra, Rafael; Terrazas, Luis I; Robledo-Avila, Frank H; Vazquez-Mendoza, Alicia; Fernández, Jacquelina; Satoskar, Abhay R; Partida-Sánchez, Santiago; Rodriguez-Sosa, Miriam

    2016-01-01

    Macrophage migration inhibitory factor (MIF) mediates immunity against Toxoplasma gondii infection by inducing inflammatory cytokines required to control the parasite replication. However, the role of this inflammatory mediator in the cell-mediated immune response against this infection is still poorly understood. Here, we used T. gondii-infected WT and Mif (-/-) mice to analyze the role of MIF in the maturation of CD11b(+) and CD8α (+) dendritic cells (DCs). We found that MIF promotes maturation of CD11b(+) but not CD8α (+) DCs, by inducing IL-12p70 production and CD86 expression. Infected Mif (-/-) mice showed significantly lower numbers of TNF and inducible nitric oxide synthase- (iNOS-) producing DCs (TipDCs) compared to infected WT mice. The adoptive transfer of Ly6C(high) monocytes into infected WT or Mif (-/-) mice demonstrated that MIF participates in the differentiation of Ly6C(high) monocytes into TipDCs. In addition, infected Mif (-/-) mice display a lower percentage of IFN-γ-producing natural killer (NK) cells compared to WT mice, which is associated with reducing numbers of TipDCs in Mif (-/-) mice. Furthermore, administration of recombinant MIF (rMIF) into T. gondii-infected Mif (-/-) mice restored the numbers of TipDCs and reversed the susceptible phenotype of Mif (-/-) mice. Collectively, these results demonstrate an important role for MIF inducing cell-mediated immunity to T. gondii infection.

  11. A CHRONIC INHALATION STUDY OF METHYL BROMIDE TOXICITY IN B6C3F1 MICE. (FINAL REPORT TO THE NATIONAL TOXICOLOGY PROGRAM)

    SciTech Connect

    HABER, S.B.

    1987-06-26

    This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.

  12. Degradation of Swainsonine by the NADP-Dependent Alcohol Dehydrogenase A1R6C3 in Arthrobacter sp. HW08

    PubMed Central

    Wang, Yan; Zhai, A’guan; Zhang, Yanqi; Qiu, Kai; Wang, Jianhua; Li, Qinfan

    2016-01-01

    Swainsonine is an indolizidine alkaloid that has been found in locoweeds and some fungi. Our previous study demonstrated that Arthrobacter sp. HW08 or its crude enzyme extract could degrade swainsonie efficiently. However, the mechanism of swainsonine degradation in bacteria remains unclear. In this study, we used label-free quantitative proteomics method based on liquid chromatography-electrospray ionization-tandem mass spectrometry to dissect the mechanism of swainsonine biodegradation by Arthrobacter sp. HW08. The results showed that 129 differentially expressed proteins were relevant to swainsonine degradation. These differentially expressed proteins were mostly related to the biological process of metabolism and the molecular function of catalytic activity. Among the 129 differentially expressed proteins, putative sugar phosphate isomerase/epimerase A1R5X7, Acetyl-CoA acetyltransferase A0JZ95, and nicotinamide adenine dinucleotide phosphate (NADP)-dependent alcohol dehydrogenase A1R6C3 were found to contribute to the swainsonine degradation. Notably, NADP-dependent alcohol dehyrodgenase A1R6C3 appeared to play a major role in degrading swainsonine, but not as much as Arthrobacter sp. HW08 did. Collectively, our findings here provide insights to understand the mechanism of swainsonine degradation in bacteria. PMID:27196926

  13. Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.

    PubMed

    Guo, Tai L; Germolec, Dori R; Collins, Bradley J; Luebke, Robert W; Auttachoat, Wimolnut; Smith, Matthew J; White, Kimber L

    2011-01-01

    Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm.

  14. Urethral carcinoma and hyperplasia in male and female B6C3F1 mice treated with 3,3′,4,4′- Tetrachloroazobenzene (TCAB)

    PubMed Central

    Singh, BP; Nyska, A; Kissling, GE; Lieuallen, W; Johansson, SL; Malarkey, DE; Hooth, MJ

    2010-01-01

    B6C3F1 mice chronically exposed to 3,3′,4,4′-tetrachloroazobenzene (TCAB), a contaminant of dichloroaniline-derived herbicides, developed a number of neoplastic and nonneoplastic lesions including carcinoma of the urinary tract. Groups of 50 male and 50 female B6C3F1 mice were exposed by gavage to TCAB at dose levels of 0, 3, 10 and 30 mg/kg 5 days a week for 2 years. Control animals received corn oil:acetone (99:1) vehicle. Decreased survival of male mice in the mid-dose group and of male and female mice in the high dose groups was mainly related to the occurrence of urethral transitional cell (urothelial) carcinoma and resulting urinary obstruction. Increased urethral transitional cell carcinomas were seen in all treated male groups in a dose-related manner as well as in the females treated with 30 mg/kg TCAB. Administration of TCAB was also associated with increased transitional cell hyperplasia of the urethra. Most nonneoplastic lesions of the urogenital tract were considered secondary to local invasion and urinary obstruction by the urethral transitional cell carcinomas. The mechanism of tumor induction is uncertain but the high frequency of tumors in the proximal urethra of male mice suggests that the neoplasms result from the exposure of a susceptible population of urothelial cells to a carcinogenic metabolite of TCAB. PMID:20233943

  15. Amination of the pyridinium cations in betaines. Synthesis of substituted pyrimido(5,6-c)-1'-azaquinolizine and its dihydro analogs

    SciTech Connect

    Kochkanyan, R.O.; Lukanyuk, S.S.

    1987-11-01

    The pyridinium cations within betaines can be aminated under mild conditions with aqueous ammonia, ultimately undergoing cyclization to a new tricyclic system: 4-substituted-3,5-dioxopyrimido(5,6-c)-1'-azaquinolizine. Intermediates in the reaction are 4-substituted-3,5-dioxo-2,2-dihydropyrimido(5,6-c)-6H-1'-quinolizines. Formation of the methylene group is coupled with transfer of an atom of hydrogen or deuterium from the ..cap alpha..-carbon of the dihydropyridine in compound II to the carbon atom of the azomethine group. The NMR spectrum is represented by the methylene proton signal (3.96 ppm) and by the multiplets of the pyridine and phenyl protons centered at 7.63 and 6.38 ppm respectively. Upon chloranil oxidation, and upfield shift of the pyridine protons is observed: the ..cap alpha..-proton forms a doublet (10.05 ppm, J= 6 Hz), the ..beta..-protons form a doublet and a triplet with centers at 8.57 (J = 8 Hz) and 8.22 (J = 7 Hz) ppm respectively, and the ..gamma..-proton forms a triplet at 8.8 (J = 7 Hz) ppm.

  16. Traumatic posterior atlantooccipital dislocation with Jefferson fracture and fracture-dislocation of C6-C7: a case report with survival.

    PubMed

    Park, J B; Ha, K Y; Chang, H

    2001-12-01

    Atlantooccipital dislocation (AOD) is a rare and usually fatal injury. In the current study, the authors reported an extremely rare case of posterior AOD with Jefferson fracture and fracture-dislocation of C6-C7. The patient survived the injury and had only incomplete quadriplegia below the C7 segment with anterior cord syndrome. He was successfully managed with in situ occipitocervical fusion using the Cotrel-Dubousset rod system, corpectomy of C6, and anterior interbody fusion of C5-C7 with plating. To our knowledge, this is the first report of posterior AOD with two other non-contiguous cervical spine injuries. A high index of suspicion and careful examination of the upper cervical spine should be considered as the key to the diagnosis of AOD in cases that involve multiple or lower cervical spine injuries.

  17. An overview of hazard and risk assessment of the OECD high production volume chemical category--long chain alcohols [C(6)-C(22)] (LCOH).

    PubMed

    Sanderson, Hans; Belanger, Scott E; Fisk, Peter R; Schäfers, Christoph; Veenstra, Gauke; Nielsen, Allen M; Kasai, Yutaka; Willing, Andreas; Dyer, Scott D; Stanton, Kathleen; Sedlak, Richard

    2009-05-01

    This review summarizes the findings of the assessment report for the category, long chain alcohols (LCOH) with a carbon chain length range of C(6)-C(22) covering 30 substances, and >1.5million tonnes/year consumed globally. The category was evaluated under the Organization for Economic Co-operation and Development (OECD) high production volume chemicals program in 2006. The main findings of the assessment include: (1) no unacceptable human or environmental risks were identified; (2) these materials are rapidly and readily biodegradable; (3) a parabolic relationship was demonstrated between carbon chain length and acute and chronic aquatic toxicity; (4) category-specific (quantitative) structure-activity relationships were developed enabling prediction of properties across the entire category; (5) LCOH occur naturally in the environment in an equilibrium between synthesis and degradation; (6) industry coming together and sharing resources results in minimizing the need for additional animal tests, produces cost savings, and increases scientific quality of the assessment.

  18. NTP Toxicology and Carcinogenesis Studies of Ethylene Oxide (CAS No. 75-21-8) in B6C3F1 Mice (Inhalation Studies).

    PubMed

    1987-11-01

    Ethylene oxide is a major industrial chemical used primarily as an intermediate in the manufacture of other chemicals; e.g., ethylene glycol, a major component of automotive and other antifreeze products. Exposure to ethylene oxide is greatest in the health care industry, where an estimated 75,000 workers are potentially exposed. Ethylene oxide was nominated for toxicology and carcinogenesis studies in B6C3F1 mice because of its extensive production; the potential for human exposure in the workplace, from medical devices, or from food; the positive results of genetic toxicology assays; and the previous use of only F344/N rats in inhalation carcinogenicity studies. Two inhalation studies reported in 1984 by Snellings et al. and by Lynch et al. demonstrated carcinogenic responses in F344/N rats. Results were similar in both studies and consisted of increased incidences of mononuclear cell leukemia, peritoneal mesotheliomas, and primary brain tumors. Experimental Design: Toxicology and carcinogenesis studies of ethylene oxide (greater than 99% pure) were conducted by exposing groups of 50 B6C3F1 mice of each sex to air containing 0, 50, or 100 ppm ethylene oxide, 6 hours per day, 5 days per week for 102 weeks. These doses were selected because, in 14-week studies, all mice exposed at 600 ppm died within 1 week, and all mice exposed at 400 ppm died by week 4. Rhinitis was observed in both sexes exposed at 200, 400, and 600 ppm as was renal tubular degeneration in both sexes at 100, 200, and 400 ppm. The latter effects observed at 100 ppm were slight and deemed not to be life threatening in 2-year studies. Two-Year Studies: Survival of exposed and control mice was comparable in the 2-year studies (male: control, 28/50; low dose, 31/50; high dose, 34/50; female: 25/50; 24/50;31/50). Final mean body weights in exposed mice were 95%-102% of those of the controls. No compound-related clinical signs were observed. Those neoplastic lesions that occurred at elevated incidences

  19. Cloning of a Novel 6-Chloronicotinic Acid Chlorohydrolase from the Newly Isolated 6-Chloronicotinic Acid Mineralizing Bradyrhizobiaceae Strain SG-6C

    PubMed Central

    Pandey, Rinku; Khan, Fazlurrahman; Dorrian, Susan J.; Balotra, Sahil; Russell, Robyn J.; Oakeshott, John G.; Pandey, Gunjan

    2012-01-01

    A 6-chloronicotinic acid mineralizing bacterium was isolated from enrichment cultures originating from imidacloprid-contaminated soil samples. This Bradyrhizobiaceae, designated strain SG-6C, hydrolytically dechlorinated 6-chloronicotinic acid to 6-hydroxynicotinic acid, which was then further metabolised via the nicotinic acid pathway. This metabolic pathway was confirmed by growth and resting cell assays using HPLC and LC-MS studies. A candidate for the gene encoding the initial dechlorination step, named cch2 (for 6-chloronicotinic acid chlorohydrolase), was identified using genome sequencing and its function was confirmed using resting cell assays on E. coli heterologously expressing this gene. The 464 amino acid enzyme was found to be a member of the metal dependent hydrolase superfamily with similarities to the TRZ/ATZ family of chlorohydrolases. We also provide evidence that cch2 was mobilized into this bacterium by an Integrative and Conjugative Element (ICE) that feeds 6-hydroxynicotinic acid into the existing nicotinic acid mineralization pathway. PMID:23226482

  20. Renal Cell Carcinomas in Vinylidene Chloride Exposed Male B6C3F1 Mice Are Characterized by Oxidative Stress and TP53 Pathway Dysregulation

    PubMed Central

    Hayes, Schantel A.; Pandiri, Arun R.; Ton, Thai-vu T.; Hong, Hue-Hua L.; Clayton, Natasha P.; Shockley, Keith R.; Peddada, Shyamal D.; Gerrish, Kevin; Wyde, Michael; Sills, Robert C.; Hoenerhoff, Mark J.

    2015-01-01

    Vinylidene Chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, adenoma, and carcinoma (RCCs). Among those differentially expressed genes between controls and RCC from VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress, as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice. PMID:26682919

  1. Mapping of the Locus for Cholestasis-Lymphedema Syndrome (Aagenaes Syndrome) to a 6.6-cM Interval on Chromosome 15q

    PubMed Central

    Bull, Laura N.; Roche, Erin; Song, Eyun J.; Pedersen, Jan; Knisely, A. S.; van der Hagen, C. B.; Eiklid, Kristin; Aagenaes, Øystein; Freimer, Nelson B.

    2000-01-01

    Patients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979–D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor. PMID:10968776

  2. Benzene metabolite levels in blood and bone marrow of B6C3F{sub 1} mice after low-level exposure

    SciTech Connect

    Bechtold, W.E.; Strunk, M.R.; Thornton-Manning, J.R.

    1995-12-01

    Studies at the Inhalation Toxicology Research Institute (ITRI) have explored the species-specific uptake and metabolism of benzene. Results have shown that metabolism is dependent on both dose and route of administration. Of particular interest were shifts in the major metabolic pathways as a function of exposure concentration. In these studies, B6C3F{sub 1} mice were exposed to increasing levels of benzene by either gavage or inhalation. As benzene internal dose increased, the relative amounts of muconic acid and hydroquinone decreased. In contrast, the relative amount of catechol increased with increasing exposure. These results show that the relative levels of toxic metabolites are a function of exposure level. Based on these results and assuming a linear relationship between exposure concentration and levels of bone marrow metabolites, it would be difficult to detect an elevation of any phenolic metabolites above background after occupational exposures to the OSHA Permissible Exposure Limit of 1 ppm benzene.

  3. A family of single-isomer, dicationic cyclodextrin chiral selectors for capillary electrophoresis: mono-6(A)-ammonium-6(C)-butylimidazolium-β-cyclodextrin chlorides.

    PubMed

    Dai, Yun; Wang, Shuye; Zhou, Jie; Tang, Jian; Tang, Weihua

    2013-03-01

    The first member of the single-isomer, dicationic cyclodextrin (CD) family, 6(A)-ammonium-6(C)-butylimidazolium-β-cyclodextrin chlorides (AMBIMCD), has been synthesized, analytically characterized, and used to separate a variety of acidic enantiomers and amino acids by CE. Starting from mono-6(A)-azido-β-cyclodextrin, the cationic imidazolium and ammonium moieties were subsequently introduced onto primary ring of β-cyclodextrin via nucleophilic addition and Staudinger reaction. The analytically pure AC regio-isomer CD was further obtained via column chromatography. This dicationic CD exhibited excellent enantioselectivities for selected analytes at concentration as low as 0.5 mM, which were even better than those of its mono-imidazolium or ammonium-substitued counterpart CDs at 10 equivalent concentrations. The effective mobilities of all studied analytes were found to decrease with the concentration of AMBIMCD. Inclusion complexation in combination with eletrostatic interactions seemed to account for the enhanced chiral discrimination process.

  4. Dissociation Cross Sections for C2F6, c-C4F8, C3F8, CHF3, and TEOS

    NASA Astrophysics Data System (ADS)

    Morgan, W. L.

    1999-10-01

    Extensive use is made of beam measurements, ab initio calculations, and electron swarm measurements in deriving total cross sections for dissociation of C_2F_6, c-C_4F_8, C_3F_8, CHF_3, and TEOS into neutral fragments. Use is made of a numerical optimization algorithm for scaling measured or computed cross sections and manipulating model cross sections in order to satisfy the measured electron transport data. These are molecules that are important in plasma processing because they readily dissociate into reactive radical fragments. Although swarm analyses cannot tell us what the specific radical fragments are, they can provide an accurate estimate of the cross section and, hence, rate coefficient for dissociation. Further details can be found on the KR&S Web site.

  5. Evaluation of the immunomodulatory effects of the disinfection by-product, sodium chlorite, in female B6C3F1 mice: a drinking water study.

    PubMed

    Karrow, N A; Guo, T L; McCay, J A; Johnson, G W; Brown, R D; Musgrove, D L; Germolec, D R; Luebke, R W; White, K L

    2001-08-01

    Sodium chlorite is an inorganic by-product of chlorine dioxide formed during the chlorination of drinking water. Relatively little is known about the adverse health effects of exposure to sodium chlorite in drinking water. In this study, we evaluated sodium chlorite's immunomodulatory properties using female B6C3F1 mice and a panel of immune assays that were designed to evaluate potential changes in innate and acquired cellular and humoral immune responses. Female B6C3F1 mice were exposed to sodium chlorite in their drinking water (0, 0.1, 1, 5, 15, and 30 mg/L) for 28 days, and then evaluated for immunomodulation. Overall, minimal toxicological and immunological changes were observed after exposure to sodium chlorite. Increases in the percentages of blood reticulocytes, and the relative spleen weights were both observed at different sodium chlorite treatment levels; however, these increases were not dose-dependent. An increasing trend in the number of spleen antibody-forming cells was observed over the range of sodium chlorite concentrations. This increase was not, however, significant at any individual treatment level, and was not reflected by changes in serum IgM levels. A significant increase (26%) in the total number of splenic CD8+ cells was observed in mice treated with 30 mg/L of sodium chlorite, but not at the other concentrations. Splenic mixed leukocyte response and peritoneal macrophage activity were unaffected by sodium chlorite. Lastly, exposure to sodium chlorite did not affect natural killer cell activity, although a decrease in augmented natural killer cell activity (42%) was observed at the lowest sodium chlorite treatment level. These results suggest that sodium chlorite, within the range 0.1-30 mg/L, produces minimal immunotoxicity in mice.

  6. Activation of H-ras oncogenes in male B6C3F1 mouse liver tumors induced by vinthionine or 2-chloroethyl-methyl sulfide.

    PubMed

    Sohn, Y W; Lee, G H; Liem, A; Miller, J A

    1996-06-01

    Vinthionine (S-vinyl-DL-homocysteine) is hepatocarcinogenic in rats and mice. [Vinyl-14C]vinthionine binds covalently to rat liver DNA, RNA and protein in vivo, but not in vitro. This amino acid is directly mutagenic in Salmonella typhimurium TA100 and TA1535; the mechanism of its metabolic activation in vivo in bacteria and liver is under study. In the present study liver tumors were induced in 12-day-old male B6C3F1 mice by single i.p. injections of vinthionine or the alkylating agent 2-chloroethyl methyl sulfide (CEMS). At 10 months the gross tumors were examined for the presence of activated H-ras oncogenes. DNA was isolated from single tumors per mouse from 37 mice treated with vinthionine and from 31 mice treated with CEMS. These DNAs were screened for codon 61 mutations by restriction fragment length polymorphism of PCR-amplified H-ras gene fragments. Thirty seven of 37 vinthionine-induced hepatomas had H-ras mutations in this codon, which consisted of seven C-->A transversions in the first base, with 29 A-->T transversions and one A-->G transition in the second base. Twenty five of 31 CEMS-induced hepatomas had mutations in the same codon, which consisted of seven C-->A transversions in the first base, with eight A-->T transversions and 10 A-->G transitions in the second base. These mutation spectra are quite different to that noted by others in spontaneous hepatomas in untreated B6C3F1 mice. These data appear to result from the covalent binding of these carcinogens to the liver DNA.

  7. Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice.

    PubMed

    Jorgenson, T A; Meierhenry, E F; Rushbrook, C J; Bull, R J; Robinson, M

    1985-08-01

    The carcinogenic activity of chloroform administered at 0, 200, 400, 900, and 1800 mg/liter in drinking water was studied in male Osborne-Mendel rats and female B6C3F1 mice. A second control group was included in the study and was restricted to the water consumption of the high-dose group. Animals were maintained on study for 104 weeks. Group sizes were adjusted at low doses such that a detectable tumor response would result at the lowest dose if there was a linear relationship with dose, and the higher doses produced responses similar to previous carcinogenesis bioassays of chloroform. The primary finding was that chloroform increased the yield of renal tubular adenomas and adenocarcinomas in male rats in a dose-related manner. For the high-dose group, which corresponded to a time-weighted average dose of 160 mg/kg per day for 104 weeks, there was a 14% incidence of renal tubular adenomas and adenocarcinomas, vs 1% in the control group. This compares to a 24% incidence observed when 180 mg/kg per day of chloroform was administered for 78 weeks in earlier studies. In contrast, chloroform in the drinking water of mice failed to increase the incidence of hepatocellular carcinomas in female B6C3F1 mice. The highest dose group received a time-weighted average dose of 263 mg/kg for 104 weeks, resulting in a 5% combined incidence of hepatocellular adenoma and carcinoma relative to a 6% incidence in the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. NTP Toxicology and Carcinogenesis Studies of Dichlorvos (CAS No. 62-73-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1989-09-01

    Toxicology and carcinogenesis studies of dichlorvos (99% pure), a contact and stomach poison for control of insects and parasites, were conducted by administering dichlorvos in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. Previous feed studies were done by the National Cancer Institute using Osborne-Mendel rats and B6C3F1 mice. Thirteen-Week Studies: Thirteen-week studies with groups of 10 rats of each sex were conducted at doses of 0, 2, 4, 8, 16, 32, or 64 mg/kg dichlorvos in corn oil. All rats that received 32 or 64 mg/kg dichlorvos and 4/10 females that received 16 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control rats were similar. Thirteen-week studies with groups of 10 mice of each sex were conducted at doses of 0, 5, 10, 20, 40, 80, or 160 mg/kg. All 10 male mice and 9/10 female mice that received 160 mg/kg and 5/10 male mice that received 80 mg/kg dichlorvos died before the end of the studies. Final mean body weights of dosed and vehicle control mice were similar. No compound-related gross or microscopic pathologic effects were observed in rats or mice. Two-year studies of dichlorvos were conducted by administering 0, 4, or 8 mg/kg dichlorvos, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex. Groups of 50 male B6C3F1 mice were administered 0, 10, or 20 mg/kg dichlorvos on the same schedule, and groups of 50 B6C3F1 female mice were administered 0, 20, or 40 mg/kg dichlorvos. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and vehicle control rats and mice were similar. No significant differences in survival were observed between any groups of rats or mice of either sex (rats--male: vehicle control, 31/50; low dose, 25/50; high dose, 24/50; female: 31/50; 26/50; 26/50; mice-- male: 35/50; 27/50; 29/50; female: 26/50; 29/50; 34/50). Neoplastic Effects in the Two-Year Studies: Adenomas of the exocrine pancreas

  9. Organically templated uranium(IV) fluorooxalates with layer structures: (H4TREN)[U2F6(C2O4)3].4H2O (TREN = tris(2-aminoethyl)amine) and (H4APPIP)[U2F6(C2O4)3].4H2O (APPIP = 1,4-bis(3-amino-propyl)piperazine).

    PubMed

    Wang, Chih-Min; Wu, Yi-Ying; Chen, Pei-Lin; Lii, Kwang-Hwa

    2007-03-14

    Two organically-templated layered uranium(IV) fluorooxalates, (H(4)TREN)[U(2)F(6)(C(2)O(4))(3)].4H(2)O (1) (TREN = tris(2-aminoethyl)amine) and (H(4)APPIP)[U(2)F(6)(C(2)O(4))(3)].4H(2)O (2) (APPIP = 1,4-bis(3-aminopropyl)piperazine), have been synthesized by hydrothermal methods and structurally characterized by single-crystal X-ray diffraction, thermogravimetric analysis, and magnetic susceptibility. Both structures consist of anionic [U(2)F(6)(C(2)O(4))(3)](4-) layers separated by organic ammonium cations and lattice water molecules. The UF(3)O(6) polyhedra are connected by oxalate ligands in different ways within the layers. They are the first examples of organically-templated uranium fluorooxalates. Crystal data for compound 1 follow: monoclinic, P2(1)/c (No. 14), a = 19.1563(5) A, b = 8.9531(2) A, c = 16.6221(4) A, beta = 114.633(1) degrees, and Z = 4. Crystal data for compound are the same as those for 1 except a = 10.3309(8) A, b = 15.564(1) A, c = 17.537(1) A, and beta = 95.430(4) degrees.

  10. Non-Linear Thermal Lens Signal of the (Δυ = 6) C-H Vibrational Overtone of Benzene in Liquid Solutions of Hexane

    NASA Astrophysics Data System (ADS)

    Nyaupane, Parashu R.; Manzanares, Carlos

    2016-06-01

    The thermal lens technique is applied to vibrational overtone spectroscopy of solutions of benzene. The pump and probe thermal lens technique has been found to be very sensitive for detecting samples of low concentration in transparent solvents. The C-H fifth vibrational (Δυ = 6) overtone spectrum of benzene is detected at room temperature for compositions per volume in the range (1 to 1× 10-4) using n-C_6H14 as the solvent. By detecting the absorption band in a 100 ppm solution, the peak absorption of the signal is approximately (2.2 ± 0.3)× 10-7 cm-1. The parameters that determine the magnitude of the thermal lens signal such as the pump laser power and the thermodynamic properties of the solvent and solute are discussed. A plot of normalized integrated intensity as a function of composition of benzene in solution reveals a non-linear behavior. The non-linearity cannot be explained assuming solvent enhancement at low concentrations. A two color absorption model that includes the simultaneous absorption of the pump and probe lasers could explain the enhanced magnitude and the non-linear behavior of the thermal lens signal for solutions of composition below 0.01.

  11. Fine precipitation scenarios of AlZnMg(Cu) alloys revealed by advanced atomic-resolution electron microscopy study Part I: Structure determination of the precipitates in AlZnMg(Cu) alloys

    SciTech Connect

    Liu, J.Z.; Chen, J.H.; Yuan, D.W.; Wu, C.L.; Zhu, J.; Cheng, Z.Y.

    2015-01-15

    Although they are among the most important precipitation-hardened materials for industry applications, the high-strength AlZnMg(Cu) alloys have thus far not yet been understood adequately about their underlying precipitation scenarios in relation with the properties. This is partly due to the fact that the structures of a number of different precipitates involved in electron microscopy in association with quantitative image simulations have to be employed; a systematic study of these hardening precipitates in different alloys is also necessary. In Part I of the present study, it is shown that there are five types of structurally different precipitates including the equilibrium η-phase precipitate. Using two state-of-the-art atomic-resolution imaging techniques in electron microscopy in association with quantitative image simulations, we have determined and clarified all the unknown precipitate structures. It is demonstrated that atomic-resolution imaging can directly suggest approximate structure models, whereas quantitative image analysis can refine the structure details that are much smaller than the resolution of the microscope. This combination is crucially important for solving the difficult structure problems of the strengthening precipitates in AlZnMg(Cu) alloys. - Highlights: Part I: • We determine and verify all the key precipitate structures in AlMgZn(Cu) alloys. • We employ aberration-corrected scanning transmission electron microscopy (STEM). • We use aberration-corrected high-resolution TEM (HRTEM) for the investigations. • We obtain atomic-resolution images of the precipitates and model their structures. • We refine all precipitate structures with quantitative image simulation analysis. Part II: • The hardening precipitates in AlZnMg alloys shall be classified into two groups. • Two precipitation scenarios coexist in the alloys. • The precipitation behavior of such an alloy depends on the alloy's composition. • Very detailed phase

  12. Equilibrium binding assays reveal the elevated stoichiometry and salt dependence of the interaction between full-length human sex-determining region on the Y chromosome (SRY) and DNA.

    PubMed

    Baud, Stephanie; Margeat, Emmanuel; Lumbroso, Serge; Paris, Françoise; Sultan, Charles; Royer, Catherine; Poujol, Nicolas

    2002-05-24

    In an effort to better define the molecular mechanism of the functional specificity of human sex-determining region on the Y chromosome (SRY), we have carried out equilibrium binding assays to study the interaction of the full-length bacterial-expressed protein with a DNA response element derived from the CD3epsilon gene enhancer. These assays are based on the observation of the fluorescence anisotropy of a fluorescein moiety covalently bound to the target oligonucleotide. The low anisotropy value due to the fast tumbling of the free oligonucleotide in solution increases substantially upon binding the protein to the labeled target DNA. Our results indicate that the full-length human wild-type SRY (SRY(WT)) forms a complex of high stoichiometry with its target DNA. Moreover, we have demonstrated a strong salt dependence of both the affinity and specificity of the interaction. We have also addressed the DNA bending properties of full-length human SRY(WT) in solution by fluorescence resonance energy transfer and revealed that maximal bending is achieved with a protein to DNA ratio significantly higher than the classical 1:1. Oligomerization thus appears, at least in vitro, to be tightly coupled to SRY-DNA interactions. Alteration of protein-protein interactions observed for the mutant protein SRY(Y129N), identified in a patient presenting with 46,XY sex reversal, suggests that oligomerization may play an important role in vivo as well.

  13. NTP Toxicology and Carcinogenesis Studies of Chlorobenzene (CAS No. 108-90-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1985-10-01

    Chlorobenzene is a colorless, volatile liquid under standard environmental conditions (vapor pressure=11.8 mm Hg at 25 degrees C, 760 mm Hg). It is used primarily as a solvent (e.g. resins, dyes, pesticides, and perfumes), a degreasing agent, and a chemical intermediate, particularly in the synthesis of nitrobenzenes. Although still considerable, estimates of the yearly production volume of chlorobenzene in the United States indicate declining use in recent years, due to the reduced demand for organochlorine pesticides utilizing chlorobenzene as an intermediate. Toxicology and carcinogenesis studies of chlorobenzene (<99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and 50 female B6C3F1 mice at doses of 60 or 120 mg/kg. Groups of 50 male B6C3F1 mice received 30 or 60 mg/kg. Chlorobenzene was administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls, and additional groups of 50 rats and 50 mice of each sex served as untreated controls. The chlorobenzene doses were chosen on the basis of 90-day studies, in which doses 2-fold or greater in excess of the doses used in the 2-year study caused death, hepatocellular necrosis, renal tubular injury, thymic necrosis, or lymphoid or myeloid depletion of bone marrow, spleen or thymus. Mean body weights of dosed rats and mice were essentially the same or greater than those of the controls during the 2-year studies. Survivals of low dose male rats, dosed female rats, dosed male mice, and dosed female mice were not adversely affected by administration of chlorobenzene. Survival of high dose male rats in the 2-year study was significantly (P=0.033) lower than that of the vehicle controls. No chlorobenzene-induced toxic lesions responsible for this reduction in survival were observed. Based on the prechronic results and on the above data, the

  14. Effect of diet and housing on growth, body weight, survival and tumor incidences of B6C3F1 mice in chronic studies.

    PubMed

    Rao, Ghanta N; Crockett, Patrick W

    2003-01-01

    Diet is one of the most important environmental factors influencing growth, body weight, survival, and age-related diseases of rodents in chronic studies. NIH-07 open formula diet was the selected diet for the NTP studies from 1980 to 1994. A new diet designated as NTP-2000 diet is the current diet for mice in the NTP studies beginning in 1994. This report is a summary of results of untreated control groups of B6C3F1 mice fed NTP-2000 or NIH-07 diet from several retrospective 2-year dosed-feed and inhalation studies for differences in growth, body weight, survival, and tumor incidences. The dosed-feed studies were conducted in 3 different facilities located in the United States, and all the inhalation studies were conducted in 1 facility. During dosed-feed studies, male and female mice housed in polycarbonate cages and fed the NTP-2000 diet had lower maximum body weights than those fed NIH-07 diet. However, during inhalation studies, mice housed in wire mesh cages and fed the NTP-2000 diet had higher maximum body weights than the mice fed NIH-07 diet. Survival was higher in groups fed NTP-2000 diet irrespective of sex, housing conditions, or body weight compared to the corresponding groups fed NIH-07 diet. Survival was higher in mice housed in polycarbonate cages irrespective of diet and sex compared to the respective sex and diet groups housed in wire mesh cages. During inhalation studies, survival of male and female mice fed NTP-2000 diet was higher than that of the groups fed NIH-07 diet, although the body weights of NTP-2000 diet groups were higher than those of the groups fed NIH-07 diet. When the NTP-2000 diet was used, male and female mice in dosed-feed studies and male mice in inhalation studies had markedly lower incidences of liver tumors than the corresponding groups fed NIH-07 diet. Significant decreases in the incidences of lung tumors were observed only in the male groups fed NTP-2000 diet during dosed-feed studies. These results suggest that body

  15. Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure.

    PubMed Central

    Melnick, R L; Huff, J E; Roycroft, J H; Chou, B J; Miller, R A

    1990-01-01

    1,3-Butadiene, a large-production volume chemical used mainly in the manufacture of synthetic rubber, was found to induce multiple-organ carcinogenicity in male and female B6C3F1 mice at exposure concentrations (625 and 1250 ppm) equivalent to and below the OSHA standard of 1000 ppm. Since this study was terminated after 60 weeks of exposure because of reduced survival due to fatal tumors, and because dose-response relationships for 1,3-butadiene-induced neoplastic and nonneoplastic lesions were not clearly established, a second long-term inhalation study of 1,3-butadiene in B6C3F1 mice was conducted at lower exposure concentrations, ranging from 6.25 to 625 ppm. Both the histopathological findings from animals dying through week 65 and the results of evaluations of animals exposed for 40 and 65 weeks are presented in this report. Exposure to 1,3-butadiene caused a regenerative anemia at concentrations of 62.5 ppm and higher. Testicular atrophy was induced at 625 ppm, and ovarian atrophy was observed at 20 ppm and higher. During the first 50 weeks of the study, lymphocytic lymphoma was the major cause of death of mice exposed to 625 ppm 1,3-butadiene. Neoplasms of the heart, forestomach, lung, Harderian gland, mammary gland, ovary, and liver were frequently observed in 1,3-butadiene-exposed mice that died between week 40 and week 65 of the study. Studies in which exposure to 1,3-butadiene was stopped after limited periods were also included to assess the relationship between exposure levels and duration of exposures on the outcome of 1,3-butadiene-induced carcinogenicity. In these studies, lymphocytic lymphomas were induced in male mice exposed to 625 ppm 1,3-butadiene for only 13 weeks. The incidence of lymphocytic lymphoma in male mice exposed to 625 ppm 1,3-butadiene for 26 weeks was two times that in mice exposed to 625 ppm for 13 weeks. However, when the exposure concentration was reduced by half to 312 ppm and the exposure duration extended to 52 weeks, the

  16. Characterization of the toxicity, mutagenicity, and carcinogenicity of methacrylonitrile in F344 Rats and B6C3F1 mice.

    PubMed

    Nyska, Abraham; Ghanayem, Burhan I

    2003-04-01

    Methacrylonitrile is an unsaturated aliphatic nitrile. It is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics, and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. Methacrylonitrile was nominated for study by the National Cancer Institute (USA) because of the potential for human exposure, structural similarity to the known carcinogen acrylonitrile, and a lack of toxicity and carcinogenicity data. Doses selected for the 2-year study were based on the results of the 13-week gavage studies. Groups of 50 male and 50 female animals were exposed by gavage to 0, 3, 10, or 30 mg/kg in F344 rats, and 0, 1.5, 3 or 6 mg/kg in B6C3F1 mice, 5 days per week for 2 years. Urinary excretion of N-acetyl- S-(2-cyanopropyl)- l-cysteine (NACPC) and N-acetyl- S-(2-hydroxypropyl)- l-cysteine (NAHPC) were measured as markers of exposure at various time points after methacrylonitrile administration, and demonstrated that exposure of animals to methacrylonitrile occurred as intended. Urinary excretion of NACPC and NAHPC increased in rats and mice in a dose-dependent manner. In contrast to observations in rats, the ratios of NACPC/creatinine were generally higher in female than in male mice. Further, the ratios of NAHPC/creatinine in rats were significantly greater at all time points and all doses than the corresponding ratios of NACPC/creatinine in male and female mice. In both rats and mice, survival was not affected by treatment. In rats, mean body weights of the 30 mg/kg groups were less than those of the vehicle controls after weeks 21 and 37 for males and females, respectively. No treatment-related effect on body weight was seen in mice. There were no neoplasms (in either species) or non-neoplastic lesions (mice only) that were attributed to methacrylonitrile administration. In rats, the incidences of olfactory epithelial atrophy and metaplasia of the nose were significantly greater in 30 mg

  17. Effect of varying exposure regimens on methylene chloride-induced lung and liver tumors in female B6C3F1 mice.

    PubMed

    Kari, F W; Foley, J F; Seilkop, S K; Maronpot, R R; Anderson, M W

    1993-05-01

    Methylene chloride is a high production chemical used in a variety of applications resulting in estimated occupational and consumer exposures of at least one million people per day. Results of previously reported chronic evaluations of inhaled methylene chloride indicated that it caused mammary tumors in Fischer 344 rats and neoplasia in the lungs and liver of B6C3F1 mice. Mechanism(s) for methylene chloride-induced carcinogenesis have not been adequately elucidated. In this paper we describe the histologic evaluation of animals at a number of intermittent times for the purposes of assessing the progressive development of liver and lung neoplasia. Additionally, a series of stop-exposure treatments was conducted to evaluate the role of different methylene chloride exposure durations on the induction of hepatic and pulmonary neoplasia in female mice. Inhalation exposure to 2000 p.p.m. methylene chloride for 6 h per day, 5 days per week, for 104 weeks resulted in an 8-fold increase in the incidence of exposed animals having a lung adenoma or carcinoma (63 versus 7.5%; P < 0.01) and a 13-fold increase in the total number of pulmonary adenomas and carcinomas per animal at risk (0.97 versus 0.075; P < 0.01). This exposure also caused a 2.5-fold increase in the incidence of mice having liver tumors (69 versus 27%; P < 0.01) and a 3-fold increase in the total number of hepatic adenomas and carcinomas per animal at risk (1.34 versus 0.46; P < 0.01). Methylene chloride exposure hastened the first appearance of lung tumors (by 1 year) compared to that observed in control animals; chemical-induced and spontaneous liver tumors first occurred simultaneously. A shorter exposure duration was sufficient to attain maximal numbers of lung tumors than that needed for a maximal liver tumor burden. Lung tumor multiplicity was substantially increased by having additional time after cessation of the chemical treatment. This contrasts with the findings in liver, where additional post

  18. Theoretical computation of thermophysical properties of high-temperature F2, CF4, C2F2, C2F4, C2F6, C3F6 and C3F8 plasmas

    NASA Astrophysics Data System (ADS)

    Wang, WeiZong; Wu, Yi; Rong, MingZhe; Éhn, László; Černušák, Ivan

    2012-07-01

    The calculated values of thermodynamic and transport properties of pure F2 and fluorocarbon compounds CF4, C2F2, C2F4, C2F6, C3F6 and C3F8 at high temperatures are presented in this paper. The thermodynamic properties are determined by the method of Gibbs free energy minimization, using standard thermodynamic tables. The transport properties, including electron diffusion coefficients, viscosity, thermal conductivity and electrical conductivity, are evaluated using the Chapman-Enskog method expanded up to the third-order approximation (second order for viscosity). The most accurate cross-section data that could be located are used to evaluate collision integrals. The calculations based on the assumption of local thermodynamic equilibrium are performed for atmospheric-pressure plasmas in the temperature range from 300 to 30 000 K for different pressures between 0.1 and 10 atm. The results of F2, CF4, C2F2, C2F4 and C2F6 are compared with those of previously published studies. Larger discrepancies occur for transport coefficients; these are explained in terms of the different values of the collision integrals that were used. The results presented here are expected to be more accurate because of the improved collision integrals employed.

  19. Carcinogenicity of glycidamide in B6C3F1 mice and F344/N rats from a two-year drinking water exposure.

    PubMed

    Beland, Frederick A; Olson, Greg R; Mendoza, Maria C B; Marques, M Matilde; Doerge, Daniel R

    2015-12-01

    Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F1 mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide glycidamide. We have now examined the carcinogenic effects of glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into glycidamide.

  20. Genetic Alterations in K-ras and p53 Cancer Genes in Lung Neoplasms From B6C3F1 Mice Exposed to Cumene

    PubMed Central

    Hong, Hue-Hua L.; Ton, Thai-Vu. T.; Kim, Yongbaek; Wakamatsu, Nobuko; Clayton, Natasha P.; Chan, Po-Chuen; Sills, Robert C.; Lahousse, Stephanie A.

    2009-01-01

    The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the controls. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87 % cumene-induced lung neoplasms, and the predominant mutations were exon 1 codon 12 G to T transversions and exon 2 codon 61 A to G transitions. P53 protein expression was detected by immunohistochemistry in 56 % cumene-induced neoplasms and mutations were detected in 52 % neoplasms. The predominant mutations were exon 5, codon 155 G to A transitions and codon 133 C to T transitions. No p53 mutation and one of 7 (14 %) K-ras mutation was detected in spontaneous neoplasms. Cumene-induced lung carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13 %) and on chromosome 6 near the K-ras gene (12 %). No LOH was observed in spontaneous carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung tumors suggests that DNA damage and genomic instability may be contributing factors to the mutation profile and development of lung cancer in mice exposed to cumene. PMID:18648094

  1. Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene

    SciTech Connect

    Tice, R.R.; Boucher, R.; Luke, C.A.; Shelby, M.D.

    1987-01-01

    Groups of male B6C3F1 mice were exposed to ambient air or to gaseous 1,3-butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days. Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI): and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (% PCE), and 6) a significant increase in the level of micronucleated PCE (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE, followed by MN-PCE levels, and then by CA and MN-NCE frequencies. The most sensitive measure of cytotoxic damage was AGT followed by % PCE and then my MI. The extent of concordance ranged from a very good correlation between the induction of MN-PCE and the induction of SCE to the lack of a significant correlation between the depression in the MI and any other endpoint.

  2. DNA damage in normal and choline deficient male B6C3F1 mice treated by oral gavage with fly ash

    SciTech Connect

    Andrews, P.W.; Tice, R.R.; Schmitt, M.T.; Yager, J.W.

    1994-12-31

    This study evaluated the ability of fly ash containing 199 mg/kg total arsenic to induce DNA damage in tissues of male B6C3F1 mice maintained on a choline sufficient (CS) or a choline deficient (CD) diet. DNA damage was assessed using the Single Cell Gel (SCG) assay in cells sampled from the blood, bladder, liver, lung, and skin; and micronuclei (MN) induction in bone marrow polychromatic erythrocytes (PCE). Sodium arsenite was given by oral gavage in water once or on 4 consecutive days at doses of 12.5, 25.0, and 50.0 mg/kg. Cell samples were collected at 3, 6, 24 and 48 hrs after the single treatment and at 4 hrs after the last of 4 treatments. In addition, urine was collected at 24, 48, and 72 hours after treatment to evaluate arsenic excretion kinetics. A significant depression in DNA migration (indicative of DNA crosslinking) was detected in blood cells of both CS and CD mice, and in bladder and liver cells of CS mice. Levels of MN-PCE or %PCE were not affected by a single treatment with fly ash. These preliminary data demonstrate indicate that fly ash may exhibit in vivo genotoxicity and the ability of hepatic methylation status to modulate the pattern and magnitude of the response.

  3. Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

    PubMed Central

    Arseneault, Madeleine; Monlong, Jean; Vasudev, Naveen S.; Laskar, Ruhina S.; Safisamghabadi, Maryam; Harnden, Patricia; Egevad, Lars; Nourbehesht, Nazanin; Panichnantakul, Pudchalaluck; Holcatova, Ivana; Brisuda, Antonin; Janout, Vladimir; Kollarova, Helena; Foretova, Lenka; Navratilova, Marie; Mates, Dana; Jinga, Viorel; Zaridze, David; Mukeria, Anush; Jandaghi, Pouria; Brennan, Paul; Brazma, Alvis; Tost, Jorg; Scelo, Ghislaine; Banks, Rosamonde E.; Lathrop, Mark; Bourque, Guillaume; Riazalhosseini, Yasser

    2017-01-01

    Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively. PMID:28332632

  4. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from B6C3F1 mice exposed to cumene.

    PubMed

    Hong, Hue-Hua L; Ton, Thai-Vu T; Kim, Yongbaek; Wakamatsu, Nobuko; Clayton, Natasha P; Chan, Po-Chuen; Sills, Robert C; Lahousse, Stephanie A

    2008-07-01

    The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the control animals. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87% of cumene-induced lung neoplasms, and the predominant mutations were exon 1 codon 12 G to T transversions and exon 2 codon 61 A to G transitions. P53 protein expression was detected by immunohistochemistry in 56% of cumene-induced neoplasms, and mutations were detected in 52% of neoplasms. The predominant mutations were exon 5, codon 155 G to A transitions, and codon 133 C to T transitions. No p53 mutations and one of seven (14%) K-ras mutations were detected in spontaneous neoplasms. Cumene-induced lung carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13%) and on chromosome 6 near the K-ras gene (12%). No LOH was observed in spontaneous carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung tumors suggests that DNA damage and genomic instability may be contributing factors to the mutation profile and development of lung cancer in mice exposed to cumene.

  5. Near-Threshold Total Dissociation Electron Impact Cross Sections for C2F6, C3F8, and CHF3

    NASA Astrophysics Data System (ADS)

    Flaherty, David; Kasper, Michael; Graves, David; Winters, Harold

    2004-09-01

    Absolute total dissociation electron impact cross sections, σ _TD, are reported near threshold (8-30eV) for C_2F_6, C_3F_8, and CHF3 using the technique described by Winters and Inokuti [1]. Total neutral dissociation cross sections, σ _ND, are obtained by subtraction using total ionization cross sections, e.g. [2]. σ _ND for C_2F6 and C_3F8 are compared with values inferred from swarm data and to reported partial dissociation cross sections for production of CF3 and C_2F5 over the range of electron energies measured [3,4]. Work supported in part by the NSF/SRC ERC for Environmentally Benign Semiconductor Manufacturing. [1] H. Winters and M. Inokuti, Phys. Rev. A 25, 1420 (1982). [2] L. Christophorou and J. Olthoff, J. Phys. Chem. Ref. Data 28, 131, (1999) [3] S. Motlagh and J. Moore, J. Chem. Phys., Vol. 109 (2), 432, (1998) [4] Hayashi and Niwa, Gaseous Dielectrics V, Pergamon, New York, p. 27, (1987).

  6. Definition of the locus responsible for systemic carnitine deficiency within a 1.6-cM region of mouse chromosome 11 by detailed linkage analysis

    SciTech Connect

    Okita, Kohei; Tokino, Takashi; Nishimori, Hiroyuki

    1996-04-15

    Carnitine is an essential cofactor for oxidation of mitochondrial fatty acids. Carnitine deficiency results in failure of energy production by mitochondria and leads to metabolic encephalopathy, lipid-storage myopathy, and cardiomyopathy. The juvenile visceral steatosis (JVS) mouse, an animal model of systemic carnitine deficiency, inherits the JVS phenotype in autosomal recessive fashion, through a mutant allele mapped to mouse chromosome 11. As a step toward identifying the gene responsible for JVS by positional cloning, we attempted to refine the jvs locus in the mouse by detailed linkage analysis with 13 microsatellite markers, using 190 backcross progeny. Among the 13 loci tested, 5 (defined by markers D11Mit24, D11Mit111,D11Nds9, D11Mit86, and D11Mit23) showed no recombination, with a maximum lod score of 52.38. Our results implied that the jvs gene can be sought on mouse chromosome 11 within a genetic distance no greater than about 1.6 cM. 21 refs., 2 figs.

  7. The effect of cesium carbonate on 1-(3-methoxycarbonyl)propyl-1-phenyl[6,6]C61 aggregation in films

    DOE PAGES

    Lindemann, William R.; Wang, Wenjie; Fungura, Fadzai; ...

    2014-11-11

    Surface-pressure isotherms, X-ray reflectivity, and X-ray near-total reflection fluorescence were used to study the properties of 1-(3-methoxycarbonyl)propyl-1-phenyl[6,6]C61 (PCBM) that was pre-mixed with cesium carbonate and spread as a film at the air-water interface. The pre-mixed PCBM with cesium carbonate demonstrated a strikingly strong effect on the organization of the film. Whereas films formed from pure PCBM solution were rough due to strong inter-molecular interactions, the films formed from the mixture were much smoother. This indicates that the cesium carbonate moderates the inter-molecular interactions among PCBM molecules, hinting that the cesium diffusion observed in inverted organic photovoltaics and the likely ensuingmore » ionic Cs-PCBM interaction decrease aggregation tendency of PCBM. As a result, this implies that the use of cesium salts affects the morphology of the organic layer and consequently improves the efficiency of these devices.« less

  8. The effect of cesium carbonate on 1-(3-methoxycarbonyl)propyl-1-phenyl[6,6]C{sub 61} aggregation in films

    SciTech Connect

    Lindemann, William R.; Wang, Wenjie; Shinar, Joseph; Vaknin, David; Fungura, Fadzai; Shinar, Ruth

    2014-11-10

    Surface-pressure versus molecular area isotherms, X-ray reflectivity, and X-ray near-total reflection fluorescence were used to study the properties of 1-(3-methoxycarbonyl)propyl-1-phenyl[6,6]C{sub 61} (PCBM) that was pre-mixed with cesium carbonate and spread as a film at the air-water interface. The pre-mixed PCBM with cesium carbonate demonstrated a strikingly strong effect on the organization of the film. Whereas films formed from pure PCBM solution were rough due to strong inter-molecular interactions, the films formed from the mixture were much smoother. This indicates that the cesium carbonate moderates the inter-molecular interactions among PCBM molecules, hinting that the cesium diffusion observed in inverted organic photovoltaic structures and the likely ensuing ionic Cs-PCBM interaction decrease aggregation tendency of PCBM. This implies that the use of cesium salts affects the morphology of the organic layer and consequently improves the efficiency of these devices.

  9. The effect of cesium carbonate on 1-(3-methoxycarbonyl)propyl-1-phenyl[6,6]C61 aggregation in films

    SciTech Connect

    Lindemann, William R.; Wang, Wenjie; Fungura, Fadzai; Shinar, Joseph; Shinar, Ruth; Vaknin, David

    2014-11-11

    Surface-pressure isotherms, X-ray reflectivity, and X-ray near-total reflection fluorescence were used to study the properties of 1-(3-methoxycarbonyl)propyl-1-phenyl[6,6]C61 (PCBM) that was pre-mixed with cesium carbonate and spread as a film at the air-water interface. The pre-mixed PCBM with cesium carbonate demonstrated a strikingly strong effect on the organization of the film. Whereas films formed from pure PCBM solution were rough due to strong inter-molecular interactions, the films formed from the mixture were much smoother. This indicates that the cesium carbonate moderates the inter-molecular interactions among PCBM molecules, hinting that the cesium diffusion observed in inverted organic photovoltaics and the likely ensuing ionic Cs-PCBM interaction decrease aggregation tendency of PCBM. As a result, this implies that the use of cesium salts affects the morphology of the organic layer and consequently improves the efficiency of these devices.

  10. Influence of Helicobacter hepaticus infection on the chronic toxicity and carcinogenicity of triethanolamine in B6C3F1 mice

    PubMed Central

    Stout, Matthew D.; Kissling, Grace E.; Suárez, Fernando A.; Malarkey, David E.; Herbert, Ronald A.; Bucher, John R.

    2009-01-01

    Helicobacter hepaticus (H. hepaticus) infection causes hepatitis and increased hepatocellular neoplasms in male mice; although females are also infected, liver lesions are not typically expressed. In the 1990s, B6C3F1 mice from some chronic National Toxicology Program (NTP) studies were found to be infected with H. hepaticus. In these studies, there was hepatitis in many of the males, and there were more hepatocellular neoplasms in control males compared to studies with uninfected mice. In one of these studies, increased hepatocellular neoplasms at the high doses in male and female mice exposed topically to triethanolamine (TEA) provided the only evidence of carcinogenic activity. This study was repeated in mice free of H. hepaticus. However, the NTP mouse production colony and the diet differed between studies; these differences were the result of NTP programmatic decisions. In repeat study males, although control incidences were similar between studies, exposure did not result in increased hepatocellular neoplasms. In repeat study females, the control incidence of hepatocellular neoplasms was half that observed in the initial study, and these neoplasms were increased over controls at all doses. These data suggest that in the initial study, H. hepaticus influenced the induction of hepatocellular neoplasms in males, but not females. PMID:18812577

  11. Spectroscopic (FT-IR, FT-Raman) and quantum mechanical studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one thiosemicarbazone.

    PubMed

    Savithiri, S; Arockia doss, M; Rajarajan, G; Thanikachalam, V; Bharanidharan, S; Saleem, H

    2015-02-05

    In this study, the molecular structure and vibrational spectra of 3t-pentyl2r,6c-diphenylpiperidin-4-one thiosemicarbazone (PDPOTSC) were studied. The ground-state molecular geometry was ascertained by using the density functional theory (DFT)/B3LYP method using 6-31++G(d,p) as a basis set. The vibrational (FT-IR and FT-Raman) spectra of PDPOTSC were computed using DFT/B3LYP and HF methods with 6-31++G(d,p) basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED⩾10%) of the vibrational modes, calculated with scaled quantum mechanics (SQM) methods PQS program. The electrical dipole moment (μ) and first hyperpolarizability (βo) values have been computed using DFT/B3LYP and HF methods. The calculated result (βo) shows that the title molecule might have nonlinear optical (NLO) behavior. Atomic charges of C, N, S and molecular electrostatic potential (MEP) were calculated using B3LYP/6-31G++(d,p). The HOMO-LUMO energies were calculated and natural bonding orbital (NBO) analysis has also been carried out.

  12. Spectroscopic (FT-IR, FT-Raman) and quantum mechanical studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Savithiri, S.; Arockia doss, M.; Rajarajan, G.; Thanikachalam, V.; Bharanidharan, S.; Saleem, H.

    2015-02-01

    In this study, the molecular structure and vibrational spectra of 3t-pentyl2r,6c-diphenylpiperidin-4-one thiosemicarbazone (PDPOTSC) were studied. The ground-state molecular geometry was ascertained by using the density functional theory (DFT)/B3LYP method using 6-31++G(d,p) as a basis set. The vibrational (FT-IR and FT-Raman) spectra of PDPOTSC were computed using DFT/B3LYP and HF methods with 6-31++G(d,p) basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED ⩾ 10%) of the vibrational modes, calculated with scaled quantum mechanics (SQM) methods PQS program. The electrical dipole moment (μ) and first hyperpolarizability (βo) values have been computed using DFT/B3LYP and HF methods. The calculated result (βo) shows that the title molecule might have nonlinear optical (NLO) behavior. Atomic charges of C, N, S and molecular electrostatic potential (MEP) were calculated using B3LYP/6-31G++(d,p). The HOMO-LUMO energies were calculated and natural bonding orbital (NBO) analysis has also been carried out.

  13. Sperm-head morphology study in B6C3F1 mice following inhalation exposure to 1,3-butadiene: Final technical report

    SciTech Connect

    Hackett, P.L.; McClanahan, B.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.

    1988-04-01

    The present report describes the results of a study of the morphology of epididymal sperm heads of B6C3F1 mice that were exposed to varying concentrations of 1,3-butadiene. During the fifth post-exposure week, the animals were killed and examined for gross lesions of the reproductive tract; suspensions of the epididymal sperm were prepared for morphologic evaluations. No mortality was observed in any of the inhalation exposure groups. Transient toxic signs, including piloerection and dyspnea, were evident during a 20- to 30-minute period following exposure to 5000 ppM. Mean values for body weights and weight gains of the mice exposed to 1,3-butadiene were not significantly different from control values. A concentration-related increase in the incidence of sperm-head abnormalities was evident and the percentage of sperm heads that were morphologically abnormal was significantly higher in mice exposed to 1000 and 5000 ppM than in the controls. 23 refs., 2 figs., 6 tabs.

  14. Forestomach tumor induction by 2,4-hexadienal in F344N rats and B6C3F1 mice.

    PubMed

    Chan, Po C; Mahler, Joel; Peddada, Shyamal; Lomnitski, Liat; Nyska, Abraham

    2003-09-01

    2,4-Hexadienal (2,4-Hx) was studied for its toxicity and carcinogenicity because of its alpha, beta-unsaturated aldehyde structure and potential link between exposure to lipid peroxidation products in the diet and human malignancies. Male and female F344N rats and B6C3F1 mice received 2,4-Hx in corn oil by gavage for 16 days, 14 weeks, or 2 years. In the 16-day studies 2,4-Hx induced forestomach necrosis and ulceration at 240 mg/kg and forestomach epithelial hyperplasia at 80 mg/kg in rats and mice. In the 14-week studies the chemical induced forestomach hyperplasia and nasal olfactory atrophy or necrosis at 120 mg/kg in rats and mice. In the 2-year studies 2,4-Hx induced squamous cell papilloma and carcinoma of the forestomach in male and female rats at 45 and 90 mg/kg and in male and female mice at 120 mg/kg. Two male mice in the 120 mg/kg group had uncommon squamous cell carcinoma of the oral cavity (tongue). Mechanistic studies indicated that the forestomach carcinogenesis in rats and mice may be due to depletion of glutathione as a result of oxidative stress induced by 2,4-Hx.

  15. Overcoming recruitment barriers revealed high readiness to participate and low dropout rate among people with schizophrenia in a randomized controlled trial testing the effect of a Guided Self-Determination intervention

    PubMed Central

    2014-01-01

    Background Recruitment is one of the most serious challenges in performing randomized controlled trials. Often clinical trials with participants diagnosed with schizophrenia are terminated prematurely because of recruitment challenges resulting in a considerable waste of resources in the form of time, funding, and the participants’ efforts. Dropout rates in schizophrenia trials are also high. Recruitment challenges are often due to patients not wanting to participate in research but can also be due to clinicians’ concerns regarding individuals diagnosed with schizophrenia as participants in research. This paper reports how overcoming recruitment challenges not related to patients revealed high readiness to take part and low dropout rates in a one year long randomized controlled trial testing Guided Self-Determination (GSD) among outpatients with schizophrenia receiving treatment in Assertive Outreach Teams in the northern part of Denmark. Methods GSD is a shared decision-making and mutual problem-solving method using reflection sheets, which was developed in diabetes care and adjusted for this study and utilized by patients with schizophrenia. Descriptive data on strategies to overcome recruitment challenges were derived from notes and observations made during the randomized controlled trial testing of GSD in six outpatient teams. Results Three types of recruitment challenges not related to patients were identified and met during the trial: 1) organizational challenges, 2) challenges with finding eligible participants and 3) challenges with having professionals invite patients to participate. These challenges were overcome through: 1) extension of time, 2) expansion of the clinical recruitment area and 3) encouragement of professionals to invite patients to the study. Through overcoming these challenges, we identified a remarkably high patient-readiness to take part (101 of 120 asked accepted) and a low dropout rate (8%). Conclusion Distinction between

  16. Biochemical analysis and structure determination of Paucimonas lemoignei poly(3-hydroxybutyrate) (PHB) depolymerase PhaZ7 muteins reveal the PHB binding site and details of substrate-enzyme interactions.

    PubMed

    Jendrossek, Dieter; Hermawan, Siska; Subedi, Bishwa; Papageorgiou, Anastassios C

    2013-11-01

    Five amino acids (Y105, Y176, Y189, Y189, W207) that constitute the substrate binding site of PHB depolymerase PhaZ7 were identified. All residues are located at a single surface-exposed location of PhaZ7. Exchange of these amino acids by less hydrophobic, hydrophilic or negatively charged residues reduced binding of PhaZ7 to PHB. Modifications of other residues at the PhaZ7 surface (F9, Y66, Y103, Y124, Y169, Y172, Y173, F198, Y203, Y204, F251, W252) had no effect on substrate binding. The PhaZ7 wild-type protein, three muteins with single amino acid exchanges (Y105A, Y105E, Y190E), a PhaZ7 variant with deletion of residues 202-208, and PhaZ7 in which the active-site serine had been replaced by alanine (S136A) were crystallized and their structures were determined at 1.6-2.0 Å resolution. The structures were almost identical but revealed flexibility of some regions. Structural analysis of PhaZ7 (S136A) with bound 3-hydroxybutyrate tetramer showed that the substrate binds in a cleft that is composed of Y105, Y176, Y189 and Y190 and thus confirmed the data obtained by site-directed mutagenesis. To the best of our knowledge this is the first example in which the substrate binding site of a PHB depolymerase is documented at a molecular and structural level.

  17. Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride given in drinking water to F344/N rats and B6C3F1 mice.

    PubMed

    Lamb, J C; Huff, J E; Haseman, J K; Murthy, A S; Lilja, H

    1986-01-01

    Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 wk. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1 N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the 300-ppm dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower than that in controls. Mean body weight was reduced in 300-ppm-dose female rats and 300-ppm-dose male and female mice compared to controls. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Under the conditions of these studies, there was clear evidence of carcinogenicity for F344/N rats and for B6C3F1 mice in that 4,4'-methylenedianiline dihydrochloride caused increased incidences of (1) follicular-cell carcinomas of the thyroid gland (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%; p less than or equal to 0.012) and neoplastic nodules of the liver (controls, 1/50, 2%; low dose, 12/50, 24%; high dose, 25/50, 50%; p less than or equal to 0.001) in male rats, (2) follicular-cell adenomas (controls, 0/47; low dose, 2/47, 4%; high dose, 17/48, 35%; p less than or equal to 0.001) and C-cell adenomas (controls, 0/47; low dose, 3/47, 6%; high dose, 6/48, 13% p less than or equal to 0.029) of the thyroid gland in female rats, (3) follicular-cell adenomas of the thyroid gland (controls, 0/47; low dose, 3/49, 6%; high dose, 16/49, 33%; p less than or equal to 0.001), carcinomas of the liver (controls, 10/49, 20%; low dose, 33/50, 66%; high dose, 29/50, 58%; p less than or equal to 0.001), and pheochromocytomas of the adrenal

  18. Expression of ovarian microsomal epoxide hydrolase and glutathione S-transferase during onset of VCD-induced ovotoxicity in B6C3F{sub 1} mice

    SciTech Connect

    Keating, Aileen F.; Sipes, I. Glenn; Hoyer, Patricia B.

    2008-07-01

    4-vinylcyclohexene diepoxide (VCD) specifically destroys small pre-antral follicles in the rodent ovary. VCD can be detoxified to an inactive tetrol by microsomal epoxide hydrolase (mEH), or by conjugation to glutathione (GSH) by glutathione S-transferase (GST). Formation of VCD-GSH adducts in the mouse ovary 4 h after VCD exposure (0.57 mmol/kg/day) has been demonstrated. Because the mouse ovary expresses both mEH and GST, expression of mEH and GST pi and mu during a time-course of VCD-induced ovotoxicity was evaluated in a neonatal mouse ovarian culture system. Ovaries from postnatal day 4 (PND4) B6C3F{sub 1} mice were incubated with VCD (15 {mu}M) for 2, 4, 6, 8, 10, 12, or 15 days. Following incubation, ovaries were histologically evaluated, or assessed for mRNA or protein expression. VCD did not cause follicle loss (p > 0.05) on days 2, 4, or 6 of culture. At days 8, 10, 12, and 15, VCD reduced (p < 0.05) both primordial and primary follicle numbers. Increased (p < 0.05) expression of mEH, GST pi and GST mu mRNA was detected after 4 days of VCD exposure. This expression was reduced on days 6 and 8, when follicle loss was underway, but increased (p < 0.05) after 10 days of exposure. mEH and GST pi proteins were elevated (p < 0.05) following 8 days of VCD-exposure however there was no increase in GST mu protein. These findings suggest that with continuous exposure to VCD, increased expression of detoxification enzymes may participate in retarding the onset of follicle loss, but that this loss cannot ultimately be prevented.

  19. Evaluation of SF6, C2Cl4, and CO to approximate fossil fuel CO2 in the Northern Hemisphere using a chemistry transport model

    NASA Astrophysics Data System (ADS)

    Rivier, L.; Ciais, P.; Hauglustaine, D. A.; Bakwin, P.; Bousquet, P.; Peylin, P.; Klonecki, A.

    2006-08-01

    The distribution of the fossil fuel component in atmospheric CO2 cannot be measured directly at a cheap cost. Could anthropogenic tracers with source patterns similar to fossil fuel CO2 then be used for that purpose? Here we present and evaluate a methodology using surrogate tracers, CO, SF6, and C2Cl4, to deduce fossil fuel CO2. A three-dimensional atmospheric chemistry transport model is used to simulate the relationship between each tracer and fossil fuel CO2. In summertime the regression slopes between fossil fuel CO2 and surrogate tracers show large spatial variations for chemically active tracers (CO and C2Cl4), although C2Cl4 presents less scatter than CO. At two tall tower sites in the United States (WLEF, Wisconsin, and WITN, North Carolina), we found that in summertime the C2Cl4 (CO) versus fossil CO2 slope is on average up to 15% (25%) higher than in winter. We show that for C2Cl4 this seasonal variation is due to OH oxidation. For CO the seasonal variation is due to both chemistry and mixing with nonanthropogenic CO sources. In wintertime the three surrogate tracers SF6, C2Cl4, and CO are about equally as good indicators of the presence of fossil CO2. However, our model strongly underestimates the variability of SF6 at both towers, probably because of unaccounted for emissions. Hence poor knowledge of emission distribution hampers the use of SF6 as a surrogate tracer. From a practical point of view we recommend the use of C2Cl4 as a proxy of fossil CO2. We also recommend the use of tracers to separate fossil CO2. Despite the fact that the uncertainty on the regression slope is on the order of 30%, the tracer approach is likely to have less bias than when letting one model with one inventory emission map calculate the fossil CO2 distribution.

  20. Toxicities of ethylene glycol and ethylene glycol monoethyl ether in Fischer 344/N rats and B6C3F/sub 1/ mice

    SciTech Connect

    Melnick, R.L.

    1984-08-01

    The toxicities of ethylene glycol (EG) and ethylene glycol monoethyl ether (EGEE) were studied in Fischer 344/N rats and B6C3F/sub 1/ mice. In a 13-week study, EG was administered in feed to groups of 10 rats and 10 mice of both sexes at dose levels of 0 (control), 0.32, 0.63, 1.25, 2.5, and 5.0%. Kidney/body weight ratios were elevated in the 2.5 and 5.0% dose groups of male and female rats relative to controls, while serum urea nitrogen and serum creatinine levels were elevated in the two highest dose groups of male rats. Toxic nephrosis and crystal deposits in renal tubules were observed in the 2.5 and 5.0% dose groups of male rats. Crystals were also observed in brains of male rats in the 5.0% dose group. Nephrosis was the only lesion observed in female rats (5.0% dose group). Mild, compound-related lesions were seen in kidneys (nephrosis) and livers (centrilobular degeneration) of male mice in the 2.5 and 5.0% dose groups. Groups of 50 rats and 50 mice of both sexes were administered EGEE by gavage in a 2-year study at dose levels of 0 (control), 0.5, 1.0 and 2.0 g/kg body weight. Gross lesions noted at necropsy indicate that chronic treatment of rats with EGEE at dose levels of 0.5 or 1.0 g/kg body weight caused an apparent enlargement of the adrenal gland in male rats and interfered with the development of spontaneous lesions of the spleen (males and females), pituitary (males and females), testis (males), and subcutaneous tissue in the mammary gland region (females) that commonly occur in the aging Fischer 344/N rat. 12 references, 4 figures, 8 tables.

  1. Toxicity of inhaled isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies

    SciTech Connect

    Bucher, J.R.; Gupta, B.N.; Adkins, B. Jr.; Thompson, M.; Jameson, C.W.; Thigpen, J.E.; Schwetz, B.A.

    1987-06-01

    Male and female F344/N rats and B6C3F1 mice were exposed to lethal and sublethal concentrations of methyl isocyanate by inhalation. Mortality, clinical signs, body and organ weights, and changes in clinical pathology and hematology were monitored immediately after 2-hr exposures and during the ensuing 3 months. Additional studies investigated the possible involvement of cyanide in the toxicity of methyl isocyanate. Deaths of rats and mice exposed to lethal concentrations (20 to 30 ppm) began within 15-18 hr, with males more prone to early death than females. A second wave of deaths occurred after 8 to 10 days, affecting primarily female rats and mice exposed to 20 to 30 ppm of methyl isocyanate, and male and female rats exposed to 10 ppm. Most deaths occurred during the first month following the exposures and were preceded by periods of severe respiratory distress. Body weights decreased in proportion to dose early, but then weight gain resumed in survivors at control rates. The only organ with a consistent, dose-related weight change was the lung, which was heavier throughout the studies in animals exposed to high concentrations of methyl isocyanate. Blood and brain cholinesterase were not inhibited. Studies attempting to measure cyanide in the blood of methyl isocyanate-exposed rats, and attempting to affect lethality with a cyanide antidote (sodium nitrite and sodium thiosulfate) gave negative results. The findings indicate that at these doses, methyl isocyanate inhalation causes deaths and persistent pulmonary changes, but no evidence of extrapulmonary toxicity in rodents. Cyanide does not appear to be involved in methyl isocyanate toxicity.

  2. In Utero exposure to genistein enhanced intranasal house dust mite allergen-induced respiratory sensitization in young adult B6C3F1 mice.

    PubMed

    Guo, Tai L; Meng, Andrew H

    2016-06-24

    Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental immunotoxic effects are increasing. To understand how in utero GEN exposure may modulate postnatal respiratory sensitization, we conducted a time course study using a common household allergen (house dust mites: HDM; 10μg/mouse) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20mg/kg bw). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly doses of HDM extracts, and they were euthanized at day 3 following the final HDM exposure at four different time points (postnatal day (PND) 80, 120, 160, and 200). In utero GEN combined with postnatal HDM exposures (GEN+HDM) increased total IgE production in both young female and male B6C3F1 offspring (e.g., PND 80 in females and PND 120 in males). Increased antigen-specific IgG1, IgG2a and IgG2b levels were also observed at various time points in both female and male offspring. In addition, increases in macrophage number in bronchoalveolar lavage fluid of both female and male GEN+HDM offspring at PND 80 and PND 120, respectively, were observed when compared to the vehicle group. For T cells, an increase over the vehicle in female GEN+HDM offspring was observed at PND 80. Due to similar patterns of increases, it seems likely that GEN+HDM-induced increases in total IgE and macrophages are related. Overall, in utero GEN plus later-life HDM exposures exert increases in total IgE and HDM-specific IgG production as well as macrophage recruitments to the lung in young adult mice.

  3. Transcriptomic responses in the oral cavity of F344 rats and B6C3F1 mice following exposure to Cr(VI): Implications for risk assessment

    PubMed Central

    Rager, Julia E.; Suh, Mina; Ring, Caroline L.; Proctor, Deborah M.; Haws, Laurie C.; Fry, Rebecca C.; Harris, Mark A.

    2016-01-01

    Exposure to hexavalent chromium [Cr(VI)] in drinking water was previously reported to increase oral tumor incidence in F344 rats. To investigate the mode of action for these tumors, transcriptomic profiles in oral mucosa samples of F344 rats and B6C3F1 mice were analyzed following exposure to 0.1–180 ppm Cr(VI) for 7 or 90 days. In rats, genome‐wide microarray analyses identified no significantly differentially expressed genes (DEGs) at either time point. In mice, 14 and 1 DEGs were respectively identified after 7 and 90 days of exposure. Therefore, relaxed statistical criteria were employed to identify potential DEGs (pDEGs), followed by high‐throughput benchmark dose modeling to identify responsive pDEGs for pathway enrichment analysis. This identified 288 and 168 pDEGs in the rat oral mucosa, of which only 20 and 7 showed evidence of dose‐response. No significant pathway enrichment was obtained with either pDEG or dose‐responsive pDEG lists. Similar results were obtained in mice. These analyses indicate a negligible transcriptional response in the oral mucosa of both species. Comparison of the total number of gene changes in the oral mucosa of rats and mice with responses in the duodenum of animals from the same study demonstrated remarkable dose‐response concordance across tissues and species as a function of tissue chromium concentration. The low chromium levels in the oral mucosa and negligible transcript response are consistent with an absence of tissue lesions. These findings are used to compare the merits of linear and nonlinear approaches for deriving toxicity criteria based on the oral tumors in rats. Environ. Mol. Mutagen. 57:706–716, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. PMID:27859739

  4. Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water.

    PubMed

    Frawley, Rachel P; Smith, Matthew J; White, Kimber L; Elmore, Susan A; Herbert, Ron; Moore, Rebecca; Staska, Lauren M; Behl, Mamta; Hooth, Michelle J; Kissling, Grace E; Germolec, Dori R

    2016-09-01

    Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0-2000 mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3(+) T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity.

  5. Expression of ovarian microsomal epoxide hydrolase and glutathione S-transferase during onset of VCD-induced ovotoxicity in B6C3F(1) mice.

    PubMed

    Keating, Aileen F; Sipes, I Glenn; Hoyer, Patricia B

    2008-07-01

    4-vinylcyclohexene diepoxide (VCD) specifically destroys small pre-antral follicles in the rodent ovary. VCD can be detoxified to an inactive tetrol by microsomal epoxide hydrolase (mEH), or by conjugation to glutathione (GSH) by glutathione S-transferase (GST). Formation of VCD-GSH adducts in the mouse ovary 4 h after VCD exposure (0.57 mmol/kg/day) has been demonstrated. Because the mouse ovary expresses both mEH and GST, expression of mEH and GST pi and mu during a time-course of VCD-induced ovotoxicity was evaluated in a neonatal mouse ovarian culture system. Ovaries from postnatal day 4 (PND4) B6C3F(1) mice were incubated with VCD (15 microM) for 2, 4, 6, 8, 10, 12, or 15 days. Following incubation, ovaries were histologically evaluated, or assessed for mRNA or protein expression. VCD did not cause follicle loss (p>0.05) on days 2, 4, or 6 of culture. At days 8, 10, 12, and 15, VCD reduced (p<0.05) both primordial and primary follicle numbers. Increased (p<0.05) expression of mEH, GST pi and GST mu mRNA was detected after 4 days of VCD exposure. This expression was reduced on days 6 and 8, when follicle loss was underway, but increased (p<0.05) after 10 days of exposure. mEH and GST pi proteins were elevated (p<0.05) following 8 days of VCD-exposure however there was no increase in GST mu protein. These findings suggest that with continuous exposure to VCD, increased expression of detoxification enzymes may participate in retarding the onset of follicle loss, but that this loss cannot ultimately be prevented.

  6. ras proto-oncogene activation in dichloroacetic acid-, trichloroethylene- and tetrachloroethylene-induced liver tumors in B6C3F1 mice.

    PubMed

    Anna, C H; Maronpot, R R; Pereira, M A; Foley, J F; Malarkey, D E; Anderson, M W

    1994-10-01

    The frequency and mutation spectra of proto-oncogene activation in hepatocellular neoplasms induced by tetrachloroethylene, trichloroethylene and dichloroacetic acid were examined to help define the molecular basis for their carcinogenicity. H-ras codon 61 activation was not significantly different among dichloroacetic acid- and trichloroethylene-induced and combined historical and concurrent control hepatocellular tumors (62%, 51% and 69% respectively). The mutation spectra of H-ras codon 61 mutations showed a significant decrease in AAA and increase in CTA mutations for dichloroacetic acid- and trichloroethylene-induced tumors when compared to combined controls. The H-ras codon 61 mutation frequency for tetrachloroethylene-induced tumors was significantly lower (24%) than that of combined controls and also that of the two other chemicals. Mutations at codons 13 and 117 plus a second exon insert contributed 4% to the total H-ras frequencies for trichloroethylene and tetrachloroethylene. There was also a higher incidence of K-ras activation (13%) in tetrachloroethylene-induced tumors than in the other chemically induced or control tumors. Four liver tumors were found to contain insertions of additional bases within the second exon of K- or H-ras. These findings suggest that exposure to dichloroacetic acid, trichloroethylene and tetrachloroethylene provides a selective growth advantage to spontaneously occurring mutations in codon 61 of H-ras and, at the same time, is responsible for a small number of unique molecular lesions suggestive of either a random genotoxic mode of action or a non-specific result of secondary DNA damage. However, the absence of ras activation in many of the liver neoplasms suggests that alternative mechanisms are also important in B6C3F1 mouse hepatocarcinogenesis.

  7. Synthesis, spectroscopic (FT-IR, FT-Raman, UV and NMR) and computational studies on 3t-pentyl-2r,6c-diphenylpiperidin-4-one semicarbazone

    NASA Astrophysics Data System (ADS)

    Arockia doss, M.; Savithiri, S.; Rajarajan, G.; Thanikachalam, V.; Saleem, H.

    2015-09-01

    The structural and spectroscopic studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one semicarbazone (PDPOSC) were made by adopting B3LYP/HF levels theory using 6-311++G(d,p) basis set. The FT-IR and Raman spectra were recorded in solid phase, the fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. DFT method indicates that B3LYP is superior to HF method for molecular vibrational analysis. UV-vis spectrum of the compound was recorded in different solvents in the region of 200-800 nm and the electronic properties such as excitation energies, oscillator strength, wavelengths, HOMO and LUMO energies were evaluated by time-dependent DFT (TD-DFT) approach. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. The hyperconjugative interaction energy (E(2)) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. In addition, MEP and atomic charges of carbon, nitrogen and oxygen were calculated using B3LYP/6-311++G(d,p) level theory. Moreover, thermodynamic properties of the title compound were calculated by B3LYP/HF, levels using 6-311++G(d,p) basis set. The 1H and 13C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results.

  8. Synthesis, spectroscopic (FT-IR, FT-Raman, UV and NMR) and computational studies on 3t-pentyl-2r,6c-diphenylpiperidin-4-one semicarbazone.

    PubMed

    Arockia doss, M; Savithiri, S; Rajarajan, G; Thanikachalam, V; Saleem, H

    2015-09-05

    The structural and spectroscopic studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one semicarbazone (PDPOSC) were made by adopting B3LYP/HF levels theory using 6-311++G(d,p) basis set. The FT-IR and Raman spectra were recorded in solid phase, the fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. DFT method indicates that B3LYP is superior to HF method for molecular vibrational analysis. UV-vis spectrum of the compound was recorded in different solvents in the region of 200-800 nm and the electronic properties such as excitation energies, oscillator strength, wavelengths, HOMO and LUMO energies were evaluated by time-dependent DFT (TD-DFT) approach. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. The hyperconjugative interaction energy (E((2))) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. In addition, MEP and atomic charges of carbon, nitrogen and oxygen were calculated using B3LYP/6-311++G(d,p) level theory. Moreover, thermodynamic properties of the title compound were calculated by B3LYP/HF, levels using 6-311++G(d,p) basis set. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results.

  9. Toxicity and carcinogenicity of 2,3-dibromo-1-propanol in F344/N rats and B6C3F1 mice.

    PubMed

    Eustis, S L; Haseman, J K; Mackenzie, W F; Abdo, K M

    1995-06-01

    2,3-Dibromo-1-propanol is a metabolite of the flame retardant tris(2,3-dibromopropyl) phosphate, previously shown to be a mutagen and carcinogen in experimental animals. Toxicology and carcinogenesis studies of 2,3-dibromo-1-propanol were conducted by applying the chemical in 95% ethanol to the interscapular skin of male and female F344/N rats and B6C3F1 mice 5 days a week for 13 weeks in the prechronic study and 48-55 weeks (rats) or 36-42 weeks (mice) in the carcinogenicity study. In the 13-week study, 10 rats and 10 mice of each sex received doses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associated with chemical application occurred only in the high-dose (750 mg/kg) male mice. Chemical-related lesions were seen in the kidney of male rats, liver of female rats, and liver and lung of both sexes of mice. Based on the toxicity observed in the 13-week study, 50 rats of each sex received doses of 0, 188, or 375 mg/kg and 50 mice of each sex received 0, 88, or 177 mg/kg in the carcinogenicity study. The planned 2-year study was terminated early because of reduced survival of rats related to chemical-induced neoplasia and because of the appearance of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Nearly all dosed rats had malignant neoplasms at one or more sites, while only one control male and one control female had malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanol occurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa, esophagus, forestomach, intestines, liver, kidney, mammary gland (females), clitoral gland (females), spleen (males), and mesothelium (males). In mice, chemical-induced neoplasms occurred in the skin, forestomach, liver (males), and lung (males).

  10. NTP Toxicology and Carcinogenesis Studies of Glutaraldehyde (CAS NO. 111-30-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1999-09-01

    Glutaraldehyde is used in large volume in a variety of industries as a disinfectant, preservative, fixative and cross-linking agent, and as a chemical intermediate in the synthesis of pharmaceuticals and pesticides. Glutaraldehyde was nominated by the National Cancer Institute, the Occupational Safety and Health Administration, and the National Institute of Environmental Health Sciences for carcinogenicity studies because of potential occupational exposure. Male and female F344/N rats and B6C3F1 mice were exposed to glutaraldehyde (25% aqueous solution) (approximately 93% pure) by inhalation for 2 years. In vitro genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells; in vivo studies were conducted to measure sex-linked recessive lethal mutations in Drosophila melanogaster, chromosomal aberrations and micronucleated erythrocytes in mouse bone marrow, and micronucleated erythrocytes in mouse peripheral blood. The results of 13-week inhalation studies with glutaraldehyde were reported previously (NTP, 1993 -- TOX-25 ). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 250, 500, or 750 ppb glutaraldehyde vapor by inhalation, 6 hours per day, 5 days per week, for 104 weeks. Survival of 500 and 750 ppb female rats was less than that of the chamber controls. Mean body weights of all exposed groups of male rats and 500 and 750 ppb female rats were generally less than those of the chamber controls. Some female rats exposed to 750 ppb were thin to emaciated at the time they were killed moribund. Increased incidences of nonneoplastic nasal lesions occurred primarily within the anterior section of the nose in 500 and 750 ppb rats and to a lesser extent in 250 ppb rats. The more significant lesions included hyperplasia and inflammation of the squamous and respiratory epithelia and squamous metaplasia of the respiratory epithelium. 2-YEAR STUDY IN MICE: Groups

  11. NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies).

    PubMed

    1984-08-01

    1,3-Butadiene is used as an intermediate in the production of elastomers, polymers, and other chemicals. Of the 1,3-butadiene used in 1978, 44% was used to manufacture styrene-butadiene rubber (a substitute for natural rubber, produced by copolymerization of 1,3-butadiene with styrene), and 19% was used to produce polybutane elastomer (a substance that increases resistance of tire products to wear, heat degradation, and blowouts). Chloroprene monomer, derived from 1,3-butadiene, is used exclusively to manufacture neoprene elastomers for non-tire and latex applications. Commercial nitrile rubber, used largely in rubber hoses, seals, and gaskets for automobiles, is a copolymer of 1,3-butadiene and acrylonitrile. Acrylonitrile- butadiene- styrene resins, usually containing 20%-30% 1,3-butadiene by weight, are used to make parts for automobiles and appliances. Other polymer uses include specialty polybutadiene polymers, thermoplastic elastomers, nitrile barrier resins, and K resins(R). 1,3-Butadiene is used as an intermediate in the production of a variety of industrial chemicals, including two fungicides, captan and captofol. It is approved by the U.S. Food and Drug Administration for use in the production of adhesives used in articles for packaging, transporting, or holding food; in components of paper and paperboard that are in contact with dry food; and as a modifier in the production of semigrid and rigid vinyl chloride plastic food-contact articles. No information was located on the levels of monomer or on its elution rate from any of the commercially available polymers. It is not known if unreacted 1,3-butadiene migrated from packaging materials. Male and female B6C3F1 mice were exposed to air containing 1,3-butadiene (greater than 99% pure) at concentrations of 0-8,000 ppm in 15-day and 14-week inhalation studies. In the 15-day studies, survival was unaffected by dose, and no pathologic effects were observed; slight decreases in mean body weight occurred at the

  12. Comparative toxicities of o-, m-, and p-nitrotoluene in 13-week feed studies in F344 rats and B6C3F1 mice.

    PubMed

    Dunnick, J K; Elwell, M R; Bucher, J R

    1994-04-01

    Nitrotoluenes are high-production-volume chemicals used in the synthesis of agricultural chemicals and in various dyes. Because of differences in the metabolism of the three isomers and their capabilities to bind to DNA, comparative toxicity studies of o-, m-, and p-nitrotoluene were conducted in F344 rats and B6C3F1 mice. o-, m-, or p-Nitrotoluene was administered in the feed to male and female rats and mice at doses ranging from 625 to 10,000 ppm for 13 weeks. These doses delivered approximately 40 to 700 mg/kg body wt/day for rats and 100 to 1700 mg/kg/day for mice. There were no treatment-related effects on survival in any of the studies. Decreased body weights relative to controls occurred in dosed rats and mice in all studies at the higher dose levels and were most pronounced in rats receiving o-nitrotoluene. Mesotheliomas of the tunica vaginalis were observed in 3 of 10 male rats receiving o-nitrotoluene at 5000 ppm, and mesothelial cell hyperplasia was observed in 2 of 10 male rats receiving o-nitrotoluene at 10,000 ppm. Kidney toxicity was observed in male rats receiving o-, m-, or p-nitrotoluene and included hyaline droplet nephropathy and an associated increase in the renal concentration of alpha 2U-globulin. Evidence of liver toxicity in the male rats receiving o-nitrotoluene included hepatocyte vacuolization, oval cell hyperplasia, and increased serum bile acids, sorbitol dehydrogenase, and alanine aminotransferase. Although there was no histopathologic evidence of hepatic toxicity in male or female rats given the m- or p-isomers or in female rats given the o-isomer, treatment-related hepatic effects were detected in these groups, as measured by an increase in the relative liver weights and by elevations in serum bile acids and liver-specific enzymes. The spleens of treated male and female rats had a mild increase in hematopoiesis, hemosiderin deposition, and/or congestion. These splenic changes were slightly more prominent in rats administered the o

  13. Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship with CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

    PubMed Central

    Chau, Tran Thi Hong; Fisher, Martin; Nelson, Mark; Winston, Alan; Else, Laura; Carr, Daniel F.; Taylor, Steven; Ustianowski, Andrew; Back, David; Pirmohamed, Munir; Solomon, Tom; Farrar, Jeremy; Törok, M. Estée; Khoo, Saye

    2016-01-01

    Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitro and in vivo data. The effect of the CYP2B6 c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitro toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitro toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6 genotype, particularly in those

  14. Effects of dietary fish oil on the depletion of carcinogenic PAH-DNA adduct levels in the liver of B6C3F1 mouse.

    PubMed

    Zhou, Guo-Dong; Zhu, Huiping; Phillips, Tracie D; Wang, Jianbo; Wang, Shi-Zhou; Wang, Fen; Amendt, Brad A; Couroucli, Xanthi I; Donnelly, Kirby C; Moorthy, Bhagavatula

    2011-01-01

    Many carcinogenic polycyclic aromatic hydrocarbons (PAHs) and their metabolites can bind covalently to DNA. Carcinogen-DNA adducts may lead to mutations in critical genes, eventually leading to cancer. In this study we report that fish oil (FO) blocks the formation of DNA adducts by detoxification of PAHs. B6C3F1 male mice were fed a FO or corn oil (CO) diet for 30 days. The animals were then treated with seven carcinogenic PAHs including benzo(a)pyrene (BaP) with one of two doses via a single intraperitoneal injection. Animals were terminated at 1, 3, or 7 d after treatment. The levels of DNA adducts were analyzed by the (32)P-postlabeling assay. Our results showed that the levels of total hepatic DNA adducts were significantly decreased in FO groups compared to CO groups with an exception of low PAH dose at 3 d (P = 0.067). Total adduct levels in the high dose PAH groups were 41.36±6.48 (Mean±SEM) and 78.72±8.03 in 10(9) nucleotides (P = 0.011), respectively, for the FO and CO groups at 7 d. Animals treated with the low dose (2.5 fold lower) PAHs displayed similar trends. Total adduct levels were 12.21±2.33 in the FO group and 24.07±1.99 in the CO group, P = 0.008. BPDE-dG adduct values at 7 d after treatment of high dose PAHs were 32.34±1.94 (CO group) and 21.82±3.37 (FO group) in 10(9) nucleotides with P value being 0.035. Low dose groups showed similar trends for BPDE-dG adduct in the two diet groups. FO significantly enhanced gene expression of Cyp1a1 in both the high and low dose PAH groups. Gstt1 at low dose of PAHs showed high levels in FO compared to CO groups with P values being 0.014. Histological observations indicated that FO played a hepatoprotective role during the early stages. Our results suggest that FO has a potential to be developed as a cancer chemopreventive agent.

  15. NTP Toxicology and Carcinogenesis Studies of Acetonitrile (CAS No. 75-05-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1996-04-01

    Acetonitrile is used primarily as a solvent in extractive distillation and crystallization of pharmaceutical and agricultural products and as a catalyst in chemical reactions. It was nominated for testing by the National Cancer Institute due to its presence in drinking water supplies and the environment, due to lack of information on the carcinogenicity of alkyl cyanides, and because of widespread worker exposure. Male and female F344/N rats and B6C3F1 mice were exposed to acetonitrile (at least 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood of B6C3F1 mice exposed to acetonitrile for 13 weeks. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. Six male and three female rats that received 1,600 ppm and one male that received 800 ppm died during the study. At exposure concentrations up to and including 800 ppm, the final mean body weights and body weight gains were generally similar to those of the controls. At 1,600 ppm, body weight gain was lower and the final mean body weights of both males and females were significantly lower than those of the controls. Hypoactivity and ruffled fur were observed during the first week of the study in males receiving 800 ppm and males and females receiving 1,600 ppm. Additional clinical findings in 1,600 ppm males that died during week 1 were ataxia, abnormal posture, and clonic convulsions. Clinical pathology findings included nonresponsive, normocytic, normochromic anemia in 1,600 ppm males and females and in 800 ppm females, and decreased triiodothyronine (T3) concentrations in 1,600 ppm females. Absolute and relative thymus weights were significantly lower than those of the controls in the 800 and 1

  16. NTP Toxicology and Carcinogenesis Studies of Propylene (CAS No. 115-07-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1985-11-01

    Propylene is used as a starting material in the production of polypropylene plastics and various other chemicals, including acrylonitrile, isopropyl alcohol, propylene oxide, butyraldehyde, cumene, dodecane, nonene, and allyl chloride. The major derivatives are polypropylene (25%), acrylonitrile (15%), isopropyl alcohol (10%), and propylene oxide (10%). It is also a valuable feed-stock chemical for the production of gasoline. Other miscellaneous applications include use as a starting material for polymerization reactions to form vinyl chloride copolymers and low-molecular-weight homopolymers that are used as additives in lubricating oils and in the manufacture of hydroquinone. The chemical is also used as an aerosol propellant or component. The major end uses of propylene are in the production of fabricated plastics (50%) and fibers (15%). Toxicology and carcinogenesis studies of propylene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats and 49 or 50 B6C3F1 mice of each sex to propylene in air by inhalation at concentrations of 5,000 or 10,000 ppm, 6 hours per day, 5 days per week, for 103 weeks. Other groups of 50 rats and 50 mice of each sex in chambers received air only on the same schedule and served as chamber controls. The highest concentration of propylene that was considered safe for these studies was 10,000 ppm because of the risk of explosion that can occur at higher concentrations. The survival of exposed and control rats and mice was comparable. Throughout most of the studies, mean body weights of exposed male and female rats were slightly lower (0%-5%) than those of the controls, but the decrements were not concentration related. After week 59 of the study, mean body weights of 10,000-ppm male mice were usually slightly lower (5%) than those of the controls, whereas those in other exposed groups of male and female mice were generally comparable with those of the controls. No compound-related adverse clinical signs were

  17. NTP Toxicology and Carcinogenesis Studies of Pentachloroanisole (CAS No. 1825-21-4) in F344 Rats and B6C3F1 Mice (Feed Studies).

    PubMed

    1993-04-01

    Pentachloroanisole is a chlorinated aromatic compound which is widely distributed at low levels in the environment and in food products. Formation of pentachloroanisole in the environment may result from the degradation of structurally related, commercially important, ubiquitous chlorinated aromatic compounds such as pentachlorophenol and pentachloronitrobenzene which are known rodent toxins or carcinogens. Toxicology and carcinogenesis studies were conducted by administering pentachloroanisole (>99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 16-DAY STUDIES IN RATS: Groups of five male and five female F344/N rats were administered pentachloroanisole in corn oil by gavage once per day, 5 days per week, for 16 days at doses of 0, 100, 125, 150, 175, or 200 mg/kg body weight. Deaths occurred during days 2 and 3 in rats receiving doses of 125 mg/kg or greater; these deaths were considered directly related to pentachloroanisole administration. No biologically significant changes in mean body weight gains or final body weights were noted in the 100 mg/kg groups of rats. Because of the high early mortality rate, valid comparisons of body weight differences in other dose groups could not be made. Inactivity was noted in all dose groups. Rats administered doses of 125 mg/kg or greater also exhibited dyspnea. 16-DAY STUDIES IN MICE: Groups of five male and five female B6C3F1 mice were administered pentachloroanisole in corn oil by gavage once per day, 5 days per week, for 16 days at doses of 0, 100, 175, 250, 325, or 400 mg/kg. Deaths occurred during days 2 and 3 in mice receiving doses of 175 mg/kg or greater; these deaths were considered directly related to chemical administration. No biologically significant changes in mean body weight gains or final body weights

  18. Efficient Reverse Genetics Reveals Genetic Determinants of Budding and Fusogenic Differences between Nipah and Hendra Viruses and Enables Real-Time Monitoring of Viral Spread in Small Animal Models of Henipavirus Infection

    PubMed Central

    Yun, Tatyana; Park, Arnold; Hill, Terence E.; Pernet, Olivier; Beaty, Shannon M.; Juelich, Terry L.; Smith, Jennifer K.; Zhang, Lihong; Wang, Yao E.; Vigant, Frederic; Gao, Junling; Wu, Ping

    2014-01-01

    ABSTRACT Nipah virus (NiV) and Hendra virus (HeV) are closely related henipaviruses of the Paramyxovirinae. Spillover from their fruit bat reservoirs can cause severe disease in humans and livestock. Despite their high sequence similarity, NiV and HeV exhibit apparent differences in receptor and tissue tropism, envelope-mediated fusogenicity, replicative fitness, and other pathophysiologic manifestations. To investigate the molecular basis for these differences, we first established a highly efficient reverse genetics system that increased rescue titers by ≥3 log units, which offset the difficulty of generating multiple recombinants under constraining biosafety level 4 (BSL-4) conditions. We then replaced, singly and in combination, the matrix (M), fusion (F), and attachment glycoprotein (G) genes in mCherry-expressing recombinant NiV (rNiV) with their HeV counterparts. These chimeric but isogenic rNiVs replicated well in primary human endothelial and neuronal cells, indicating efficient heterotypic complementation. The determinants of budding efficiency, fusogenicity, and replicative fitness were dissociable: HeV-M budded more efficiently than NiV-M, accounting for the higher replicative titers of HeV-M-bearing chimeras at early times, while the enhanced fusogenicity of NiV-G-bearing chimeras did not correlate with increased replicative fitness. Furthermore, to facilitate spatiotemporal studies on henipavirus pathogenesis, we generated a firefly luciferase-expressing NiV and monitored virus replication and spread in infected interferon alpha/beta receptor knockout mice via bioluminescence imaging. While intraperitoneal inoculation resulted in neuroinvasion following systemic spread and replication in the respiratory tract, intranasal inoculation resulted in confined spread to regions corresponding to olfactory bulbs and salivary glands before subsequent neuroinvasion. This optimized henipavirus reverse genetics system will facilitate future investigations into

  19. NTP Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    2000-07-01

    Methyleugenol is used as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream. It is also used as a fragrance in perfumes, creams, lotions, detergents, and soaps. Methyleugenol has also been used as an insect attractant in eradication programs and as an anesthetic in rodents. Methyleugenol was nominated for testing because of its widespread use and because of its structural resemblance to safrole, a known carcinogen, and isosafrole and estragole. Male and female F344/N rats and B6C3F1 mice received methyleugenol (approximately 99% pure) in 0.5% methylcellulose by gavage for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 9 or 10 male and 10 female F344/N rats were administered 0, 10, 30, 100, 300, or 1,000 mg methyleugenol/kg body weight in 0.5% methylcellulose by gavage 5 days per week for 14 weeks. A water control group of 10 male and 10 female rats received deionized water by gavage. All rats survived until the end of the study. The final mean body weights of 300 and 1,000 mg/kg males and of all dosed groups of females were significantly less than those of the vehicle controls. Erythrocyte microcytosis was demonstrated by decreased mean cell volumes in 300 mg/kg males and 1,000 mg/kg males and females. There was evidence of a thrombocytosis at all time points, demonstrated by increased platelet counts in the 100 mg/kg or greater groups. The serum activities of alanine aminotransferase and sorbitol dehydrogenase were increased in the 100 mg/kg or greater rats at various time points, suggesting hepatocellular injury. Additionally, bile acid concentrations were generally increased in the 300 and 1,000 mg/kg groups at all time points, consistent with cholestasis or altered hepatic function. A hypoproteinemia and hypoalbuminemia, evidenced by decreased

  20. NTP Toxicology and Carcinogenesis Studies of Nitromethane (CAS No. 75-52-5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1997-02-01

    Nitromethane is used as a rocket and engine fuel; as a synthesis intermediate for agricultural fumigants, biocides, and other products; as a solvent; and as an explosive in mining, oil-well drilling, and seismic exploration. It has been detected in air, in surface and drinking water, and in cigarette smoke. Nitromethane was studied because of the potential for widespread human exposure and because it is structurally related to the carcinogens 2-nitropropane and tetranitromethane. Male and female F344/N rats and B6C3F1 mice received nitromethane (purity 98% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived until the end of the study. The mean body weight gain of male rats in the 1,500 ppm group was slightly but significantly less than that of the controls; the final mean body weights and mean body weight gains of exposed females were similar to those of the controls. Clinical findings in all male and female rats in the 1,500 ppm groups included increased preening, rapid breathing, hyperactivity early in the study, and hypoactivity and loss of coordination in the hindlimbs near the end of the study. The relative liver weights of all exposed groups of male rats and the absolute and relative liver weights of females exposed to 375 ppm or greater were significantly greater than those of the controls. Minimal to mild degeneration of the olfactory epithelium was observed in the nose of males and females exposed to 375 ppm or greater. Sciatic nerve degeneration was present in all male and female rats exposed to 375 ppm or greater; rats exposed to 750 or 1,500 ppm also had reduced myelin around sciatic axons. 16

  1. Toxicology and carcinogenesis studies of two pentachlorophenol technical-grade mixtures (CAS No. 87-86-5) in B6C3F1 mice (feed studies). Technical report series

    SciTech Connect

    McConnell, E.E.

    1989-03-01

    Two-year toxicology and carcinogenicity studies were conducted by administering diets containing 100 or 200 ppm technical-grade pentachlorophenol or 100, 200 or 600 ppm Dowicide EC-7 to groups of 50 male and 50 female mice. Two groups of 35 male and 35 female mice were fed control diets. Under the conditions of the studies, there was clear evidence of carcinogenic activity for male B6C3F1 mice fed diets containing technical-grade pentachlorophenol, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was some evidence of carcinogenic activity for female B6C3F1 mice exposed to technical-grade pentachlorophenol, as shown by increased incidences of hemangiosarcomas and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for male B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for female B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms and hemangiosarcomas.

  2. NTP Toxicology and Carcinogenesis Studies of Dimethyl Methylphosphonate (CAS No. 756-79-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1987-11-01

    Dimethyl methylphosphonate (98% pure) is one of four chemicals nominated by the U.S. Army for toxicology and carcinogenesis studies because it was being considered for use to simulate the physical and spectroscopic (but not the biologic) properties of anticholinesterase (nerve) agents. Dimethyl methylphosphonate is also used as a flame retardant, a preignition additive for gasoline, an antifoam agent, a plasticizer and stabilizer, a textile conditioner and antistatic agent, and an additive for solvents and low-temperature hydraulic fluids. The United States produces 0.2-2 million pounds (91,000-910,000 kg) of per year. Gavage was chosen as the route of administration for all four candidate "simulants" to mimic potential exposure. Experimental Design: Dimethyl methylphosphonate was administered in corn oil by gavage to male and female F344/N rats and B6C3F1 mice in single-administration, 15-day, and 13-week studies to obtain toxicity data, to establish dose levels for the 2-year studies, and to identify target tissues. Additional studies were also performed to determine toxicity to the reproductive system of male F344/N rats and B6C3F1 mice and to study the potential for genetic damage in bacteria, mammalian cells, and Drosophila. Single-Administration Studies: In the single-administration studies, dimethyl methylphosphonate was given to rats and mice at doses up to 6,810 mg/kg body weight. No compound-related deaths were seen in male or female rats or male mice; two high dose female mice died. Rats exhibited inactivity, unsteady gait, and prostration after dosing; mice were inactive after dosing. Fifteen-Day Studies: Rats and mice received doses of 0, 1,250, 2,500, 5,000, 10,000, or 15,000 mg/kg dimethyl methylphosphonate per day. Compound-related deaths occurred in the three highest dose groups of rats and the two highest dose groups of mice. Rats receiving doses of 2,500 mg/kg or higher were inactive and at 5,000 or 10,000 mg/kg had an unsteady gait after dosing

  3. X-ray crystallographic characterization of new soluble endohedral fullerenes utilizing the popular C82 bucky cage. Isolation and structural characterization of Sm@C3v(7)-C82, Sm@C(s)(6)-C82, and Sm@C2(5)-C82.

    PubMed

    Yang, Hua; Jin, Hongxiao; Wang, Xinqing; Liu, Ziyang; Yu, Meilan; Zhao, Fukun; Mercado, Brandon Q; Olmstead, Marilyn M; Balch, Alan L

    2012-08-29

    Three isomers of Sm@C(82) that are soluble in organic solvents were obtained from the carbon soot produced by vaporization of hollow carbon rods doped with Sm(2)O(3)/graphite powder in an electric arc. These isomers were numbered as Sm@C(82)(I), Sm@C(82)(II), and Sm@C(82)(III) in order of their elution times from HPLC chromatography on a Buckyprep column with toluene as the eluent. The identities of isomers, Sm@C(82)(I) as Sm@C(s)(6)-C(82), Sm@C(82)(II) as Sm@C(3v)(7)-C(82), and Sm@C(82)(III) as Sm@C(2)(5)-C(82), were determined by single-crystal X-ray diffraction on cocrystals formed with Ni(octaethylporphyrin). For endohedral fullerenes like La@C(82), which have three electrons transferred to the cage to produce the M(3+)@(C(82))(3-) electronic distribution, generally only two soluble isomers (e.g., La@C(2v)(9)-C(82) (major) and La@C(s)(6)-C(82) (minor)) are observed. In contrast, with samarium, which generates the M(2+)@(C(82))(2-) electronic distribution, five soluble isomers of Sm@C(82) have been detected, three in this study, the other two in two related prior studies. The structures of the four Sm@C(82) isomers that are currently established are Sm@C(2)(5)-C(82), Sm@C(s)(6)-C(82), Sm@C(3v)(7)-C(82), and Sm@C(2v)(9)-C(82). All of these isomers obey the isolated pentagon rule (IPR) and are sequentially interconvertable through Stone-Wales transformations.

  4. Determination of structure of the MinD-ATP complex reveals the orientation of MinD on the membrane and the relative location of the binding sites for MinE and MinC

    PubMed Central

    Wu, Wei; Park, Kyung-Tae; Holyoak, Todd; Lutkenhaus, Joe

    2011-01-01

    Summary The three Min proteins spatially regulate Z ring positioning in E. coli and are dynamically associated with the membrane. MinD binds to vesicles in the presence of ATP and can recruit MinC or MinE. Biochemical and genetic evidence indicate the binding sites for these two proteins on MinD overlap. Here we solved the structure of a hydrolytic-deficient mutant of MinD truncated for the C-terminal amphipathic helix involved in binding to the membrane. The structure solved in the presence of ATP is a dimer and reveals the face of MinD abutting the membrane. Using a combination of random and extensive site-directed mutagenesis additional residues important for MinE and MinC binding were identified. The location of these residues on the MinD structure confirms that the binding sites overlap and reveals that the binding sites are at the dimer interface and exposed to the cytosol. The location of the binding sites at the dimer interface offers a simple explanation for the ATP-dependency of MinC and MinE binding to MinD. PMID:21231967

  5. How Are Preferences Revealed?

    PubMed Central

    Beshears, John; Choi, James J.; Laibson, David; Madrian, Brigitte C.

    2009-01-01

    Revealed preferences are tastes that rationalize an economic agent’s observed actions. Normative preferences represent the agent’s actual interests. It sometimes makes sense to assume that revealed preferences are identical to normative preferences. But there are many cases where this assumption is violated. We identify five factors that increase the likelihood of a disparity between revealed preferences and normative preferences: passive choice, complexity, limited personal experience, third-party marketing, and intertemporal choice. We then discuss six approaches that jointly contribute to the identification of normative preferences: structural estimation, active decisions, asymptotic choice, aggregated revealed preferences, reported preferences, and informed preferences. Each of these approaches uses consumer behavior to infer some property of normative preferences without equating revealed and normative preferences. We illustrate these issues with evidence from savings and investment outcomes. PMID:24761048

  6. Nucleophilic behaviour of dioxo- and thiooxophosphorane complexes [MoCp(CO)2{E,P-EP(O)(2,4,6-C6H2(t)Bu3)}](-) (E = O, S).

    PubMed

    Alonso, María; Alvarez, M Angeles; García, M Esther; García-Vivó, Daniel; Ruiz, Miguel A

    2014-11-14

    The title anions were prepared as (DBU-H)(+) salts upon reaction of the oxophosphinidene complex (H-DBU)[MoCp(CO)2{P(O)R*}] with either dimethyldioxirane or elemental sulphur (R* = 2,4,6-C6H2(t)Bu3; Cp = η(5)-C5H5, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene). The dioxophosphorane complex failed to react with MeI at room temperature, but reacted readily with (Me3O)BF4 to give the phosphonite complex [MoCp{O,P-OP(OMe)R*}(CO)2]. In contrast, the thiooxophosphorane complex reacted with MeI to give the thiolophosphinide derivative [MoCp{S,P-(MeS)P(O)R*}(CO)2], whereas its reaction with (Me3O)BF4 gave a mixture of the latter complex and the phosphonothiolate isomer [MoCp{S,P-SP(OMe)R*}(CO)2] in similar amounts. Other electrophiles were added selectively to the terminal O atom of the R*POS ligand. Thus the thiooxophosphorane complex reacted with ClC(O)C2H3, [NH4]PF6, ClSiMe3, ClSnMe3 and [ZrCp2Cl2] to give the corresponding derivatives [MoCp{S,P-SP(OX)R*}(CO)2] (X = C(O)C2H3, H, SiMe3, SnMe3, ZrCp2Cl). The structure of two of these products (X = C(O)C2H3, SiMe3) was determined by single-crystal X-ray diffraction studies. Density functional theory (DFT) calculations of the title anions and some of their derivatives indicated that attachment of an external electrophile to the terminal O atom of the thiooxophosphorane ligand is favoured under the conditions of charge control, while the sulphur atom is the favoured site under the conditions of orbital control, although it leads to less stable products.

  7. Mixed triorganobismuthines RAr2Bi [Ar = C6F5, 2,4,6-(C6F5)3C6H2] and hypervalent racemic Bi-chiral diorganobismuth(iii) bromides RArBiBr (Ar = C6F5, Mes, Ph) with the ligand R = 2-(Me2NCH2)C6H4. Influences of the organic substituent.

    PubMed

    Olaru, Marian; Nema, Mihai G; Soran, Albert; Breunig, Hans J; Silvestru, Cristian

    2016-06-21

    Triorganobismuthines R(C6F5)2Bi (1) and R[2,4,6-(C6F5)3C6H2]2Bi (2) [R = 2-(Me2NCH2)C6H4] were synthesized by reaction of RBiBr2 with C6F5MgBr and 2,4,6-(C6F5)3C6H2Li, respectively, in a 1 : 2 molar ratio. The Bi-chiral bromides R(C6F5)BiBr (3), R(Mes)BiBr (4), and R(Ph)BiBr (5) were obtained from RBiBr2 and C6F5MgBr, MesMgBr or PhMgBr, or from PhBiBr2 and RLi, in a 1 : 1 molar ratio. The molecular structures of 1-5 were determined by single-crystal X-ray diffraction and are discussed taking into account the chirality of the species. Supramolecular aspects in the solid state are presented. The solution behaviour of the title compounds, including dynamic aspects, are discussed on the basis of multinuclear ((1)H, (13)C, (19)F) NMR spectroscopy.

  8. Determination of the Chronic Mammalian Toxicological Effects of TNT (twenty-Four Month Chronic Toxicity/Carcinogenicity Study of Trinitrotoluene (TNT) in the B6C3F1 Hybrid Mouse). Volume 1

    DTIC Science & Technology

    1984-12-01

    8217 ..g/kg/day and slight body weight loss at the 700 mg/kg/day dose level. Major toxic effects Included hemolysis of red cells as W suggested by...economically Important crops . Ir, adcitiun, extensive chemical and biological fate and persistence ies s re conducted to provide Information on the behavior of a...reductions In body weight gain at 100 mg/kg/Cay ard U sl ijht body weight loss at the 700 m6/kg/day dose level. Requests for Volume II should be directed

  9. Evaluation of on-line pyrolysis coupled to isotope ratio mass spectrometry for the determination of position-specific (13)C isotope composition of short chain n-alkanes (C6-C12).

    PubMed

    Gilbert, Alexis; Yamada, Keita; Yoshida, Naohiro

    2016-06-01

    We measured (13)C intramolecular isotopic composition of commercially available short-chain hydrocarbons (n-C6-n-C12) using (13)C-NMR. Results show that the main variation is between the terminal and the sub-terminal C-atom positions. Site-preference (difference in δ(13)C values between terminal and sub-terminal C-atom positions) among all the samples varies between -12.2‰ and +8.4‰. Comparison of these results with those obtained using on-line pyrolysis coupled with GC-C-IRMS show that the thermal cracking of hydrocarbons occurs with a good isotopic fidelity between terminal and sub-terminal C-atom positions of the starting material and the related pyrolysis products (methane and ethylene). On-line pyrolysis coupled with GC-C-IRMS can thus be used for tracing hydrocarbons biogeochemical processes.

  10. Determination of the nucleotide sequence of the 23S ribosomal RNA and flanking spacers of an Enterococcus faecium strain, reveals insertion-deletion events in the ribosomal spacer 1 of enterococci.

    PubMed

    Naimi, A; Beck, G; Monique, M; Lefèbvre, G; Branlanti, C

    1999-02-01

    The usefulness of 16S-23S (ITS1) and 23S-5S (ITS2) ribosomal spacer nucleotide sequence determination, as a complementary approach to the biochemical tests traditionally used for enterococcal species identification, is shown by its application to the identification of a strain, E27, isolated from a natural bacteria mixture used for cheese production. Using combined approaches we showed, unambiguously, that strain E27 belongs to the Enterococcus faecium species. However, its ITS1 region has an interesting peculiarity. In our previous study of ITS1s from various enterococcal species (NAIMI et al., 1997, Microbiology 143, 823-834), the ITS1s of the two E. faecium strains studied, were found to contain an additional 115-nt long stem-loop structure as compared to the ITS1s of other enterococci, only one out of the 3 ITS1s of E. hirae ATCC 9790, was found to contain a similar 107-nt long stem-loop structure. The ITS1 of strain E27 is 100% identical to that of E. faecium ATCC 19434T, except that the 115-nt additional fragment is absent. This strongly suggests the existence of lateral DNA transfer or DNA recombination events at a hot spot position of the ITS1s from E. faecium and E. hirae. Small and large ITS1 nucleotide sequence determination for strain E27 generalized the notion of two kinds of ITSs in enterococci: one with a tRNA(Ala) gene, one without tRNA gene. To complete strain E27 characterization, its 23S rRNA sequence was established. This is the first complete 23S rRNA nucleotide sequence determined for an enterococcal species.

  11. Plan of study to determine if the isotopic ratios [delta]15 N and [delta]18 O can reveal the sources of nitrate discharged by the Mississippi River into the Gulf of Mexico

    USGS Publications Warehouse

    Battaglin, William A.; Kendall, Carol; Goolsby, Donald A.; Boyer, Laurie L.

    1997-01-01

    Nitrate and other nutrients discharged from the Mississippi River basin are suspected of causing a zone of depleted dissolved oxygen (hypoxic zone) in the Gulf of Mexico each summer. The hypoxic zone may have an adverse effect on aquatic life and commercial fisheries. Commercial fertilizers are the dominant source of nitrogen input to the Mississippi basin. Other nitrogen sources include animal waste, fixation of atmospheric nitrogen by legumes, precipitation, domestic and industrial effluent, and the soil. The inputs of nitrogen from most of these sources to the Mississippi basin can be estimated and the outputs in surface water can be measured. However, nitrogen from each source is affected differently by physical, chemical, and biological processes that control nitrogen cycling in terrestrial and aquatic systems. Hence, the relative contributions from the various sources of nitrogen to nitrate load in the Mississippi River are unknown because the different sources may not contribute proportionally to their inputs in the basin. It may be possible to determine the relative contributions of the major sources of nitrate in river water using the stable isotopic ratios d15N and d18O of the nitrate ion. A few researchers have used the d15N and/or d18O isotope ratios to determine sources of nitrate in ground water, headwater catchments, and small rivers, but little is known about the isotopic composition of nitrate in larger rivers. The objective of this study is to measure the isotopic composition of nitrate and suspended organic matter in the Mississippi River and its major tributaries, in discharge to the Gulf of Mexico, and in streamflow from smaller watersheds that have distinct sources of nitrogen (row crops, animal wastes, and urban effluents) or are minimally impacted by man (undeveloped). Samples from seven sites on the Mississippi River and its tributaries and from 17 sites in smaller watersheds within the Mississippi River basin will be analyzed for d15N and

  12. Effects of psychological stress on plasma interleukins-1 beta and 6, C-reactive protein, tumour necrosis factor alpha, anti-diuretic hormone and serum cortisol.

    PubMed

    Dugué, B; Leppänen, E A; Teppo, A M; Fyhrquist, F; Gräsbeck, R

    1993-10-01

    The study was undertaken to determine whether psychological stress influences immunobiological functions and is an important preanalytical factor to be considered in connection with blood specimen collection. Two kinds of stress were applied, the Stroop colour conflict test and the thrill of a novice about to make the first jump with a parachute. In both test situations, the level of the stress indicators cortisol or anti-diuretic hormone rose significantly. The concentrations of the cytokines studied did not change significantly. However, in the parachute test significant positive correlations were found, e.g. between the changes of cortisol and C-reactive protein and between anti-diuretic hormone and interleukin-1 beta. This suggests that there is an interaction between the endocrine and the immune systems in the response to a psychological stress.

  13. Nqrs Data for C3H10INO6 [C3H7NO2·HIO3·(1/2)(H2O)] (Subst. No. 0642)

    NASA Astrophysics Data System (ADS)

    Chihara, H.; Nakamura, N.

    This document is part of Subvolume A `Substances Containing Ag … C10H15' of Volume 48 `Nuclear Quadrupole Resonance Spectroscopy Data' of Landolt-Börnstein - Group III `Condensed Matter'. It contains an extract of Section `3.2 Data tables' of the Chapter `3 Nuclear quadrupole resonance data' providing the NQRS data for C3H10INO6 [C3H7NO2·HIO3·(1/2)(H2O)] (Subst. No. 0642)

  14. Central-to-axial chirality transfer revealed by liquid crystals: a combined experimental and computational approach for the determination of absolute configuration of carboxylic acids with an α chirality centre.

    PubMed

    Ferrarini, Alberta; Ferroni, Fiammetta; Pieraccini, Silvia; Rosini, Carlo; Superchi, Stefano; Spada, Gian Piero

    2011-10-01

    The conversion into 6,7-dihydro-5H-dibenz[c,e]azepine (DAZ) N-protected amides is a viable route for the determination of the absolute configuration of chiral 2-substituted carboxylic acids. The biphenyl moiety of DAZ, besides being a probe of chirality for the electronic circular dichroism (ECD) spectroscopy, makes these systems suitable for configuration assignment by exploiting the chirality amplification which occurs in nematic liquid crystals. To assess the reliability of the liquid crystal method in detecting the absolute stereochemistry of chiral amides bound to a biphenyl group, we measured the helical twisting power of a series of DAZ-N-protected amides and compared these data with the results obtained from ECD measurements. We will show that the liquid crystal method, corroborated by HTP predictions, is trustworthy with our biphenyl derivatives, even when ECD spectra are ambiguous for the presence of aryl moieties displaying strong UV absorptions in the same range of the biphenyl chromophore.

  15. Retained Austenite Phase in (26.5%Cr, 2.6%C) White Cast Iron Studied by Means of CEMS and Eddy Current

    NASA Astrophysics Data System (ADS)

    Mulaba-Bafubiandi, A. F.; Waanders, F. B.; Jones, C.

    High chrome white irons are specifically employed in the mining industry for their resistance to wear. More cost-effective materials are constantly being sought, due to the high wear rate of the drilling components, which is a high cost area for this industry. Optimum resistance to wear is often not the main criterion of material selection but parameters such as ease of fabrication; availability and low initial cost have also to be accounted for. A correctly heat-treated high chrome white iron of a right chemical composition presents the best hardness and toughness combination [1]. A (26.5 wt.% Cr, 2.6 wt.% C) white iron has been produced by casting and heat-treating. As the retained austenite phase has the ability to harden, the control of its content may result in tuning the applications of this material. Various heat-treatments were given to the above-mentioned material to achieve a spread of austenite values. The retained austenite phase amount was measured by means of X-ray diffraction (XRD), Conversion Electron Mössbauer spectroscopy (CEMS) and Eddy current techniques. A linear correlation between results from Eddy Current and CEMS, Eddy-current and XRD, and between those from CEMS and XRD was observed. As the nominal abundance values were ``technique dependent'', their conversion will be discussed. The present study results in the calibration of the Eddy current apparatus and suggests its application in the casting industry during mass production for the retained austenite content determination in high chrome white iron castings.

  16. Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network.

    PubMed

    Senkal, Can E; Ponnusamy, Suriyan; Manevich, Yefim; Meyers-Needham, Marisa; Saddoughi, Sahar A; Mukhopadyay, Archana; Dent, Paul; Bielawski, Jacek; Ogretmen, Besim

    2011-12-09

    Mechanisms that regulate endoplasmic reticulum (ER) stress-induced apoptosis in cancer cells remain enigmatic. Recent data suggest that ceramide synthase1-6 (CerS1-6)-generated ceramides, containing different fatty acid chain lengths, might exhibit distinct and opposing functions, such as apoptosis versus survival in a context-dependent manner. Here, we investigated the mechanisms involved in the activation of one of the major ER stress response proteins, ATF-6, and subsequent apoptosis by alterations of CerS6/C(16)-ceramide. Induction of wild type (WT), but not the catalytically inactive mutant CerS6, increased tumor growth in SCID mice, whereas siRNA-mediated knockdown of CerS6 induced ATF-6 activation and apoptosis in multiple human cancer cells. Down-regulation of CerS6/C(16)-ceramide, and not its further metabolism to glucosylceramide or sphingomyelin, activated ATF-6 upon treatment with ER stress inducers tunicamycin or SAHA (suberoylanilide hydroxamic acid). Induction of WT-CerS6 expression, but not its mutant, or ectopic expression of the dominant-negative mutant form of ATF-6 protected cells from apoptosis in response to CerS6 knockdown and tunicamycin or SAHA treatment. Mechanistically, ATF-6 activation was regulated by a concerted two-step process involving the release of Ca(2+) from the ER stores ([Ca(2+)](ER)), which resulted in the fragmentation of Golgi membranes in response to CerS6/C(16)-ceramide alteration. This resulted in the accumulation of pro-ATF-6 in the disrupted ER/Golgi membrane network, where pro-ATF6 is activated. Accordingly, ectopic expression of a Ca(2+) chelator calbindin prevented the Golgi fragmentation, ATF-6 activation, and apoptosis in response to CerS6/C(16)-ceramide down-regulation. Overall, these data suggest a novel mechanism of how CerS6/C(16)-ceramide alteration activates ATF6 and induces ER-stress-mediated apoptosis in squamous cell carcinomas.

  17. Influence of dietary selenium on the disposition of arsenate in the female B6C3F{sub 1} mouse

    SciTech Connect

    Kenyon, E.M.; Hughes, M.F.; Levander, O.A.

    1997-06-27

    Interactions between arsenic (As) and selenium (Se) at the metabolic level are multifaceted and complex. These interactions are of practical significance because populations in various parts of the world are simultaneously exposed to inorganic As in drinking water and Se mainly in the diet at varying levels. The primary goal of this study was to investigate whether differing dietary Se status would alter the profile of urinary metabolites or their time course for elimination after exposure to arsenate [As(V)]. Weanling female 86C3F, mice were maintained for 28 d on either a control diet of powdered rodent meal sufficient in Se (A 0.2 ppm) or Torula yeast-based (TYB) diets deficient (B, 0.02 ppm Se), sufficient (C, 0.2 ppm Se), or excessive (D, 2.0 ppm Se) in Se; mice then received by oral gavage 5 mg (As)/kg as sodium [{sup 73}As] arsenate. The time course for elimination of total arsenic and metabolites in urine was measured over a 48-h period, and total arsenic was determined in feces and tissues at 48 h. Mice on the Se excess diet excreted a significantly higher percentage of urinary As as inorganic As, with a significantly decreased ratio of organic to inorganic As compared to Se-sufficient mice, suggesting that As methylation was decreased. Mice on the Se-deficient diet appeared to eliminate As(V), arsenite, and dimethylarsinic acid (DMA) in urine more slowly than Se-sufficient mice; however, further studies are required to confirm this finding. Mice on the Se-sufficient meal diet (A) excreted significantly less (by percent) arsenate-derived radioactivity in urine and more in feces compared to mice on the Se-sufficient TYB diet (C), with total elimination being similar for both groups. This indicates that mice on the meal diet absorbed significantly less As(V) than mice on the TYB diet, and this may be due to more fiber or {open_quotes}bulk{close_quotes} in the meal diet. 35 refs., 6 figs., 6 tabs.

  18. Comparative analysis of novel complement-targeted inhibitors, miniFH, and the natural regulators Factor H and Factor H-like protein 1 reveal functional determinants of complement regulation

    PubMed Central

    Harder, Markus J.; Anliker, Markus; Höchsmann, Britta; Simmet, Thomas; Huber-Lang, Markus; Schrezenmeier, Hubert; Ricklin, Daniel; Lambris, John D.; Barlow, Paul N.; Schmidt, Christoph Q.

    2015-01-01

    The serum proteins Factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product Factor H-like protein 1 (FHL-1; consisting of CCPs 1–7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows ~10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs (19–20) that is cryptic in full-length native FH. Therefore we produced a FH variant lacking the central domains 10–15 (FHΔ10–15). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FHΔ10–15 and midiFH to miniFH, FH and FHL-1. Relative to FH, FHΔ10–15 exhibited an altered binding profile toward C3 activation products and a 5-fold-enhanced complement regulation on PNH patient’s erythrocytes. Contrary to dogma, FHL-1 and FH exhibited equal regulatory activity, suggesting that the role of FHL-1 in AP regulation has been underestimated. Unexpectedly, a substantially increased avidity for complement opsonins, as seen in midiFH, did not potentiate the inhibitory potential on host cells. In conclusion, comparisons of engineered and native FH-based regulators have identified features that determine high AP regulatory activity on host cells. Unrestricted availability of FH CCPs 19–20 and an optimal spatial orientation between the N- and C-terminal FH regions are key. PMID:26643478

  19. NTP Toxicology and Carcinogenesis Studies of Pyridine (CAS No. 110-86-1) in F344/N Rats, Wistar Rats, and B6C3F1 Mice (Drinking Water Studies).

    PubMed

    2000-03-01

    Pyridine is used as a denaturant in alcohol and anti freeze mixtures, as a solvent for paint, rubber, and polycarbonate resins, and as an intermediate in the manufacture of insecticides, herbicides, and fungicides. It is used in the production of piperidine, an intermediate in the manufacture of rubber and mepiquat chloride, and as an intermediate and solvent in the preparation of vitamins and drugs, dyes, textile water repellants, and flavoring agents in food. Pyridine was nominated for study because of its large production volume and its use in a variety of food, medical, and industrial products. Male and female F344/N rats, male Wistar rats, and male and female B6C3F1 mice were exposed to pyridine (approximately 99% pure) in drinking water for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 13-WEEK STUDY IN F344/N RATS: Groups of 10 male and 10 female F344/N rats were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 5, 10, 25, 55, or 90 mg pyridine/kg body weight). Two females exposed to 1,000 ppm died during week 1. Final mean body weights of 1,000 ppm males and females and 500 ppm females were significantly less than controls. Water consumption by female rats exposed to 1,000 ppm was less than that by controls. At study termination, evidence of anemia persisted in the 500 and 1,000 ppm males and all exposed groups of females. There was evidence of hepatocellular injury and/or altered hepatic function demonstrated by increased serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentrations in 500 and 1,000 ppm rats. The estrous cycle length of 1,000 ppm females was significantly longer than that of the controls. Liver weights of males and females exposed to 250 ppm or greater were

  20. Solvato-polymorph of [(η6-C6H6)RuCl (L)]PF6 (L = (2,6-dimethyl-phenyl-pyridin-2-yl methylene amine)

    NASA Astrophysics Data System (ADS)

    Gichumbi, Joel M.; Friedrich, Holger B.; Omondi, Bernard

    2016-06-01

    A half-sandwich complex salt of ruthenium containing the Schiff base ligand, 2, 6-dimethyl-N-(pyridin-2-ylmethylene)aniline has been synthesized and structurally characterized. The complex salt 1, [(η6-C6H6)RuCl(C5H4NCHdbnd N(2,6-(CH3)2C6H3)]PF6 was obtained from the reaction of the ruthenium arene precursor, [(η6- C6H6)Ru(μ-Cl)Cl]2 with the Schiff base in a 1:2 ratio followed by treatment with NH4PF6. Its acetone solvate 2, [(η6-C6H6)RuCl(C5H4NCHdbnd N (2, 6- (CH3)2C6H3)]PF6. (CH3)2CO was obtained by recrystallization of 1 from a solution of hexane and acetone. 1 and 2 crystallize in the monoclinic P21/c and P21/n space groups as blocks and as prisms respectively. The ruthenium centers in 1 and 2 are coordinated to the bidentate Schiff base, to a chloride atom, and to the arene ring to give a pseudo-octahedral geometry around them. The whole arrangement is referred to as the familiar three-legged piano stool in which the Schiff base and the Cl atom serve as the base while the arene ring serve as the apex of the stool. Polymorph 2 has an acetone molecule in the asymmetric unit. Of interest is the similar behavior of the solvate on heating which shows the crystals shuttering at about 531.6 and 523.4 K for 1 and 2 respectively.

  1. Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids.

    PubMed

    Maes, M; Smith, R; Christophe, A; Cosyns, P; Desnyder, R; Meltzer, H

    1996-04-26

    Recently, there were some reports that major depression may be accompanied by alterations in serum total cholesterol, cholesterol ester and omega 3 essential fatty acid levels and by an increased C20: 4 omega 6/C20: 5 omega 3, i.e., arachidonic acid/eicosapentaenoic, ratio. The present study aimed to examine fatty acid composition of serum cholesteryl esters and phospholipids in 36 major depressed, 14 minor depressed and 24 normal subjects. Individual saturated (e.g., C14:0; C16:0, C18:0) and unsaturated (e.g., C18:1, C18:2, C20:4) fatty acids in phospholipid and cholesteryl ester fractions were assayed and the sums of the percentages of omega 6 and omega 3, saturated, branched chain and odd chain fatty acids, monoenes as well as the ratios omega 6/omega 3 and C20:4 omega 6/C20:5 omega 3 were calculated. Major depressed subjects had significantly higher C20:4 omega 6/C20:5 omega 3 ratio in both serum cholesteryl esters and phospholipids and a significantly increased omega 6/omega 3 ratio in cholesteryl ester fraction than healthy volunteers and minor depressed subjects. Major depressed subjects had significantly lower C18:3 omega 3 in cholesteryl esters than normal controls. Major depressed subjects showed significantly lower total omega 3 polyunsaturated fatty acids in cholesteryl esters and significantly lower C20:5 omega 3 in serum cholesteryl esters and phospholipids than minor depressed subjects and healthy controls. These findings suggest an abnormal intake or metabolism of essential fatty acids in conjunction with decreased formation of cholesteryl esters in major depression.

  2. Nqrs Data for C9H21CaCl2N3O6 [C9H21N3O6·CaCl2] (Subst. No. 1196)

    NASA Astrophysics Data System (ADS)

    Chihara, H.; Nakamura, N.

    This document is part of Subvolume A `Substances Containing Ag … C10H15' of Volume 48 `Nuclear Quadrupole Resonance Spectroscopy Data' of Landolt-Börnstein - Group III `Condensed Matter'. It contains an extract of Section `3.2 Data tables' of the Chapter `3 Nuclear quadrupole resonance data' providing the NQRS data for C9H21CaCl2N3O6 [C9H21N3O6·CaCl2] (Subst. No. 1196)

  3. NTP Toxicology and Carcinogenesis Studies of Penicillin VK (CAS No. 132-98-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1988-06-01

    1535, or TA1537 with or without exogenous metabolic activation. The chemical was mutagenic onl exogenous metabolic activation. The chemical was mutagenic only with activation in the mouse lymphoma L5178Y/TK± forward mutation assay. Incubation of Chinese hamster ovary cells with penicillin VK resulted in increased frequencies of sister chromatid exchanges and chromosomal aberrations in the absence of metabolic activation under the conditions of delayed harvest to compensate for chemical-induced cell cycle delay, no effects from penicillin VK exposure were observed in these cells in the presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of penicillin VK were audited. The audit findings show that the conduct of the studies is documented and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of penicillin VK for F344/N rats or for B6C3F1 mice administered 500 or 1,000 mg/kg penicillin VK in corn oil gavage, 5 days per week for 2 years. Nonneoplastic lesions were seen in the glandular stomach of dosed mice. Decreased survival of low and high dose male rats and of high dose female rats reduced the sensitivity of the studies for determining the presence or absence of a carcinogenic response in this species. Synonyms: 4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-(2-phenoxy-acetamide)-, monopotassium salt; penicillin V potassium; penicillin V potassium salt; D-a-phenoxymethylpenicillinate K salt; phenoxymethylpenicillin potassium; PVK Trade Names: Antibiocin; Apsin VK; Aracil; Arcasin; Aspin VK; Beromycin; Beromycin 400; Betapen VK; Calciopen K; Cliacil; Compocillin VK; Distakaps V-K; Distaquaine V-K; Dowpen V-K; DQV-K; Fenoxypen; Icipen; Isocillin; Ispenoral; Ledercillin VK; Megacillin oral; Oracil-VK; Orapen; Ospeneff; Pedipen; Penagen; Pencompren; Pen-Vee K; Pen-V-K powder; Penvikal

  4. Revealing power in truth

    PubMed Central

    Lee, Kelley

    2015-01-01

    Jeremy Shiffman’s editorial appropriately calls on making all forms of power more apparent and accountable, notably productive power derived from expertise and claims to moral authority. This commentary argues that relationships based on productive power can be especially difficult to reveal in global health policy because of embedded notions about the nature of power and politics. Yet, it is essential to recognize that global health is shot through with power relationships, that they can take many forms, and that their explicit acknowledgement should be part of, rather than factored out of, any reform of global health governance. PMID:25844390

  5. Quantitative phosphoproteomics reveals new roles for the protein phosphatase PP6 in mitotic cells

    PubMed Central

    Rusin, Scott F.; Schlosser, Kate A.; Adamo, Mark E.; Kettenbach, Arminja N.

    2017-01-01

    Protein phosphorylation is an important regulatory mechanism controlling mitotic progression. Protein phosphatase 6 (PP6) is an essential enzyme with conserved roles in chromosome segregation and spindle assembly from yeast to humans. We applied a baculovirus-mediated gene silencing approach to deplete HeLa cells of the catalytic subunit of PP6 (PP6c) and analyzed changes in the phosphoproteome and proteome in mitotic cells by quantitative mass spectrometry–based proteomics. We identified 408 phosphopeptides on 272 proteins that increased and 298 phosphopeptides on 220 proteins that decreased in phosphorylation upon PP6c depletion in mitotic cells. Motif analysis of the phosphorylated sites combined with bioinformatics pathway analysis revealed previously unknown PP6c–dependent regulatory pathways. Biochemical assays demonstrated that PP6c opposed casein kinase 2–dependent phosphorylation of the condensin I subunit NCAP-G, and cellular analysis showed that depletion of PP6c resulted in defects in chromosome condensation and segregation in anaphase, consistent with dysregulation of condensin I function in the absence of PP6 activity. PMID:26462736

  6. Toxicology and carcinogenesis studies of nitrofurantoin (CAS No. 67-20-9) in F344/n rats and B6C3F1 mice (feed studies). Technical report

    SciTech Connect

    French, J.E.

    1989-09-01

    Two-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 600, or 1,300 ppm nitrofurantoin to groups of 50 female rats for 103 weeks. Groups of 50 male rats and 50 mice of each sex were fed diets containing 0, 1,300 or 2,500 ppm for 103 weeks. Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcutaneous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis and neoplasms of the preputial gland were decreased in the 2,500-ppm group of male rats. There was no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 ppm or 1,300 ppm for 2 years. Female rats may have been able to tolerate higher doses. There was no evidence of carcinogenic activity of nitrofurantoin for male B6C3F(1) mice fed diets containing 1,300 ppm or 2,500 ppm for 2 years. There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F(1) mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary.

  7. DOE 5700.6C, 10CFR830.120, DOE-ER-STD-6001-92, and Covey-based TQM: A historical perspective on current issues in research environments

    SciTech Connect

    Bodnarczuk, M

    1994-06-01

    Three years ago there were no standards or published guidelines for quality in research environments. Today, one standard has been published, and three guidelines documents are in final draft form and about to be published. In this paper, I describe the events that led to the writing of DOE 5700.6C, 10CFR830.120, and DOE-ER-STD-6001-92, focusing on the cultural barriers that arose (largely in the community of quality assurance professionals) during this process. I go on to describe why I believe that implementing DOE 5700.6C and 10CFR830.120 must be pushed even further toward an approach that embodies the Malcolm Baldrige National Quality Award and why even this is not far enough. The reason is because the most crucial aspect of successfully implementing a quality initiative is to base it on a cohesive, unified foundation of organizational and individual values and beliefs. Stephen Covey`s 7 Habits of Highly Effective People and Principle Centered Leadership provide such a foundations.

  8. Carcinogenesis studies of trichloroethylene (without epichlorohydrin) (CAS No. 79-01-6) in F344/N rats and B6C3F1 mice (gavage studies). Technical report series (Final)

    SciTech Connect

    Not Available

    1990-05-01

    Carcinogenesis studies of epichlorohydrin-free trichloroethylene were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Dose levels were 500 and 1,000 mg/kg for rats and 1,000 mg/kg for mice. Under the conditions of these studies, epichlorohydrin-free trichloroethylene caused renal tubular-cell neoplasms in male F344/N rats, produced toxic nephrosis in both sexes, and shortened the survival time of males. The experiment in male F344/N rats was considered to be inadequate to evaluate the presence or absence of a carcinogenic response to trichloroethylene. For female F344/N rats receiving trichloroethylene containing no epichlorohydrin, there was no evidence of carcinogenicity. Trichloroethylene (without epichlorohydrin) was carcinogenic for B6C3F1 mice, causing increased incidences of hepatocellular carcinomas in males and females and hepatocellular adenomas in females.

  9. The Universe Revealed

    NASA Astrophysics Data System (ADS)

    Spence, Pam

    1998-10-01

    The Universe is a bewildering place to the uninitiated. The concepts and theories that govern space seem complex and often contradictory. The Universe Revealed provides the keys to unlocking the wonders of the cosmos. Elegantly written and lavishly illustrated, it begins with the Sun and stretches through our solar system into deepest space. Lucid prose, written by many of the people who have shaped our current thinking on space, and spectacular photographs make the physics of the Universe accessible and provide a solid background for understanding the most recent astronomical discoveries. Covering the most intriguing features of the cosmos, the topics discussed range from the Earth and global warming to cosmic collisions and the size of the Universe. Major sections examine the Solar System, stars, galaxies, cosmology, and the observational techniques used by astronomers, both amateur and professional. The Universe Revealed represents the collaboration of internationally renowned experts in astronomy and cosmology, with contributions from authors including David Malin, F. Duccio Macchetto, Iain Nicholson, Neil Bone, Ian Ridpath, Seth Shostak, Mike Lancaster, Steve Miller, Ken Croswell, Geoff McNamara, and Steven Young. This extraordinary blend of astronomy, astrophysics, and cosmology, will appeal to amateur and armchair astronomers alike.

  10. Gusev's Rim Revealed

    NASA Technical Reports Server (NTRS)

    2004-01-01

    NASA's Mars Exploration Rover Spirit took this panoramic camera image on sol 91 (April 5, 2004). Spirit is looking to the southeast, and through the martian haze has captured the rim of Gusev Crater approximately 80 kilometers (49.7 miles) away on the horizon.

    The right side of this image reveals the portion of the crater edge that descends into the mouth of Ma'adim Vallis, a channel that opens into Gusev Crater. Spirit is currently traveling toward the informally named 'Columbia Hills,' which lie to the left of the region pictured here.

    This image is similar to a panoramic camera image taken on sol 68, but Gusev's ridge is more visible here because the atmospheric dust caused by winter dust storms has settled. Scientists expect to get even clearer images than this one in upcoming sols.

    This image has been modified to make the crater rim more visible.

  11. Ancient River revealed

    NASA Astrophysics Data System (ADS)

    Recent flights of the Spaceborne Imaging Radar-C/X-band Synthetic Aperture Radar (SIR-C/X-SAR) mission aboard the space shuttle Endeavour discovered a previously unknown branch of an ancient river. The images, released at AGU's Spring Meeting, show the river channel buried under thousands of years worth of windblown sand in a region of North Africa's Sahara Desert near the Kufra Oasis in southeast Libya, centered at 23.3°N latitude, 22.9°E longitude. The image from the flight last October reveals a system of old, now inactive stream valleys, called “paleodrainage systems,” which carried running water northward across the Sahara during periods of wetter climate.

  12. NTP Toxicology and Carcinogenesis Studies of Polybrominated Biphenyls (CAS No. 67774-32-7)(Firemaster FF-1(R)) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    PubMed

    1993-08-01

    Polybrominated biphenyls are synthetic chemicals used as flame retardants. The technical product used in these studies, Firemaster FF-1(R)), is a mixture of brominated biphenyls. Firemaster FF-1(R)) is a known liver carcinogen in rats and mice and is one of three compounds chosen by the National Toxicology Program to investigate the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of polybrominated biphenyls (Firemaster FF-1(R)) were conducted in F344/N rats and B6C3F1 mice of each sex. The studies were designed to determine: a) the effects of polybrominated biphenyls in rats and mice receiving adult ( F1) exposure only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of polybrominated biphenyls in rats and mice receiving perinatal (F0) exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and c) the effects of combined perinatal and adult exposure to polybrominated biphenyls. STUDIES IN F344/N RATS: The exposure levels selected for F1 exposure, based on studies of polybrominated biphenyls in the literature, were 3, 10, and 30 ppm. In a preliminary study to determine the perinatal dietary concentrations for the 2-year study, female rats were administered 1 to 30 ppm polybrominated biphenyls in the feed beginning 60 days prior to breeding and continuing throughout gestation, lactation, and up to 4 weeks postweaning. The mean preweaning litter weight of the 30 ppm group was less than 80% of the mean litter weight of the control group at days 0, 4, and 12. At weaning, the mean weight of litters in this group was 80% of the control group mean. The final mean body weights (28 days after weaning) of males and females receiving 30 ppm were 13% to 19% lower than the final mean body weights of the controls. Therefore, dietary concentrations of 0, 1, 3, and 10 ppm were selected for the F0 exposure levels in the 2-year study. The eight

  13. Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice

    SciTech Connect

    Auttachoat, Wimolnut; Zheng Jianfeng; Chi, Rui P.; Meng, Andrew; Guo, Tai L. . E-mail: tlguo@vcu.edu

    2007-02-01

    Previously, we have reported that thalidomide (Thd) can enhance neutrophil function in female B6C3F1 mice. The present study was intended to evaluate the mechanisms underlying the enhanced neutrophil responses following Thd treatment intraperitoneally (100 mg/kg) for 14 or 28 days. Treatment with Thd increased the numbers of neutrophils in the spleen, peripheral blood, bone marrow, peritoneal cavity and lungs of female B6C3F1 mice when compared to the vehicle control mice. Thd treatment for 14 days increased the percentage and the number of neutrophils in the spleen in the first 8 h (peaking at 2 h) after the last Thd treatment, and it returned to the baseline after 24 h. However, Thd treatment for 28 days increased the percentage and number of neutrophils in the spleen even at the 24-h time point after the last Thd treatment. These neutrophils were demonstrated to be functional by the myeloperoxidase activity assay. Further studies have ruled out the possibility of an increased bone marrow granulopoiesis following Thd treatment. Flow cytometric analysis of the surface expression of adhesion molecules suggested that Thd treatment for either 14 or 28 days decreased the surface expression of either CD18 or CD44 by bone marrow neutrophils. On the other hand, the surface expression of both CD18 and CD44 by splenic neutrophils was increased following Thd treatment for 28 days but not for 14 days. No effect was produced for other cell surface molecules such as CD62L and CD11a. It was possible that decreased surface expressions of CD18 and CD44 facilitated neutrophils' release from the bone marrow; increased surface expressions of CD44 and CD18 by splenic neutrophils after 28 days of Thd treatment increased their ability to remain in the periphery. Taken together, Thd treatment increased neutrophils in female B6C3F1 mice, at least partially, through differentially modulating the surface expression of CD18 and CD44 by the neutrophils in the bone marrow and spleen00.

  14. First-Principles Study of the Electronic Structure and Bonding Properties of X8C46 and X8B6C40 (X: Li, Na, Mg, Ca) Carbon Clathrates

    NASA Astrophysics Data System (ADS)

    KoleŻyński, Andrzej; Szczypka, Wojciech

    2016-03-01

    Results from theoretical analysis of the crystal structure, electronic structure, and bonding properties of C46 and B6C40 carbon clathrates doped with selected alkali and alkaline earth metals cations (Li, Na, Mg, Ca) are presented. The ab initio calculations were performed by means of the WIEN2k package (full potential linearized augmented plane wave method (FP-LAPW) within density functional theory (DFT)) with PBESol and modified Becke-Johnson exchange-correlation potentials used in geometry optimization and electronic structure calculations, respectively. The bonding properties were analyzed by applying Bader's quantum theory of atoms in molecules formalism to the topological properties of total electron density obtained from ab initio calculations. Analysis of the results obtained (i.a. equilibrium geometry, equation of state, cohesive energy, band structure, density of states—both total and projected on to particular atoms, and topological properties of bond critical points and net charges of topological atoms) is presented in detail.

  15. Enhanced short-circuit current density in poly(3-hexylthiophene) and 1-(3-methoxycarbonyl)-propyl-1-phenyl-(6,6)C61 based organic solar cells by doping small molecular perylene

    NASA Astrophysics Data System (ADS)

    Lou, Yanhui; Wang, Zhaokui; Naka, Shigeki; Okada, Hiroyuki

    2011-07-01

    The authors investigate the effects of a small molecular dye, perylene, on the performance of organic solar cells based on poly(3-hexylthiophene) (P3HT) and 1-(3-methoxycarbonyl)-propyl-1-phenyl-(6,6)C61 (PCBM) blends. The short-circuit current density is improved, and a maximum 27% enhancement in power conversion efficiency is achieved by doping suitable perylene into P3HT:PCBM blends. It is attributed to be the enhanced absorption of perylene doped P3HT:PCBM blends, which is also confirmed in single-carrier devices. Moreover, the barrier height at the anode/blend is largely lowered from 0.61 eV to 0.28 eV through evaluating temperature dependence of current-voltage characteristics.

  16. Comparison of the Effects of Hexavalent Chromium in the Alimentary Canal of F344 Rats and B6C3F1 Mice Following Exposure in Drinking Water: Implications for Carcinogenic Modes of Action

    PubMed Central

    Thompson, Chad M.; Proctor, Deborah M.; Suh, Mina; Haws, Laurie C.; Hébert, Charles D.; Mann, Jill F.; Shertzer, Howard G.; Hixon, J. Gregory; Harris, Mark A.

    2012-01-01

    Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1–182 mg/l Cr(VI), administered as 0.3–520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well. PMID:22011396

  17. Comparison of the effects of hexavalent chromium in the alimentary canal of F344 rats and B6C3F1 mice following exposure in drinking water: implications for carcinogenic modes of action.

    PubMed

    Thompson, Chad M; Proctor, Deborah M; Suh, Mina; Haws, Laurie C; Hébert, Charles D; Mann, Jill F; Shertzer, Howard G; Hixon, J Gregory; Harris, Mark A

    2012-01-01

    Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1-182 mg/l Cr(VI), administered as 0.3-520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well.

  18. Skf 525-A induces cocaine N-demethylase, ethoxyresorufin O-deethylase, and pentoxyresorufin O-dealkylase activities by induction of cytochrome p-450 2B in female B6C3F1 mice.

    PubMed

    Jeong, Tae Cheon; Chang, Hyeun Wook; Lee, Eung Seok; Jeon, Tae Won; Jeong, Hye Gwang; Holsapple, Michael P

    2004-12-01

    Studies demonstrated that cocaine-induced immunosuppression is mediated by metabolites of cocaine. Although SKF 525-A inhibited cocaine N-demethylation in liver S9 fractions isolated from female B6C3F1 mice, our study showed that pretreatment of mice with SKF 525-A potentiated cocaine-induced suppression of the antibody response to sheep red blood cells. An increase in formaldehyde generation was subsequently shown following incubation of cocaine with the S9 fractions prepared from SKF 525-A-treated mice, indicating the possibility of cytochrome P-450 (CYP) induction. Therefore, the inductive effects of SKF 525-A on CYP enzyme activities and proteins were investigated in female B6C3F1 mice to elucidate the potentiation of cocaine-induced immunosuppression by SKF 525-A. When SKF 525-A was administered at 10, 20, or 40 mg/kg/d intraperitoneally for 7 consecutive days, both ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase activities were induced dose-dependently. Furthermore, the induction of enzymatic activity was time dependent. Meanwhile, when the type of isozyme induced by SKF 525-A was analyzed by Western immunoblotting with monospecific anti-CYP 1A and anti-CYP 2B antibodies, only the CYP 2B appeared to be induced. From in vitro inhibition studies with monoclonal antibodies, it was confirmed that the induced activity of ethoxyresorufin O-deethylase by SKF 525-A was due to increased levels of CYP 2B proteins. Our present results provide an explanation for the potentiation of cocaine-induced immunosuppression by repeated exposure to SKF 525-A. Our results also indicate that ethoxyresorufin O-deethylase, a selective substrate for CYP 1A, may also be catalyzed by CYP 2B.

  19. Inflammatory and chloracne-like skin lesions in B6C3F1 mice exposed to 3,3′,4,4′-tetrachloroazobenzene for 2 years

    PubMed Central

    Ramot, Yuval; Nyska, Abraham; Lieuallen, Warren; Maly, Alex; Flake, Gordon; Kissling, Grace E.; Brix, Amy; Malarkey, David E.; Hooth, Michelle J.

    2009-01-01

    Exposure to dioxin and dioxin-like compounds (DLCs) has been connected to the induction of chloracne in humans and animals. 3,3′,4,4′-Tetrachloroazobenzene (TCAB) is an environmental contaminant that induces chloracne in humans. TCAB has been studied only to a limited extent in laboratory animals. While performing a 2-year gavage study in B6C3F1 mice to evaluate the toxic and carcinogenic effects of TCAB, we also explored potential chloracnegenic properties. Groups of 50 male and 50 female B6C3F1 mice were exposed by gavage to TCAB at dose levels of 0, 3, 10 and 30 mg/kg for 5 days a week for 2 years. The animals developed treatment-related gross inflammatory skin lesions, which were characterized histologically by inflammation, fibrosis, hyperplasia, and ulcers. Additionally, many of the animals developed follicular dilatation and sebaceous-gland atrophy, consistent with chloracne-like lesions. This current 2-year study supports recently published papers showing susceptibility to chloracne in mouse strains other than hairless mice. The chloracne-like lesions were not clinically evident; therefore, our study highlights the need for careful examination of the skin in order to identify subtle lesions consistent with chloracne-like changes in rodents exposed to dioxin and DLCs. Since previous short term studies did not demonstrate any skin lesions, we suggest that reliable assessment of all safety issues involving dioxin and DLCs requires evaluation following chronic exposure. Such studies in animal models will help to elucidate the mechanisms of dioxin-related health hazards. PMID:19737593

  20. Interference Contrast Reveals Debonding

    SciTech Connect

    Boatner, Lynn A; Longmire, Hu Foster; Gray, Allison S

    2007-11-01

    The elastic constants of single crystals can be determined by the high-frequency 'pulse-echo' superposition method, in which a piezoelectric transducer that is bonded to a single crystal sends stress pulses into the sample. The round-trip transit time of these pulses, t, is measured by overlapping the leading cycles of the first two echoes that are reflected back to the transducer. The sound velocity is then found by the relationship V = 2l/t, where l represents the length of the sample. By transmitting the ultrasonic waves along different crystallographic directions, values for the various elastic constants can be calculated by the relationship C = {rho}V{sup 2}.

  1. Eye Movements Reveal Dynamics of Task Control

    ERIC Educational Resources Information Center

    Mayr, Ulrich; Kuhns, David; Rieter, Miranda

    2013-01-01

    With the goal to determine the cognitive architecture that underlies flexible changes of control settings, we assessed within-trial and across-trial dynamics of attentional selection by tracking of eye movements in the context of a cued task-switching paradigm. Within-trial dynamics revealed a switch-induced, discrete delay in onset of…

  2. NTP Toxicity Studies of Methyl Ethyl Ketoxime Administered in Drinking Water to F344/N Rats and B6C3F1 Mice (CAS No. 96-29-7).

    PubMed

    1999-08-01

    Methyl ethyl ketoxime is used primarily as an antiskinning agent in alkyd coating resins. Methyl ethyl ketoxime was selected for study because of the potential for human exposure and because of interest in oximes as a chemical class. Toxicity studies of methyl ethyl ketoxime (greater than 99% pure) were carried out in male and female F344/N rats and B6C3F1 mice. The compound was administered in drinking water for 14 days or 13 weeks. In addition, the genetic toxicity of methyl ethyl ketoxime was evaluated by determining mutagenicity in Salmonella typhimurium and induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in vitro, with and without S9 activation. The frequency of micronucleated normochromatic erythrocytes in the peripheral blood of mice from the 13-week study was also determined. In the 14-day studies, groups of five male and five female rats and mice were given drinking water containing 0, 106, 312, 625, 1,250, or 2,500 ppm methyl ethyl ketoxime. The mean body weight gain of male rats in the 2,500 ppm group was significantly less than that of the controls; the final mean body weight of male mice in the 2,500 ppm group was also less than that of the controls. Spleen weights were increased in male and female rats in the 1,250 and 2,500 ppm groups. No chemical-related gross lesions were observed. Microscopic tissue evaluations were not performed. In the 13-week studies, groups of 10 male and 10 female rats were given drinking water containing 0, 312, 625, 1,250, 2,500, or 5,000 ppm and groups of 10 male and 10 female mice were given drinking water containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm. Mean body weights and body weight gains of 2,500 and 5,000 ppm male rats and 10,000 ppm male and female mice were less than those of the controls; mean body weight gains of male rats in the 1,250, 2,500 and 5,000 ppm groups and females in the 2,500 and 5,000 ppm groups were also less than those of the

  3. NTP technical report on the toxicity studies of a Chemical Mixture of 25 Groundwater Contaminants Administered in Drinking Water to F344/N Rats and B6C3F(1) Mice.

    PubMed

    Yang, R.

    1993-08-01

    Toxicity studies were performed with a chemically defined mixture of 25 groundwater contaminants, using dose levels considered to have environmental relevance. The mixture contained 19 organic compounds and six metals (shown below); the selection of these compounds was based primarily on the frequency of their occurrence in United States Environmental Protection Agency surveys of groundwater contamination in the vicinity of hazardous waste disposal sites. This report focuses primarily on 26-week drinking water toxicity studies with male and female F344/N rats and B6C3F(1) mice. The endpoints evaluated included histopathology, clinical pathology, neurobehavioral studies, and reproductive toxicity. Additional studies using this same chemical mixture are briefly reviewed in this report and include an evaluation of spermatogenesis in B6C3F(1) mice exposed to the chemical mixture for 13 weeks, a continuous breeding study with Sprague-Dawley rats and CD-1(R) Swiss mice, studies of myelotoxicity in B6C3F(1) mice exposed to the chemical mixture for up to 31.5 weeks, studies of immunosuppression in B6C3F(1) mice exposed for up to 13 weeks, in vitro mutagenicity assays in Salmonella typhimurium and Escherichia coli, and measures of genetic damage in bone marrow and peripheral blood of F344/N rats and B6C3F(1) mice in 2-week drinking water studies. In a 26-week drinking water study in which rats were administered the chemical mixture at composite contaminant concentrations of 0, 11, 38, 113, or 378 ppm, no deaths occurred and the body weight gain of high-dose males was slightly less than that of the controls. Water consumption decreased with dose and was 24% to 28% less than that of the controls at the highest concentration. Changes in organ weights occurred primarily in high-dose rats and included increased absolute and relative liver and kidney weights in females, increased relative kidney weight in males, and decreased absolute and relative thymus weights in males and

  4. Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

    PubMed

    2012-07-01

    Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male

  5. Titan Casts Revealing Shadow

    NASA Astrophysics Data System (ADS)

    2004-05-01

    A rare celestial event was captured by NASA's Chandra X-ray Observatory as Titan -- Saturn's largest moon and the only moon in the Solar System with a thick atmosphere -- crossed in front of the X-ray bright Crab Nebula. The X-ray shadow cast by Titan allowed astronomers to make the first X-ray measurement of the extent of its atmosphere. On January 5, 2003, Titan transited the Crab Nebula, the remnant of a supernova explosion that was observed to occur in the year 1054. Although Saturn and Titan pass within a few degrees of the Crab Nebula every 30 years, they rarely pass directly in front of it. "This may have been the first transit of the Crab Nebula by Titan since the birth of the Crab Nebula," said Koji Mori of Pennsylvania State University in University Park, and lead author on an Astrophysical Journal paper describing these results. "The next similar conjunction will take place in the year 2267, so this was truly a once in a lifetime event." Animation of Titan's Shadow on Crab Nebula Animation of Titan's Shadow on Crab Nebula Chandra's observation revealed that the diameter of the X-ray shadow cast by Titan was larger than the diameter of its solid surface. The difference in diameters gives a measurement of about 550 miles (880 kilometers) for the height of the X-ray absorbing region of Titan's atmosphere. The extent of the upper atmosphere is consistent with, or slightly (10-15%) larger, than that implied by Voyager I observations made at radio, infrared, and ultraviolet wavelengths in 1980. "Saturn was about 5% closer to the Sun in 2003, so increased solar heating of Titan may account for some of this atmospheric expansion," said Hiroshi Tsunemi of Osaka University in Japan, one of the coauthors on the paper. The X-ray brightness and extent of the Crab Nebula made it possible to study the tiny X-ray shadow cast by Titan during its transit. By using Chandra to precisely track Titan's position, astronomers were able to measure a shadow one arcsecond in

  6. Short-term and long-term in vivo exposure to an ephedra- and caffeine-containing metabolic nutrition system does not induce cardiotoxicity in B6C3F1 mice.

    PubMed

    Ray, Sidhartha; Phadke, Santosh; Patel, Chintan; Hackman, Robert M; Stohs, Sidney

    2005-06-01

    Although conventional biomedical research has largely focused on mechanisms of weight loss and genetic aspects of obesity, most medical solutions are plagued by side-effects and fraught with complex questions. As a consequence, consumers are seriously considering herbal products, nutraceuticals and functional foods as alternatives to conventional medications. This is evidently driven by a growing consumer understanding of diet/disease links, aging-related consequences, rising health care costs, and advances in food technology and nutrition. This study investigated the effects of up to 12 months exposure to a multinutrient and botanical extract supplement (Metabolic Nutrition System Orange (MNSO) - sold by AdvoCare, Carrollton, TX, USA) at five dietary concentrations on serum biochemistry and target organ histopathology of the hearts of B6C3F1 mice. The MNSO is a unique combination of vitamins, minerals, omega-3 fatty acids and herbal extracts designed to provide a strong foundation of nutritional support, and to enhance thermogenesis and perception of energy. The MNSO contain extracts of citrus, ephedra, guarana, gingko, green tea and Ocimum. In this study, female B6C3F1 mice were fed control (-MNSO) or MNSO (one time to ten times, one time = daily human dose) diets. Animals were sacrificed after 4, 8 and 12 months', at which time blood was collected for serum chemistry analysis, and hearts were prepared for histopathology and tissue biochemistry. Food consumption and body weight changes were also monitored throughout the study. The MNSO exposure did not significantly affect any of the cardiosensitive enzymes [including creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST)] and normal histopathological architecture of the heart was observed. Although animals given the MNSO diet consumed more food, they were relatively leaner and more active compared to controls. The results indicate that ingestion of ephedra and caffeine for one

  7. Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine

    SciTech Connect

    Kim, Sungkyoon; Kim, David; Pollack, Gary M.; Collins, Leonard B.; Rusyn, Ivan

    2009-07-01

    Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was {approx} 74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 h, 0.081 ml/h; TCA: 12 h, 3.80 ml/h; DCVG: 1.4 h, 16.8 ml/h; DCVC: 1.2 h, 176 ml/h. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities ({approx} 3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment.

  8. Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3F1 mice: comparison of administration by gavage in corn oil vs ad libitum in drinking water.

    PubMed

    Larson, J L; Wolf, D C; Butterworth, B E

    1994-01-01

    Chloroform increases the incidence of liver tumors in B6C3F1 mice when administered in by gavage in corn oil, but not when given in the drinking water at similar daily doses. Since cytotoxicity and regenerative cell proliferation have been implicated in the tumorigenic process for this nongenotoxic agent, these effects of chloroform in corn oil and drinking water were evaluated under conditions similar to the two bioassays. Female B6C3F1 mice were administered oral doses of 0, 3, 10, 34, 90, 238, or 477 mg/kg chloroform dissolved in corn oil 5 days/week for periods of 4 days or 3 weeks, or were continually exposed to chloroform in the drinking water at concentrations of 0, 60, 200, 400, 900, or 1800 ppm for 4 days or 3 weeks, at which time they were necropsied. 5-Bromo-2'-deoxyuridine (BrdU) was delivered via osmotic pumps implanted 3.5 days prior to necropsy. Cell proliferation was evaluated as the percentage of hepatocytes that entered S-phase over 3.5 days (labeling index, LI), measured by immunohistochemical detection of BrdU incorporated into the DNA. Dose-dependent changes included centrilobular necrosis and markedly elevated LI in mice given 238 or 477 mg/kg chloroform in corn oil (the average daily doses that produced tumors in the cancer bioassay). The no-observed-effect level for histopathological changes was 10 mg/kg/day and for induced cell proliferation was 34 mg/kg/day for chloroform given in corn oil. Chloroform given in the drinking water did not increase the hepatic LI after either 4 days or 3 weeks in any of the dose groups, nor were any microscopic alterations observed in the livers, even though the cumulative daily amount of chloroform ingested in the 1800-ppm exposure group was 329 mg/kg/day. The sustained increase in LI in the livers of mice administered hepatocarcinogenic doses of chloroform in corn oil, but not for chloroform in drinking water, is evidence that chloroform-induced mouse liver cancer is secondary to events associated with

  9. Revealing the Beast Within

    NASA Astrophysics Data System (ADS)

    2003-07-01

    Deeply Embedded Massive Stellar Clusters Discovered in Milky Way Powerhouse Summary Peering into a giant molecular cloud in the Milky Way galaxy - known as W49 - astronomers from the European Southern Observatory (ESO) have discovered a whole new population of very massive newborn stars . This research is being presented today at the International Astronomical Union's 25th General Assembly held in Sydney, Australia, by ESO-scientist João Alves. With the help of infrared images obtained during a period of excellent observing conditions with the ESO 3.5-m New Technology Telescope (NTT) at the La Silla Observatory (Chile), the astronomers looked deep into this molecular cloud and discovered four massive stellar clusters, with hot and energetic stars as massive as 120 solar masses. The exceedingly strong radiation from the stars in the largest of these clusters is "powering" a 20 light-year diameter region of mostly ionized hydrogen gas (a "giant HII region"). W49 is one of the most energetic regions of star formation in the Milky Way. With the present discovery, the true sources of the enormous energy have now been revealed for the first time, finally bringing to an end some decades of astronomical speculations and hypotheses. PR Photo 21a/03 : Colour Composite of W49A (NTT+SOFI). PR Photo 21b/03 : Radio and Near-Infrared Composite of W49A Giant molecular clouds Stars form predominantly inside Giant Molecular Clouds which populate our Galaxy, the Milky Way. One of the most prominent of these is W49 , which has a mass of a million solar masses. It is located some 37,000 light-years away and is the most luminous star-forming region known in our home galaxy: its luminosity is several million times the luminosity of our Sun. A smaller region within this cloud is denoted W49A - this is one of the strongest radio-emitting areas known in the Galaxy . Massive stars are excessive in all ways. Compared to their smaller and ligther brethren, they form at an Olympic speed and

  10. NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    2000-09-01

    Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed to gallium arsenide for 14 weeks. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived to the end of the study. The final mean body weights of all exposed groups of males and females were similar to those of the chamber controls. Compared to chamber controls, the liver and lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased; the thymus weights of all exposed groups of males were decreased. Gallium arsenide particles were visible in the alveolar spaces and, to a lesser extent, within alveolar macrophages of exposed rats. Moderate proteinosis (surfactant mixed with small amounts of fibrin) and minimal histiocytic cellular infiltrate were observed in the alveoli of exposed males and females. Epithelial hyperplasia and squamous metaplasia of the larynx were observed primarily in males exposed to 150 mg/m(3). 16-DAY STUDY IN MICE: Groups of five male and four or five female mice were exposed to particulate aerosols of gallium

  11. Rate coefficients for the reaction of O(1D) with the atmospherically long-lived greenhouse gases NF3, SF3CF3, CHF3, C2F6, c-C3F8, n-C5F12, and n-C6F14

    NASA Astrophysics Data System (ADS)

    Baasandorj, M.; Hall, B. D.; Burkholder, J. B.

    2012-09-01

    The contribution of atmospherically persistent (long-lived) greenhouse gases to the radiative forcing of Earth has increased over the past several decades. The impact of highly fluorinated saturated compounds, in particular perfluorinated compounds, on climate change is a concern because of their long atmospheric lifetimes, which are primarily determined by stratospheric loss processes, as well as their strong absorption in the infrared "window" region. A potentially key stratospheric loss process for these compounds is their gas-phase reaction with electronically excited oxygen atoms, O(1D). Therefore, accurate reaction rate coefficient data is desired for input to climate change models. In this work, rate coefficients, k, were measured for the reaction of O(1D) with several key long-lived greenhouse gases, namely NF3, SF5CF3, CHF3 (HFC-23), C2F6, c-C4F8, n-C5F12, and n-C6F14. Room temperature rate coefficients for the total reaction, kTot, corresponding to loss of O(1D), and reactive channel, kR, corresponding to the loss of the reactant compound, were measured for NF3 and SF5CF3 using competitive reaction and relative rate methods, respectively. kR was measured for the CHF3 reaction and improved upper-limits were determined for the perfluorinated compounds included in this study. For NF3, kTot was determined to be (2.55 ± 0.38) × 10-11 cm3 molecule-1 s-1 and kR, which was measured using CF3Cl, N2O, CF2ClCF2Cl (CFC-114), and CF3CFCl2 (CFC-114a) as reference compounds, was determined to be (2.21 ± 0.33) × 10-11 cm3 molecule-1 s-1 corresponding to a reactive branching ratio of 0.87 ± 0.13. For SF5CF3, kTot = (3.24 ± 0.50) × 10-13 cm3 molecule-1 s-1 and kR < 5.8 × 10-14 cm3 molecule-1 s-1 were measured, where kR is a factor of three lower than the current recommendation of kTot for use in atmospheric modeling. For CHF3, kR was determined to be (2.35 ± 0.35) × 10-12 cm3 molecule-1 s-1, which corresponds to a reactive channel yield of 0.26 ± 0.04, and

  12. Synthesis and structure of fullerene halides in the C{sub 60}-(TiCl{sub 4} + Br{sub 2}) system: Molecular structures of (C{sub 60}Cl{sub 5}){sub 2}, C{sub 60}X{sub 6}, C{sub 60}X{sub 8}, and C{sub 60}X{sub 24}(X = Cl, Br)

    SciTech Connect

    Troyanov, S. I. Burtsev, A. V.; Kemnitz, E.

    2009-03-15

    The reactions in the C{sub 60}-(TiCl{sub 4} + Br{sub 2}) system have been performed in ampoules at elevated temperatures. The molecular structure of the fullerene halides (C{sub 60}Cl{sub 5}){sub 2}, C{sub 60}X{sub 6}, C{sub 60}X{sub 8}, and C{sub 60}X{sub 24} (X = Cl, Br) has been determined and refined using single-crystal X-ray diffraction. It has been established that an increase in the bromine concentration results in an increase in the number of halogen atoms attached to the fullerene cage and in an increase in the relative fraction of bromine atoms in mixed halogen derivatives from almost pure chlorides (C{sub 60}Cl{sub 5}){sub 2} and C{sub 60}Cl{sub 6} to halides C{sub 60}X{sub 8} and C{sub 60}X{sub 24} with a high relative bromine content.

  13. Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (gorlin) syndrome and fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3

    SciTech Connect

    Farndon, P.A.; Hardy, C.; Kilpatrick, M.W.

    1994-09-15

    Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S12/D9S151) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map. 19 refs., 2 figs., 1 tab.

  14. NTP Toxicology and Carcinogenesis Studies of Tris(2-ethylhexyl)phosphate (CAS No. 78-42-2) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1984-08-01

    Tris(2-ethylhexyl)phosphate is one of a family of triakyl phosphates that have been widely used as fire retardants and plasticizers. Another triakyl phosphate, tris(2,3-dibromopropyl)phosphate (Tris-BP), once used as a flame retardant in children's sleepwear, has been shown to be carcinogenic, but tris(2-ethylhexyl)phosphate has not been previously studied. Tris(2-ethylhexyl)phosphate, a clear, viscous liquid, is used as a component of vinyl stabilizers, grease additives, and flame-proofing compositions; however, it is used primarily as a plasticizer for vinyl plastic and synthetic rubber compounds. In 1974, approximately 3 million pounds of tris(2-ethylhexyl)phosphate was produced in the United States; imports during that year were negligible. Substantial human exposure probably occurs during production of tris(2-ethylhexyl)phosphate and during the manufacture and use of products containing it, but data on the magnitude of exposure are not available. Two-year toxicology and carcinogenesis studies of tris(2-ethylhexyl)phosphate were conducted by administering the test chemical in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Male rats received doses of 2,000 or 4,000 mg/kg body weight, female rats received 1,000 or 2,000 mg/kg, and male and female mice received 500 or 1,000 mg/kg. Fifty vehicle control animals of each sex and species received 10 ml/kg body weight (rats) or 3.3 ml/kg (mice) corn oil by gavage on the same schedule. Inflammation of the gastric mucosa in mice and mild weight depression in rats and mice were the only dose-related effects observed in the preliminary studies. In the 2-year studies, survival rates and mean body weight gains of dosed female rats and dosed mice were comparable to those of their perspective controls. Survival rates of dosed male rats were comparable to that of the vehicle controls, but body weight gains were depressed. One nonneoplastic lesion, follicular

  15. Creep rupture behavior due to molybdenum rich M{sub 6}C carbide in 1.0Cr-1.0Mo-0.25V bainitic steel weldment

    SciTech Connect

    Oh, Y.K.; Kim, G.S.; Indacochea, J.E.

    1999-06-04

    Some reports show that Cr-Mo-V steel structures fabricated by welding has a high percent of failures in the microstructurally altered and inhomogeneous heat affected zone (HAZ). The failure usually takes place either at the coarse grain HAZ (CGHAZ) or intercritical HAZ (ICHAZ). Failure at creep condition is related to either cracking at grain boundary triple junctions or the formation of cavities (or voids) on grain boundaries that are approximately normal to the applied stress. Cavities are normally formed by grain boundary sliding causing stress concentrations at precipitates in the grain boundaries. Cavities will then develop at the precipitates whenever plastic flow or diffusion is not fast enough to prevent it. The precipitates that provide cavity nucleation sites are mostly sulfides and carbides. The carbides that provide cavity sites are usually M{sub 23}C{sub 6} and M{sub 6}C. Although considerable researchers have been carried out in the carbides that provide cavitation, the mechanism governs creep behavior during welding remains uncertain. Therefore, the objective of this study is to correlate carbide morphology and its effect on creep rupture behavior in 1.0 Cr-1.0Mo-0.25V bainitic steel weldment.

  16. Ntp technical report on toxicity, reproductive, and developmental studies of 60-Hz magnetic fields, administered by whole body exposure to F344/N rats, Sprague-Dawley rats, and B6C3F1 mice. Toxicity report series

    SciTech Connect

    Boorman, G.A.

    1996-09-01

    Electric and magnetic fields are associated with the production, transmission, and use of electricity; thus the potential for human exposure is high. These electric and magnetic fields are predominantly of low frequency (60 Hz) and generally of low intensity. The prevailing view among physicists is that exposure to these low-frequency, low-intensity fields does not pose a health hazard. However, this view has been challenged by reports linking magnetic field exposure to the development of leukemia and other cancers. Because multiple epidemiologic studies suggested a potential for increased cancer rates with increasing exposure, and because of public concern, the effects of 60-Hz magnetic field exposure were examined in F344/N rats and B6C3F1 mice in 8-week full-body-exposure studies. Animals were evaluated for hematology and clinical chemistry (rats only) parameters, pineal gland hormone concentrations, and histopathology. Additional studies were performed in Sprague-Dawley rats to examine teratologic and reproductive effects of magnetic field exposure.

  17. Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal.

    PubMed

    Hong, Hue-Hua L; Hoenerhoff, Mark J; Ton, Thai-Vu; Herbert, Ronald A; Kissling, Grace E; Hooth, Michelle J; Behl, Mamta; Witt, Kristine L; Smith-Roe, Stephanie L; Sills, Robert C; Pandiri, Arun R

    2015-08-01

    Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents.

  18. Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal

    PubMed Central

    Hong, Hue-Hua L.; Hoenerhoff, Mark J.; Ton, Thai-Vu; Herbert, Ronald A.; Kissling, Grace E.; Hooth, Michelle J.; Behl, Mamta; Witt, Kristine L.; Smith-Roe, Stephanie L.; Sills, Robert C.; Pandiri, Arun R.

    2015-01-01

    Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kras, Egfr and Tp53 mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD) induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors, and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors, and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominantly in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assays indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. PMID:26059825

  19. NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

    PubMed

    Irwin, R

    1992-03-01

    Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

  20. Lemon (Citrus limon, Burm.f.) essential oil enhances the trans-epidermal release of lipid-(A, E) and water-(B6, C) soluble vitamins from topical emulsions in reconstructed human epidermis.

    PubMed

    Valgimigli, L; Gabbanini, S; Berlini, E; Lucchi, E; Beltramini, C; Bertarelli, Y L

    2012-08-01

    Topical bioavailability of lipid- and water-soluble vitamins is a critical issue for protecting or anti-ageing formulations. Using 17-day-old SkinEthic(®) reconstructed human epidermis, we investigated (at 34°C) the role of lemon EO in enhancing the penetration of α-tocopherol (E) and retinyl acetate (A), pyridoxine (B(6)) and ascorbic acid (C), released from O/W or W/O emulsions. D-limonene, α-pinene and p-cymene (65.9, 2.2 and 0.5%w/w of the oil) had skin permeability coefficients Ps (10(-3) cm h(-1)) of 0.56 ± 0.03 (or 0.73 ± 0.02), 0.72 ± 0.05 (or 0.98 ± 0.05) and 0.84 ± 0.04 (or 1.14 ± 0.04), respectively, when incorporated in a W/O (or O/W) emulsion. Vitamins B6, C and A had Ps values of (3.0 ± 0.4) × 10(-3), (7.9 ± 0.6) × 10(-3) and (0.37 ± 0.02) × 10(-5) cm h(-1), respectively, and their flux through the skin was enhanced by a factor of 4.1, 3.4 and 5.8, respectively, in the presence of lemon EO. The penetration of vitamin E was nine-fold enhanced. Lemon EO produced only reversible modification of TEWL, and it is a safe and effective penetration enhancer for topical administration of lipid- and water-soluble vitamins.

  1. Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90days of exposure to hexavalent chromium in drinking water.

    PubMed

    Kopec, Anna K; Kim, Suntae; Forgacs, Agnes L; Zacharewski, Timothy R; Proctor, Deborah M; Harris, Mark A; Haws, Laurie C; Thompson, Chad M

    2012-02-15

    Chronic administration of high doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90days of exposure to 0, 0.3, 4, 14, 60, 170 or 520mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated dose-response modeling identified >80% of the differentially expressed genes exhibited sigmoidal dose-response curves with EC(50) values ranging from 10 to 100mg/L SDD. Only 16 genes satisfying the dose-dependent differential expression criteria had EC(50) values <10mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation.

  2. Characterization of liver toxicity in F344/N rats and B6C3F1 mice after exposure to a flame retardant containing lower molecular weight polybrominated diphenyl ethers.

    PubMed

    Dunnick, June K; Nyska, Abraham

    2009-01-01

    Lower molecular weight polybrominated diphenyl ethers (PBDEs), components of flame retardants, are found in the environment and in human and animal tissues. Toxicity studies were conducted in F344/N rats and B6C3F1 mice by administering a flame retardant containing these lower molecular weight PBDEs (BDE-47, BDE-99, BDE-100, and BDE153) by oral gavage 5 days/week for 13 weeks at doses of 0.01, 5, 50, 100 or 500mg/kg/day. Liver was the primary target organ in rats and mice. Treatment-related increases in liver weights, liver cytochrome P450 (1A1, 1A2, 2B) and UDPGT (rats only) levels, and liver lesions were seen in both rats and mice. Hepatocyte hypertrophy and vacuolization increased in incidence and severity with treatment, and occurred at levels of 50mg/kg and above in rats, and at 100mg/kg and above in mice. Liver Cyp 1A1, 1A2, and 2B levels were increased at exposure levels of 50mg/kg and above in rats and mice. In addition, treatment-related thyroid lesions occurred particularly in rats. The most sensitive parameter for PBDE toxicity was the increase in liver weights which occurred at 5mg/kg above in rats and 50mg/kg and above in mice. These results suggest that liver may be a target organ for carcinogenesis processes after long-term administration of PBDEs. A chronic PBDE study is currently being conducted by the National Toxicology Program.

  3. Comparative carcinogenicity of two structurally similar phenylenediamine dyes (HC blue no. 1 and HC blue no. 2) in F344/N rats and B6C3F1 mice.

    PubMed

    Kari, F W; Mennear, J H; Farnell, D; Thompson, R B; Huff, J E

    1989-06-01

    Toxicology and carcinogenesis studies of 2 structurally-related p-phenylenediamines, HC Blue No. 1, and HC Blue No. 2 were conducted by administering each chemical in feed for 103 weeks to both sexes of Fischer 344/N rats and B6C3F1 (C57BL/6N x C3H/HEN) mice. Diets containing 0, 1500, or 3000 ppm HC Blue 1 were fed to male and female rats and male mice; female mice received diets with 0, 3000, or 6000 ppm. Diets containing 0, 5000, or 10,000 ppm HC Blue 2 were fed to male rats and mice and the females received diets containing 0, 10,000 or 20,000 ppm. These concentrations were compatible with long-term growth and survival. The results demonstrated substantial differences in the neoplastic and non-neoplastic lesions caused by these structural analogs. HC Blue 2 caused histocytosis in lungs and hyperostosis of the skull in rats, and splenic hematopoiesis, fibrous osteodystrophy, and hyperostosis of the skull in mice. These non-neoplastic lesions were not observed in rats or mice treated with HC Blue 1. Contrasting, in male and female mice, HC Blue 1 produced dose-related increases in the incidences of both adenomas and carcinomas of the liver. HC Blue 1 produced a marginally positive trend in hepatocellular nodules and carcinomas in male rats and dose-related increases in hyperplasias and neoplasms of the lungs in female rats. In contrast, there was no evidence of carcinogenicity for HC Blue 2 in either sex of rats or mice, despite the fact that it was administered 3-5 times the dose of the HC Blue 1. Since these 2 nitroaromatic compounds differ only in the methyl vs. 2-hydroxyethyl substituent on the secondary amine of ring carbon 4, the great discordance in their carcinogenicity is most probably due to side group-directed alteration in their metabolic profiles.

  4. NTP toxicity studies of dimethylaminopropyl chloride, hydrochloride (CAS No. 5407-04-5) administered by Gavage to F344/N rats and B6C3F1 mice.

    PubMed

    Abdo, Km

    2007-07-01

    Dimethylaminopropyl chloride, hydrochloride is used primarily as an industrial and research organic chemical intermediate acting as an alkylating reagent in Grignard and other types of reactions. It is also used as a pharmaceutical intermediate for the synthesis of many types of drugs, as an agricultural chemical intermediate, as a photographic chemical intermediate, and as a biochemical reagent for enzyme and other studies. Human occupational or other accidental exposure can occur by inhalation, ingestion, or skin absorption. Male and female F344/N rats and B6C3F1 mice received dimethylaminopropyl chloride, hydrochloride (greater than 99% pure) in water by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg dimethylaminopropyl chloride, hydrochloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. All dosed male and female rats and mice survived until the end of the 2-week study; one vehicle control female mouse died early. Mean body weights of all dosed groups of rats and mice were similar to those of the vehicle control groups. No gross or microscopic lesions were considered related to dimethylaminopropyl chloride, hydrochloride administration. In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg/kg in deionized water by gavage, 5 days per week for 3 months. One male rat in the 50 mg/kg group died during week 12 of the study, and one female mouse in the 100 mg/kg group died during week 9 and another during week 13. The final mean body weights of 50 mg/kg male rats and 50 mg/kg female mice were significantly less than those of the vehicle controls. Possible chemical-related clinical findings in rats

  5. NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C23, 43% Chlorine) (CAS No. 108171-27-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1986-05-01

    Toxicology and carcinogenesis studies of chlorinated paraffins (C23, 43% chlorine), an extreme-pressure lubricant and flame retardant, were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Additional groups of 10 rats per sex and dose were examined at 6 and at 12 months. Male rats received doses of 0, 1,875, or 3,750 mg/kg body weight; female rats were given 0, 100, 300, or 900 mg/kg. Male and female mice received 0, 2,500, or 5,000 mg/kg. Doses selected for the 2-year studies were based on the results from 13-week studies in which rats of each sex received 0 to 3,750 mg/kg, and mice of each sex, 0 to 7,500 mg/kg. No toxicity of chlorinated paraffins (C23, 43% chlorine) was observed in male rats or in male or female mice in the 13-week studies. A dose-related inflammation of the liver was observed in female rats in the 13-week studies and in male and female rats in the 13-week studies and in male and female rats at 6 and 12 months in the 2-year studies. Chlorinated paraffins (C23, 43% chlorine) administration did not influence mean body weights of rats during the 2-year studies, but both male and female low dose mice gained less weight than did vehicle controls or the high dose groups. Survival of dosed and vehicle control groups was similar for each sex and species (male rats: vehicle control, 30/50; low dose, 32/50; high dose, 27/50; female rats: 34/50; 30/50; 33/50; 31/50; male mice: 29/50; 36/50; 28/50; female mice: 21/50; 22/50; 20/50). For female mice, 60%-70% of the early deaths in each group were attributed to utero-ovarian infection. The lower survival for female mice may have decreased the sensitivity of this study to detect a carcinogenic effect. Pheochromocytomas of the adrenal gland medulla occurred with an increased incidence in female rats exposed to chlorinated paraffins (C23, 43% chlorine) (vehicle control, 1/50; low dose, 4/50; mid dose, 6

  6. NTP Toxicology and Carcinogenesis Studies of Chloroethane (Ethyl Chloride) (CAS No. 75-00-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1989-10-01

    Toxicology and carcinogenesis studies of chloroethane (99.5% pure), an alkylating agent and chemical intermediate, as well as a topical and inhalation anesthetic, were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to chloroethane by whole-body inhalation once for 4 hours or for 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. Single-Exposure, Fourteen-Day, and Thirteen-Week Studies: In the single-exposure and 14-day inhalation studies, all rats and mice exposed to 19,000 ppm chloroethane survived. The animals were not exposed at lower concentrations. No clinical signs of toxicity were seen. In the 14-day studies, final mean body weights of exposed male rats and exposed mice were higher than those of controls. Mean body weights of exposed and control female rats were similar. In the 13-week studies, rats and mice were exposed to 0, 2,500, 5,000, 10,000, or 19,000 ppm chloroethane. No compound-related deaths occurred in rats or mice. The final mean body weight of rats exposed to 19,000 ppm was 8% lower than that of controls for males and 4% lower for females. Final mean body weights of exposed mice were generally higher than those of controls. No compound-related clinical signs or gross or microscopic pathologic effects were seen in rats or mice. The liver weight to body weight ratios for male rats and female mice exposed to 19,000 ppm were greater than those for controls. Although no chemically related toxic effects were observed in the short-term studies, concerns about potential flammability and explosion led to the selection of 0 and 15,000 ppm as the exposure concentrations for rats and mice for the 2-year studies. Body Weight and Survival in the Two-Year Studies: Mean body weights of exposed male rats were 4%-8% lower than those of controls after week 33. Mean body weights of exposed female rats were generally 5%-13% lower than those of controls

  7. NTP Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1988-05-01

    Toxicology and carcinogenesis studies of technical-grade 2-mercaptobenzothiazole (96%-97% pure), a rubber accelerant and preservative, were conducted by administering the chemical by gavage in a corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. 2-Mercaptobenzothiazole was nominated for study by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health. Sixteen-Day and Thirteen-Week Studies: In 16-day studies, mean body weight gains of rats receiving 2,500 mg/kg were 6-7 g lower than those of vehicle controls; 4/5 male and 5/5 female mice dosed with 3,000 mg/kg and 4/5 female mice dosed with 1,500 mg/kg died; lethargy and prostration occurred in most of these animals after gavage. Based on these results, doses were selected for both species in the 13-week studies were 0, 94 (mice only), 188, 375, 750, and 1,500 mg/kg. In the 13-week studies, no chemical-related deaths occurred in rats, but body weight gains in males dosed with 1,500 mg/kg and in females dosed with 750 or 1,500 mg/kg were lower than those in the vehicle control groups. Hepatomegaly occurred at the two highest doses in males and at all doses in females; however, no microscopic pathologic changes were noted in any tissue. More than half the mice dosed with 1,500 mg/kg died, but no compound-related body weight changes occurred. Clinical signs in mice were dose related and included lethargy in animals dosed with 375 mg/kg and lacrimation, salivation, and clonic seizure in some dosed with 750 or 1,500 mg/kg. No association between these clinical signs of toxicity and gross or microscopic pathologic effects were observed. Doses selected for the 2-year studies were 0, 375, and 750 mg/kg for male rats and for mice of each sex and 0, 188, or 375 mg/kg for female rats. Body weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered 2-mercaptobenzothiazole

  8. NTP Toxicology and Carcinogenesis Studies of Tetrakis(hydroxymethyl)phosphonium sulfate (THPS) (CAS No. 55566-30-8) and Tetrakis(hydroxymethyl)phosphonium chloride (THPC) (CAS No. 124-64-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1987-02-01

    Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPS was available as a 72% aqueous solution and THPC as a 75% aqueous solution. Short-term gavage studies with a range of doses were conducted first to identify toxic effects and affected sites and to determine doses for the 2-year studies. The doses selected for the 14-day studies ranged from 12.5 to 200 mg/kg THPS for rats and mice, 9.4 to 150 mg/kg THPC for rats, and 18.8 to 300 mg/kg THPC for mice. Mortality and reduction in body weight gain occurred at the two highest doses in the 14-day studies. There was hind limb paralysis in some rats and mice dosed at the highest concentrations of THPS and THPC. In the 13-week studies, doses of THPS ranged from 5 to 60 mg/kg in rats and from 2 to 180 mg/kg in mice; doses of THPC ranged from 3.75 to 60 mg/kg in rats and from 1.5 to 135 mg/kg in mice. Mortality and reduction in body weight gain occurred at the two higher doses for both sexes and species. Vascular degeneration of hepatocytes or hepatocellular necrosis was a common histopathologic finding. Hind limb paralysis was noted in rats and mice receiving the highest dose of THPC, and axonal degeneration, characterized by swollen axon sheaths, missing or fragmented axons, and some proliferation of neurolemma cells, was observed in rats. These lesions were found in the sciatic nerve, dorsal roots of the caudal spinal nerves, and the tracts of the spinal cord, particularly in the dorsal column of the lumbar cord. Two-year studies were conducted in F344/N rats by administering 0, 5, or 10 mg/kg THPS or 0, 3.75, or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days per week for 103 or 104 weeks. Groups of 49 or 50 B6C3F1 mice were administered 0, 5, or 10 mg/kg THPS (each sex), 0, 7

  9. Pharmacokinetics of the potent redox modulating manganese porphyrin, MnTE-2-PyP5+ in plasma and major organs of B6C3F1 mice

    PubMed Central

    Spasojević, Ivan; Chen, Yumin; Noel, Teresa J.; Fan, Ping; Zhang, Lichun; Rebouças, Julio S.; St. Clair, Daret K.; Batinić-Haberle, Ines

    2008-01-01

    Mn(III)tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP5+, a potent catalytic superoxide and peroxynitrite scavenger, has been beneficial in several oxidative stress-related disease thus far examined. Pharmacokinetic studies are essential for the better assessment of the therapeutic potential of MnTE-2-PyP5+ and similar compounds, as well as for the modulation of their bioavailability and toxicity. Despite high hydrophilicity, this drug entered mitochondria after single 10 mg/kg intraperitoneal injection at levels high enough (5.1 µM; 2.95 ng/mg protein) to protect it against superoxide/peroxynitrite damage. Utilizing the same analytical approach, which involves the reduction of MnTE-2-PyP5+, followed by the exchange of Mn2+ with Zn2+, and HPLC/fluorescence detection of ZnTE-2-PyP4+, we measured levels of MnTE-2-PyP5+ in mouse plasma, liver, kidney, lung, heart, spleen, and brain over a period of 7 days after a single intraperitoneal injection of 10 mg/kg. Two B6C3F1 female mice per time point were used. The pharmacokinetic profile in plasma and organs was complex; thus a non-compartmental approach was utilized to calculate the area under the curve (AUC), cmax, tmax, and drug elimination half-time (t1/2). In terms of levels of MnTE-2-PyP5+ found, the organs can be classified into 3 distinct groups: (1) high levels: kidney, liver, and spleen; (2) moderate levels: lung and heart; and (3) low levels: brain. The maximal levels in plasma, kidney, spleen, lung, and heart are reached within first 45 minutes whereas in case of liver a prolonged absorption phase was observed with the maximal concentration reached at 8 hours. Moreover, accumulation of the drug in brain continues beyond time of the experiment (7 days) and is likely driven by the presence of negatively charged phospholipids. For tissues other than brain, a slow elimination phase (single exponential decay, t1/2 = 60 to 135 hours) is observed. The calculated pharmacokinetic parameters will be used to

  10. Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water

    SciTech Connect

    Kopec, Anna K.; Kim, Suntae; Forgacs, Agnes L.; Zacharewski, Timothy R.; Proctor, Deborah M.; Harris, Mark A.; Haws, Laurie C.; Thompson, Chad M.

    2012-02-15

    Chronic administration of high doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90 days of exposure to 0, 0.3, 4, 14, 60, 170 or 520 mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated dose–response modeling identified > 80% of the differentially expressed genes exhibited sigmoidal dose–response curves with EC{sub 50} values ranging from 10 to 100 mg/L SDD. Only 16 genes satisfying the dose-dependent differential expression criteria had EC{sub 50} values < 10 mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation. Highlights: ► Mouse small intestine gene expression is highly responsive to hexavalent chromium [Cr(VI)]. ► Cr(VI) elicits more differential gene expression after 7 days of exposure than 90 days of exposure. ► Oral exposure to Cr(VI) leads to

  11. Toxicokinetics of α-thujone following intravenous and gavage administration of α-thujone or α- and β-thujone mixture in male and female F344/N rats and B6C3F1 mice

    SciTech Connect

    Waidyanatha, Suramya; Johnson, Jerry D.; Hong, S. Peter; Robinson, Veronica Godfrey; Gibbs, Seth; Graves, Steven W.; Hooth, Michelle J.; Smith, Cynthia S.

    2013-09-01

    Plants containing thujone have widespread use and hence have significant human exposure. α-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of α-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of α-thujone or a mixture of α- and β-thujone (which will be referred to as α,β-thujone). Absorption of α-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of α-thujone following administration of α-thujone or α,β-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. C{sub max} and AUC{sub ∞} increased greater than proportional to the dose in female rats following administration of α-thujone and in male and female mice following administration of α,β-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC{sub ∞} for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of α-thujone and α,β-thujone, respectively (p-value < 0.0001 for all comparisons). Following both intravenous and gavage administration, α-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of α-thujone and α,β-thujone where females were more sensitive than males of both species to α-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to α-thujone concentration. - Highlights: • Absorption of α-thujone following gavage administration was rapid in rats and mice. • Rats undergo higher exposure to α-thujone than mice. • α-Thujone brain

  12. Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice.

    PubMed

    Melnick, R L; Sills, R C; Portier, C J; Roycroft, J H; Chou, B J; Grumbein, S L; Miller, R A

    1999-05-01

    Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to 1,3-butadiene, a trans-species carcinogen, inhalation studies were performed with chloroprene to evaluate its carcinogenic potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male and female B6C3F1 mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6 h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas), Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a Weibull model for estimation of the shape of the dose-response curves, estimation of ED10 values (the estimated exposure concentration associated with an increased cancer risk of 10%) and comparison of these parameters with those for 1,3-butadiene. Butadiene has been identified as a potent carcinogen in mice and has been associated with increased risk of lymphatic and hematopoietic cancer in exposed workers. Shape parameter values for most of the neoplastic effects of chloroprene and 1,3-butadiene were consistent with linear or supralinear responses in the area near the lowest tested exposures. The most potent carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the rat lung, but greater in the rat kidney than in the mouse kidney and nearly equivalent in the mammary gland of each species.

  13. [Nephrocutaneous fistula revealing xanthogranulomatous pyelonephritis].

    PubMed

    Scotté, M; Sibert, L; Soury, P; Lebret, T; Gobet, F; Grise, P; Tenière, P

    1993-01-01

    A patient presented with a reno-cutaneous fistula revealing a xanthogranulomatous pyelonephritis secondary to staghorn calculus. Total nephrectomy was necessary because of renal destruction. This treatment allowed closure of the fistula and a good clinical result.

  14. NTP Carcinogenesis Studies of Food Grade Geranyl Acetate (71% Geranyl Acetate, 29% Citronellyl Acetate) (CAS No. 105-87-3) in F344/N Rats and B6C3F1 Mice (Gavage Study).

    PubMed

    1987-10-01

    Geranyl acetate (3,7-dimethyl-2,6-octadiene-1-ol acetate) is a colorless liquid prepared by fractional distillation of selected essential oils or by acetylation of geraniol. It is a natural constituent of more than 60 essential oils, including Ceylon citronella, palmarosa, lemon grass, petit grain, neroli bigarade, geranium, coriander, carrot, and sassafras. Geranyl acetate is used primarily as a component of perfumes for creams and soaps and as a flavoring ingredient. On the U.S. Food and Drug Administration's list of substances "generally recognized as safe," the Food Chemicals Codex (1972) specifies that geranyl acetate must contain at least 90% total esters. Carcinogenesis studies of food-grade geranyl acetate (containing approximately 29% citronellyl acetate) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 1,000 or 2,000 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 500 or 1,000 mg/kg. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. The cumulative toxicity of geranyl acetate in the 2-year study was indicated by the significantly shorter survival of high dose male rats (control, 34/50; low dose, 29/50; high dose, 18/50) and of high dose male mice (control, 31/50; low dose, 32/50; high dose, 0/50) and of dosed female mice (38/50; 15/50; 0/50) when compared with controls. Throughout most of the 2-year study, mean body weights of high dose rats and mice of each sex were lower than those of the controls. The occurrence of retinopathy or cataracts in the high dose male rats and low dose female rats as compared with the controls does not appear to be related to the administration of geranyl acetate but rather the proximity of the rats to fluorescent light. The incidence of retinopathy or cataracts (combined) was

  15. Determinants of marriage dissolution

    NASA Astrophysics Data System (ADS)

    Rahim, Mohd Amirul Rafiq Abu; Shafie, Siti Aishah Mohd; Hadi, Az'lina Abdul; Razali, Nornadiah Mohd; Azid @ Maarof, Nur Niswah Naslina

    2015-10-01

    Nowadays, the number of divorce cases among Muslim couples is very worrisome whereby the total cases reported in 2013 increased by half of the total cases reported in the previous year. The questions on the true key factors of dissolution of marriage continue to arise. Thus, the objective of this study is to reveal the factors that contribute to the dissolution of marriage. A total of 181 cases and ten potential determinants were included in this study. The potential determinants considered were age at marriage of husband and wife, educational level of husband and wife, employment status of husband and wife, income of husband and wife, the number of children and the presence at a counseling session. Logistic regression analysis was used to analyze the data. The findings revealed that four determinants, namely the income of husband and wife, number of children and the presence at a counselling session were significant in predicting the likelihood of divorce among Muslim couples.

  16. NTP Toxicology and Carcinogenesis Studies of Rhodamine 6G (C.I. Basic Red 1) (CAS No. 989-38-8) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    PubMed

    1989-09-01

    NTP Toxicology and Carcinogenesis studies of rhodamine 6G were conducted because of potential human exposure related to its use as a dye for natural and synthetic fibers and as a research chemical. These studies were conducted by administering rhodamine 6G (greater than 95% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies (0, 310, 620, 1,250, 2,500, or 5,000 ppm), all five male and five female rats that received 5,000 ppm and 1/5 male rats that received 2,500 ppm died before the end of the studies; all mice lived to the end of the study. The final mean body weights of rats that received 2,500 ppm were lower than the initial weights. The final mean body weights of mice that received 2,500 or 5,000 ppm were 8% or 18% lower than that of controls for males and 2% or 8% lower for females. In the 13-week studies, all rats lived to the end of the studies (dietary concentrations of 0 or 120-2,000 ppm). The final mean body weights of rats that received 500, 1,000 or 2,000 ppm were 12%, 13%, or 32% lower than that of controls for males and 4%, 8%, or 20% lower for females. Feed consumption by rats that received 2,000 ppm was somewhat lower than that by controls. Bone marrow atrophy was observed at increased incidences and severity in dosed rats. In the 13-week study (0 or 500-8,000 ppm), 1/10 male mice that received the highest concentration died before the end of the studies. The final mean body weights of mice that received 8,000 ppm were lower than the initial mean body weights. The final mean body weights of male mice that received 4,000 ppm and of female mice that received 2,000 or 4,000 ppm were 13%-19% lower than those of controls. Feed consumption was not related to dose. Minimal-to-moderate cytoplasmic vacuolization of

  17. NTP Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol (CAS No. 98-85-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    PubMed

    1990-01-01

    NTP Toxicology and Carcinogenesis studies of a-methylbenzyl alcohol (greater than 99% pure), a cosmetic ingredient and food flavoring agent, were conducted by administering the chemical in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. a-Methylbenzyl alcohol was nominated for study by the National Cancer Institute because of the potential for widespread human exposure. Sixteen-Day and Thirteen-Week Studies: The doses used in the 16-day studies for rats and mice ranged between 125 and 2,000 mg/kg. Six of 10 rats and all mice dosed at 2,000 mg/kg died. In addition, because 7/9 mice dosed at 1,000 mg/kg died, the doses selected for the 13-week studies for mice (47-750 mg/kg) were half those used for rats (93-1,500 mg/kg). In the 13-week studies, deaths of 1/10 male and 3/10 female rats dosed at 1,500 mg/kg were compound related; none of the mice died. Body weight gain was reduced in rats at 1,500 mg/kg; there were no significant histopathologic lesions in either rats or mice. The only compound-related effects were ataxia, labored breathing, and lethargy for up to 30 minutes after dosing in rats and mice given the two highest doses and increases in liver weight to body weight ratios for male rats given the three highest doses and for female rats at all doses. Based on the pattern of mortality and the effects on body weight gain in the short-term studies, doses of 375 and 750 mg/kg a-methylbenzyl alcohol were administered in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats and 50 mice of each sex. Two-Year Studies: Significant reduction in body weight gain commenced at weeks 20-30 in high dose male and female rats, and body weights were 20%-30% below those of vehicle controls at study termination. In the low dose groups, body weight reduction occurred only in

  18. Identification of a Novel Tetragonally-Compressed Six-Coordinate Copper (II) Complex: Preparation and Characterization of a 3-Chloroanilinium Copper Chloride Complex (3-Chloroanilinium)(8)(CuC1(6)C1(4))

    DTIC Science & Technology

    1990-10-12

    dihydrate were added approximately 150 mL of distilled water and 350 mL of concentrated hydrochloric acid. The resulting solution was heated, with...given in Tables II-IV, SIII-SVI. Results Description of the Structure. The structure of (3- chloroanilinium)8[ CuCl ,]Cl4 consists of discrete 3...other ring positions have revealed a compound formulated, from analytical data, as (3-chloroanilinium)8 CuCl 10. The compound is not very stable. A

  19. Stochastic determination of matrix determinants.

    PubMed

    Dorn, Sebastian; Ensslin, Torsten A

    2015-07-01

    Matrix determinants play an important role in data analysis, in particular when Gaussian processes are involved. Due to currently exploding data volumes, linear operations-matrices-acting on the data are often not accessible directly but are only represented indirectly in form of a computer routine. Such a routine implements the transformation a data vector undergoes under matrix multiplication. While efficient probing routines to estimate a matrix's diagonal or trace, based solely on such computationally affordable matrix-vector multiplications, are well known and frequently used in signal inference, there is no stochastic estimate for its determinant. We introduce a probing method for the logarithm of a determinant of a linear operator. Our method rests upon a reformulation of the log-determinant by an integral representation and the transformation of the involved terms into stochastic expressions. This stochastic determinant determination enables large-size applications in Bayesian inference, in particular evidence calculations, model comparison, and posterior determination.

  20. Two Unique Glioma Subtypes Revealed.

    PubMed

    Poh, Alissa

    2016-04-01

    A comprehensive analysis of 1,122 diffuse glioma samples from The Cancer Genome Atlas has revealed two new subtypes of this common brain cancer, with molecular and clinical features that diverge from the norm. The study findings also support the use of DNA methylation profiles to improve glioma classification and treatment.

  1. Ischemic Colitis Revealing Polyarteritis Nodosa

    PubMed Central

    Hamzaoui, Amira; Litaiem, Noureddine; Smiti Khanfir, M.; Ayadi, Sofiene; Nfoussi, Haifa; Houman, M. H.

    2013-01-01

    Ischemic colitis is one of the most common intestinal ischemic injuries. It results from impaired perfusion of blood to the bowel and is rarely caused by vasculitis. We report a case of ischemic colitis revealing polyarteritis nodosa (PAN) in a 55-year-old man. Histological examination of the resected colon led to the diagnosis of PAN. PMID:24382967

  2. NTP Toxicology and Carcinogenesis Studies of dl-Amphetamine Sulfate (CAS No. 60-13-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    PubMed

    1991-06-01

    dl-Amphetamine sulfate is used for the treatment of narcolepsy in adults and behavioral syndromes in children. Toxicology and carcinogenesis studies were conducted by administering dl-amphetamine sulfate (USP grade) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 14-Day Studies: The chemical was administered at dietary concentrations of 0, 47, 94, 188, 375, or 750 ppm for rats and 0, 125, 250, 500, 1,000, or 2,000 ppm for mice. Decreased body weight gain was seen at the higher concentrations, but no chemical-related deaths or toxic lesions were observed. 13-Week Studies: The chemical was administered at dietary concentrations of 0, 47, 94, 188, 375, or 750 ppm for rats and 0, 125, 250, 500, 1,000, or 2,000 ppm for mice. None of the rats died, but 6/10 male mice and 7/10 female mice that received 2,000 ppm, 3/10 male mice that received 1,000 ppm, and 8/10 male mice that received 500 ppm died before the end of the studies. Decreased body weight gain and hyperactivity were seen in dosed rats and mice. Final body weights of rats receiving 188 ppm or more were 62% to 89% those of controls, and final body weights of mice receiving 250 ppm or more were 70% to 86% those of controls. There were no lesions that were considered to be a primary effect of the chemical. Based on decreased body weight gain and hyperactivity in the 13-week studies, 2-year studies were conducted by feeding diets containing 0, 20 or 100 ppm dl-amphetamine sulfate to groups of 50 rats or 50 mice of each sex. Body Weights and Survival in the 2-Year Studies: No significant differences in survival were observed between any groups of rats or mice (male rats: control, 30/50; low dose, 31/50; high dose, 33/50; female rats: 33/50; 42/50; 37/50; male mice: 48/50; 48/50; 49/50; female mice: 35/50; 36/50; 44/50). Final body weights of dosed rats and mice

  3. NTP technical report on the toxicity studies of Butanal oxime (CAS No. 110-69-0) administered in drinking water and by gavage to F344/N rats and B6C3F1 mice.

    PubMed

    Burka, Leo T

    2004-01-01

    Butanal oxime is used as a volatile antiskinning agent in paints, inks, and similar products. Butanal oxime was chosen for toxicology testing as a representative of the aldoxime class. Male and female F344/N rats and B6C3F1 mice received butanal oxime (99 percent pure) in drinking water for 15 days or by gavage in 0.5 percent methylcellulose for 14 weeks. Animals were evaluated for clinical pathology, reproductive system effects, and histopathology. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice received 0, 312, 625, 1,250, 2,500, or 5,000 ppm butanal oxime in drinking water, resulting in average daily doses of approximately 40, 70, or 100 mg butanal oxime/kg body weight to male and female rats; 45, 90, 130, 200, or 300 mg/kg to male mice; and 45, 85, 100, 130, or 170 mg/kg to female mice. Due to body weight loss and lack of water consumption, all male and female rats receiving 2,500 or 5,000 ppm were removed from the study on day 9; average daily doses were not calculated for these groups. All other rats and mice survived until the end of the studies. Mean body weights of 1,250 ppm male and female rats and 2,500 and 5,000 ppm male and female mice were significantly less than those of the controls. Male mice receiving 5,000 ppm and females receiving 2,500 or 5,000 ppm lost weight during the study. Water consumption by rats and mice receiving 1,250 ppm or greater was less than that by the controls. Thinness in 2,500 and 5,000 ppm rats and mice was the only clinical finding of toxicity. Spleen weights were significantly decreased in 2,500 and 5,000 ppm female mice. No chemical-related lesions were observed grossly; histologic examinations were not performed. In the 14-week studies, groups of 10 male and 10 female rats and mice received butanal oxime by gavage at doses of 0, 25, 50, 100, 200, or

  4. Toxicology and carcinogenesis studies of Ginkgo biloba extract (CAS No. 90045-36-6) in F344/N rats and B6C3F1/N mice (Gavage studies).

    PubMed

    2013-03-01

    Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell

  5. [Seizures revealing phosphocalcic metabolism abnormalities].

    PubMed

    Hmami, F; Chaouki, S; Benmiloud, S; Souilmi, F Z; Abourazzak, S; Idrissi, M; Atmani, S; Bouharrou, A; Hida, M

    2014-01-01

    Hypocalcemia due to hypoparathyroidism produces a broad spectrum of clinical manifestations, but overt symptoms may be sparse. One unusual presentation is onset or aggravation of epilepsy in adolescence revealing hypoparathyroidism. This situation can lead to delayed diagnosis, with inefficacity of the antiepileptic drugs. We report five cases of adolescence-onset epilepsy with unsuccessful antiepileptic therapy, even with gradually increasing dose. Physical examination revealed signs of hypocalcemia, confirmed biologically. Full testing disclosed the origin of the seizures: hypoparathyroidism in three patients and pseudohypoparathyroidism in the other two. In four of five patients, computed tomography showed calcification of the basal ganglia, defining Fahr's syndrome. The patients were treated with oral calcium and active vitamin D (1-alphahydroxy vitamin D3). Seizure frequency progressively decreased and serum calcium levels returned to normal. These cases illustrate the importance of the physical examination and of routine serum calcium assay in patients with new-onset epileptic seizures in order to detect hypocalcemia secondary to hypoparathyroidism.

  6. Revealing the microstructure of materials

    NASA Technical Reports Server (NTRS)

    Nelson, James A.

    1990-01-01

    The objectives are to demonstrate how the microstructure of materials may be revealed by abrasive polishing and chemical etching, and to illustrate how microstructural information is used to monitor manufacturing processes, provide in-depth inspection, and perform failure analysis. Microstructural analysis is the procedure used to reveal the internal microstructural details of a material or part by sectioning and polishing the cut surface so that it may be examined under a suitable microscope. A printed wiring board was selected as the test material because it contains both metals and nonmetals that have distinctive microstructures, and because this technique is used throughout the electronic industry as a key quality control tool. The three principle component materials in printed circuit boards are glass/epoxy laminates faced with copper foil; copper, deposited by both electroless and electrolytic plating; and tin/lead solder. Sample preparation, mounting, grinding, polishing, and examination and analysis are discussed.

  7. Virulence Determination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This chapter reviews the in vitro and in vivo assays that are available for determination of pathogenic potential of Listeria monocytogenes bacteria, highlighting the value of using multiplex PCR for rapid and accurate assessment of listerial virulence....

  8. NTP Toxicology and Carcinogenesis Studies of Technical Grade Sodium Xylenesulfonate (CAS No. 1300-72-7) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

    PubMed

    1998-06-01

    Sodium xylenesulfonate is used as a hydrotrope, an organic compound that increases the ability of water to dissolve other molecules. Sodium xylenesulfonate is a component in a variety of widely used shampoos and liquid household detergents where it can constitute up to 10% of the total solution. Because of its widespread use, the potential for human exposure to sodium xylenesulfonate is great. Male and female F344/N rats and B6C3F1 mice were administered sodium xylenesulfonate in water or 50% ethanol dermally for 17 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells. 17-DAY STUDY IN RATS: Groups of five male and five female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed rats were similar to those of the control groups. Dermal applications of 300 mL of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 10, 30, 90, 260, and 800 mg sodium xylenesulfonate/kg body weight to males and 13, 40, 120, 330, and 1,030 mg/kg to females. Clinical findings generally involved the skin of dosed animals and included tan or brown skin discoloration and crusty white deposits (presumed to be dried chemical) at the site of application. Neither of these observations were considered significant findings. The relative liver weights of 133 and 400 mg/mL male and female rats were significantly greater than those of the control groups, but the absolute liver weights were not increased and the biological significance of the relative differences in liver weight was unclear. In males and females, the few lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical

  9. NTP technical report on the toxicity studies of 2- and 4-Methylimidazole (CAS No. 693-98-1 and 822-36-6) administered in feed to F344/N rats and B6C3F1 mice.

    PubMed

    Chan, P C

    2004-04-01

    [Structure-see text] 2-Methylimidazole and 4-methylimidazole are intermediate/starting materials or components in the manufacture of pharmaceuticals, photographic and photothermographic chemicals, dyes and pigments, agricultural chemicals, and rubber; these chemicals have been identified as undesirable by-products in several foods and have been detected in mainstream and sidestream tobacco smoke. The National Cancer Institute nominated 2- and 4-methylimidazole as candidates for toxicity and carcinogenicity studies. Toxicity studies were carried out in male and female F344/N rats and B6C3F1 mice. Animals were exposed to 2- or 4-methylimidazole in feed for 15 days or 14 weeks; clinical pathology studies were conducted in the 14-week studies on days 8, 29, and 86 and at week 14. Genetic toxicity studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. Groups of five male and five female rats and mice were fed diets containing 0, 1,200, 3,300, or 10,000 ppm 2-methylimidazole (equivalent to average daily doses of approximately 115, 290, or 770 mg 2-methylimidazole/ kg body weight to rats; 220, 640, or 2,100 mg/kg to male mice; 300, 800, or 2,400 to female mice) for 15 days. Groups of five male and five female rats and mice were fed diets containing 0, 300, 800, or 2,500 ppm 4-methylimidazole (equivalent to average daily doses of approximately 30, 80, or 220 mg/kg for rats and 65, 170, or 500 mg/kg for mice) for 15 days. In the 15-day 2-methylimidazole studies, all animals survived to the end of the studies. The mean body weights of 10,000 ppm male rats and female mice were significantly less than those of the controls. Feed consumption by 10,000 ppm male and female rats was reduced. Enlarged thyroid glands were observed in 3,300 and 10,000 ppm male and female rats. The incidences of diffuse hyperplasia of follicular cells of the thyroid gland in 3,300 and 10,000 ppm male and female rats and pars distalis hypertrophy of the

  10. Gender determination in populus

    SciTech Connect

    McLetchie, D.N.; Tuskan, G.A.

    1994-12-31

    Gender, the expression of maleness or femaleness, in dioecious plants has been associated with changes in morphology, physiology, ecological position, and commercial importance of several species, including members of the Salicaceae family. Various mechanisms have been proposed to explain the expression of gender in Salicaceae, including sex chromosomes, simple Mendelian genes, quantitative genes, environment, and genotype-by-environment interactions. Published reports would favor a genetic basis for gender. The objective of this study was to identify molecular markers associated with gender in a segregating family of hybrid poplars. Bulked segregant analysis and chi-squared analysis were used to test for the occurrence of sex chromosomes, individual loci, and chromosome ratios (i.e., ploidy levels) as the mechanisms for gender determination. Examination of 2488 PCR based RAPD markers from 1219 primers revealed nine polymorphic bands between male and female bulked samples. However, linkage analysis indicated that none of these markers were significantly associated with gender. Chisquared results for difference in male-to-female ratios between diploid and triploid genotypes also revealed no significant differences. These findings suggest gender is not controlled via sex chromosomes, simple Mendelian loci or ratios of autosome to gender-determining loci. It is possible that gender is determined genetically by regions of the genome not sampled by the tested markers or by a complex of loci operating in an additive threshold manner or in an epistatic manner. It is also possible that gender is determined environmentally at an early zygote stage, canalizing gender expression.

  11. Metabolomics reveals metabolic biomarkers of Crohn's disease

    SciTech Connect

    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  12. NTP Toxicology and Carcinogenesis Studies of Ozone (CAS No. 10028-15-6) and Ozone/NNK (CAS No. 10028-15-6/ 64091-91-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1994-10-01

    .0 ppm ozone for 30 months to determine the effect of extended exposure on neoplasm incidence. Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 130 weeks. Survival and Body Weights: Survival rates of exposed mice were similar to those of the controls. The mean body weights of 0.5 ppm males and females were similar to those of the controls throughout the study. The mean body weights of 1.0 ppm males and females were generally lower than those of the controls throughout the study. Hypoactivity was observed in male and female mice exposed to ozone. Pathology Findings: The incidences of alveolar/bronchiolar adenoma and carcinoma (combined) were marginally increased in exposed males (0 ppm, 16/49; 0.5 ppm, 22/49; 1.0 ppm, 21/50) and in exposed females (6/50, 8/49, 12/50). Increased incidences of metaplasia occurred in the nose, larynx, and lung of exposed groups of males and females, and the incidences of hyperplasia were increased in the larynx and nose of exposed mice. The morphology of the lesions was similar to that seen in the 2-year study. There were no ozone-related increases in alveolar epithelial hyperplasia. GENETIC TOXICOLOGY: Ozone was mutagenic in Salmonella typhimurium strain TA102, with and without S9 metabolic activation. CONCLUSIONS: Under the conditions of these 2-year and lifetime inhalation studies, there was no evidence of carcinogenic activity of ozone in male or female F344/N rats exposed to 0.12, 0.5, or 1.0 ppm. There was equivocal evidence of carcinogenic activity of ozone in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma or carcinoma. There was some evidence of carcinogenic activity of ozone in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma or carcinoma. There was no evidence that exposure to 0.5 ppm ozone enhanced the incidence of NNK-induced pulmonary neoplasms in male rats. Exposure of male

  13. Interior Evolution of Ceres Revealed by Dawn

    NASA Astrophysics Data System (ADS)

    Raymond, Carol A.; Park, Ryan S.; Konopliv, Alex S.; Bland, Michael T.; Marchi, Simone; Castillo-Rogez, Julie C.; McCord, Thomas B.; Jaumann, Ralf; Russell, Christopher T.; Prettyman, Thomas H.

    2015-11-01

    Dawn's exploration of Ceres has revealed its geophysical characteristics, informing the processes that have shaped it. Dawn has determined the average diameter of Ceres to be 940 km, smaller than the previously estimated 975 km [1]. This implies a density of 2160 kg/m3, indicating that Ceres is less differentiated than predicted [2]. The low-degree gravity field is consistent with the body being in hydrostatic equilibrium and the magnitude of J2 implies some central condensation. Ceres' entire surface is cratered, implying the lack of a thick (10's of km) water ice layer at the surface. Variability in Ceres' crater morphology indicates that the near-surface layer has variable strength and rheology, likely due to heterogeneity in the near-surface mixture of rock, ice and salt. The lack of a number of expected large impact basins on Ceres can be interpreted to be the result of viscous relaxation, resurfacing or a combination of both. These data provide insights into Ceres' thermal evolution and mechanical properties, which appear to be unique to this warm, icy body.[1] Thomas, P. C., et al., Differentiation of the asteroid Ceres as revealed by its shape, Nature, 437, 224-226, 2005; [2] McCord et al., Ceres: Its Origin, Evolution and Structure and Dawn's Potential Contribution, Space Sci Rev DOI 10.1007/s11214-010-9729-9, 2011.

  14. Archimedes: Accelerator Reveals Ancient Text

    SciTech Connect

    Bergmann, Uwe

    2004-02-24

    Archimedes (287-212 BC), who is famous for shouting 'Eureka' (I found it) is considered one of the most brilliant thinkers of all times. The 10th-century parchment document known as the 'Archimedes Palimpsest' is the unique source for two of the great Greek's treatises. Some of the writings, hidden under gold forgeries, have recently been revealed at the Stanford Synchrotron Radiation Laboratory at SLAC. An intense x-ray beam produced in a particle accelerator causes the iron in original ink, which has been partly erased and covered, to send out a fluorescence glow. A detector records the signal and a digital image showing the ancient writings is produced. Please join us in this fascinating journey of a 1,000-year-old parchment from its origin in the Mediterranean city of Constantinople to a particle accelerator in Menlo Park.

  15. Revealing Non-Covalent Interactions

    PubMed Central

    Johnson, Erin R.; Keinan, Shahar; Mori-Sánchez, Paula; Contreras-García, Julia; Cohen, Aron J.; Yang, Weitao

    2010-01-01

    Molecular structure does not easily identify the intricate non-covalent interactions that govern many areas of biology and chemistry, including design of new materials and drugs. We develop an approach to detect non-covalent interactions in real space, based on the electron density and its derivatives. Our approach reveals underlying chemistry that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids. Most importantly, the method, requiring only knowledge of the atomic coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of non-bonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands. PMID:20394428

  16. Revealing hidden genuine tripartite nonlocality

    NASA Astrophysics Data System (ADS)

    Paul, Biswajit; Mukherjee, Kaushiki; Sarkar, Debasis

    2016-11-01

    Nonlocal correlations arising from measurements on tripartite entangled states can be classified into two groups, one genuinely three-way nonlocal and other local with respect to some bipartition. Still, whether a genuinely tripartite entangled quantum state can exhibit genuine three-way nonlocality remains a challenging problem as far as measurement context is concerned. Here we introduce an approach in this regard. We consider three tripartite quantum states, none of which is genuinely three-way nonlocal in a specific Bell scenario (three parties, two measurements per party, two outcomes per measurement), but they can exhibit genuine three-way nonlocality when the initial states are subjected to stochastic local operations and classical communication. So, genuine three-way nonlocality is a resource which can be revealed by using a sequence of measurements.

  17. Revealing ontological commitments by magic.

    PubMed

    Griffiths, Thomas L

    2015-03-01

    Considering the appeal of different magical transformations exposes some systematic asymmetries. For example, it is more interesting to transform a vase into a rose than a rose into a vase. An experiment in which people judged how interesting they found different magic tricks showed that these asymmetries reflect the direction a transformation moves in an ontological hierarchy: transformations in the direction of animacy and intelligence are favored over the opposite. A second and third experiment demonstrated that judgments of the plausibility of machines that perform the same transformations do not show the same asymmetries, but judgments of the interestingness of such machines do. A formal argument relates this sense of interestingness to evidence for an alternative to our current physical theory, with magic tricks being a particularly pure source of such evidence. These results suggest that people's intuitions about magic tricks can reveal the ontological commitments that underlie human cognition.

  18. Plan competitions reveal entrepreneurial talent

    SciTech Connect

    Madison, Alison L.

    2011-05-15

    Monthly economic diversity column for Tri-City Herald business section. Excerpt below: There’s something to be said for gaining valuable real-world experience in a structured, nurturing environment. Take for instance learning to scuba dive in the comfort of my resort pool rather than immediately hanging out with sharks while I figure out little things like oxygen tanks and avoiding underwater panic attacks. Likewise, graduate students are getting some excellent, supportive real-world training through university business plan competitions. These competitions are places where smart minds, new technologies, months of preparation and coaching, and some healthy pre-presentation jitters collide to reveal not only solid new business ideas, but also some promising entrepreneurial talent. In fact, professionals from around our region descend upon college campuses every spring to judge these events, which help to bridge the gap between academics and the real technology and business-driven economy.

  19. Erosion and what it Reveals

    NASA Technical Reports Server (NTRS)

    2003-01-01

    [figure removed for brevity, see original site]

    Released 20 November 2003

    This image is located near the boundary between Syrtis Major and Isidis Planitia. The top of the image shows rough material that has eroded away from the lower portion of the image, revealing an underlying surface that has many small craters. It also reveals an ancient flow lobe that is barely discernable, crossing the southern part of the image (this flow lobe is much easier to see as a smooth region in the context image).

    Image information: VIS instrument. Latitude 16.4, Longitude 77.9 East (282.1 West). 19 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  20. Evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic modeling for in vivo inhalation gas uptake data exposure in female B6C3F1 mice

    SciTech Connect

    Evans, M.V.; Caldwell, J.C.

    2010-05-01

    Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools for calculation of internal and target organ doses of parent compound and metabolites. PBPK models, coupled with in vivo inhalation gas-uptake data, can be useful to estimate total metabolism. Previously, such an approach was used to make predictions regarding the metabolism and to make subsequent inferences of DCM's mode of action for toxicity. However, current evidence warrants re-examination of this approach. The goal of this work was to examine two different hypotheses for DCM metabolism in mice. One hypothesis describes two metabolic pathways: one involving cytochrome P450 2E1 (CYP2E1) and a second glutathione (GSH). The second metabolic hypothesis describes only one pathway mediated by CYP2E1 that includes multiple binding sites. The results of our analysis show that the in vivo gas-uptake data fit both hypotheses well and the traditional analysis of the chamber concentration data is not sufficient to distinguish between them. Gas-uptake data were re-analyzed by construction of a velocity plot as a function of increasing DCM initial concentration. The velocity (slope) analysis revealed that there are two substantially different phases in velocity, one rate for lower exposures and a different rate for higher exposures. The concept of a 'metabolic switch,' namely that due to conformational changes in the enzyme after one site is occupied - a different metabolic rate is seen - is also consistent with the experimental data. Our analyses raise questions concerning the importance of GSH metabolism for DCM. Recent research results also question the importance of this pathway in the toxicity of DCM. GSH-related DNA adducts were not formed after in vivo DCM exposure in mice and DCM-induced DNA damage has