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Sample records for a0 a1 a2

  1. Milk A1 and A2 peptides and diabetes.

    PubMed

    Clemens, Roger A

    2011-01-01

    Food-derived peptides, specifically those derived from milk, may adversely affect health by increasing the risk of insulin-dependent diabetes. This position is based on the relationship of type 1 diabetes (T1D) and the consumption of variants A1 and B β-casein from cow's milk. It appears that β-casomorphin-7 (BCM-7) from β-casein may function as an immunosuppressant and impair tolerance to dietary antigens in the gut immune system, which, in turn, may contribute to the onset of T1D. There are thirteen genetic variants of β-casein in dairy cattle. Among those variants are A1, A2, and B, which are also found in human milk. The amino acid sequences of β-casomorphins among these bovine variants and those found in human milk are similar, often differing only by a single amino acid. In vitro studies indicate BCM-7 can be produced from A1 and B during typical digestive processes; however, BCM-7 is not a product of A2 digestion. Evidence from several epidemiological studies and animal models does not support the association of milk proteins, even proteins in breast milk, and the development of T1D. Ecological data, primarily based on A1/ A2 variations among livestock breeds, do not demonstrate causation, even among countries where there is considerable dairy consumption.

  2. Atomic-resolution studies of epitaxial strain release mechanisms in L a1.85S r0.15Cu O4 /L a0.67C a0.33Mn O3 superlattices

    NASA Astrophysics Data System (ADS)

    Biškup, N.; Das, S.; Gonzalez-Calbet, J. M.; Bernhard, C.; Varela, M.

    2015-05-01

    In this paper we present an atomic-resolution electron microscopy study of superlattices (SLs) where the colossal magnetoresistant manganite L a0.67C a0.33Mn O3 (LCMO) and the high critical temperature superconducting cuprate L a1.85S r0.15Cu O4 (LSCO) are combined. Although good quality epitaxial growth can be achieved, both the choice of substrate and the relatively large lattice mismatch between these materials (around 2%) have a significant impact on the system properties [Phys. C 468, 991 (2008), 10.1016/j.physc.2008.05.001; Nature (London) 394, 453 (1998), 10.1038/28810]. Our samples, grown by pulsed laser deposition, are epitaxial and exhibit high structural quality. By means of cutting-edge electron microscopy and spectroscopy techniques we still find that the epitaxial strain is accommodated by a combination of defects, such as interface steps and antiphase boundaries in the manganite. These defects result in inhomogeneous strain fields through the samples. Also, some chemical inhomogeneities are detected, up to the point that novel phases nucleate. For example, at the LCMO/LSCO interface the AB O3 -type manganite adopts a tetragonal LSCO-like structure forming localized layers that locally resemble the composition of L a2 /3C a4 /3Mn O4 . Structural distortions are detected in the cuprate as well, which may extend over lateral distances of several unit cells. Finally, we also analyze the influence of the substrate-induced strain by examining superlattices grown on two different substrates: (LaAlO3) 0.3(Sr2AlTaO6 ) 0.7 (LSAT) and LaSrAl O4 (LSAO). We observe that SLs grown on LSAT, which are nonsuperconducting, present reduced values of the c axis compared to superlattices grown on LSAO (which are fully superconducting). This finding points to the fact that the proper distance between copper planes in LSCO is essential in obtaining superconductivity in cuprates.

  3. COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.

    PubMed

    Jeanne, Marion; Labelle-Dumais, Cassandre; Jorgensen, Jeff; Kauffman, W Berkeley; Mancini, Grazia M; Favor, Jack; Valant, Valerie; Greenberg, Steven M; Rosand, Jonathan; Gould, Douglas B

    2012-01-13

    Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH.

  4. Evidence that histidine forms a coordination bond to the A(0A) and A(0B) chlorophylls and a second H-bond to the A(1A) and A(1B) phylloquinones in M688H(PsaA) and M668H(PsaB) variants of Synechocystis sp. PCC 6803.

    PubMed

    Sun, Junlei; Hao, Sijie; Radle, Matthew; Xu, Wu; Shelaev, Ivan; Nadtochenko, Victor; Shuvalov, Vladimir; Semenov, Alexey; Gordon, Heather; van der Est, Art; Golbeck, John H

    2014-08-01

    The axial ligands of the acceptor chlorophylls, A(0A) and A(0B), in Photosystem I are the Met sulfur atoms of M688(PsaA) and M668(PsaB). To determine the role of the Met, His variants were generated in Synechocystis sp. PCC 6803. Molecular dynamics simulations on M688H(PsaA) show that there exist low energy conformations with the His coordinated to A(0A) and possibly H-bonded to A(1A). Transient EPR studies on M688H(PsaA) indicate a more symmetrical electron spin distribution in the A(1A) phyllosemiquinone ring consistent with the presence of an H-bond to the C1 carbonyl. Ultrafast optical studies on the variants show that the 150fs charge separation between P₇₀₀ and A(0) remains unaffected. Studies on the ns timescale show that 57% of the electrons are transferred from A(0A)(-) to A(1A) in M688H(PsaA) and 48% from A(0B)(-) to A(1B) in M668H(PsaB); the remainder recombine with P₇₀₀(+) with 1/e times of 25ns and 37ns, respectively. Those electrons that reach A(1A) and A(1B) in the branch carrying the mutation are not transferred to FX, but recombine with P₇₀₀(+) with 1/e times of ~15μs and ~5μs, respectively. Hence, the His is coordinated to A0 in all populations, but in a second population, the His may be additionally H-bonded to A(1). Electron transfer from A(0) to A(1) occurs only in the latter, but the higher redox potentials of A(0) and A(1) as a result of the stronger coordination bond to A(0) and the proposed second H-bond to A(1) preclude electron transfer to the Fe/S clusters.

  5. [Determination of antigens A1 and A2 in erythrocytes by phytohemagglutinins].

    PubMed

    Potapov, M I

    2004-01-01

    Phytohemagglutinins antiH2 antiA1 and antiA2, when used jointly, ensure a reliable diagnosis of subantigens A1 and A2. Vegetable extracts are easier-to-find and safer for the purpose versus rare and hard-to-standardize corresponding isosera.

  6. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  7. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  8. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  9. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  10. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  11. No evidence for disturbed COL1A1 and A2 expression in otosclerosis.

    PubMed

    Csomor, Péter; Liktor, Balázs; Liktor, Bálint; Sziklai, István; Karosi, Tamás

    2012-09-01

    Otosclerosis is a complex bone remodeling disorder of the human otic capsule that might be associated with various mutations of A1 and A2 alleles of type-I collagen. The study herein presented, investigates the possibilty of the genetic involvement of type-I collagen in the pathogenesis of histologically confirmed otosclerosis. A total of 55 ankylotic stapes footplates were analyzed. Cortical bone fragments (n = 30), incus (n = 3) and malleus (n = 2) specimens were employed as negative controls. Specimens were divided into two groups. The first group was processed using conventional H.E. hematoxylin-eosin (H.E.) staining and type-I collagen-specific immunofluorescent assay (IFA), while the second group was examined by COL1A1 and A2-specific RT-PCR. Otosclerotic- (n = 31) and non-otosclerotic stapes footplates (n = 9) as well as cortical bones (n = 20), incus (n = 2) and malleus specimens (n = 1) showed normal and quite similar A1 and A2 allele expression confirmed by IFA. RT-PCR analysis revealed normal and consistent mRNA expression of both alleles in each specimen. Expression levels and patterns of COL1A1/A2 alleles did not show significant correlation with the histological diagnosis of otosclerosis. Type-I collagen is a highly conserved structure protein, which plays a fundamental role in the integritiy of various connective tissues. Mutations of A1 and A2 alleles result in serious systemic disorders of the skeleton, tendons and skin. Since otosclerosis is an organ-specific disease, it is difficult to explain its genetic association with type-I collagen. In conclusion, we found no evidence supporting the putative link of COL1A1 and COL1A2 alleles with otosclerosis.

  12. Optimization of arylindenopyrimidines as potent adenosine A(2A)/A(1) antagonists.

    PubMed

    Shook, Brian C; Rassnick, Stefanie; Chakravarty, Devraj; Wallace, Nathaniel; Ault, Mark; Crooke, Jeffrey; Barbay, J Kent; Wang, Aihua; Leonard, Kristi; Powell, Mark T; Alford, Vernon; Hall, Daniel; Rupert, Kenneth C; Heintzelman, Geoffrey R; Hansen, Kristen; Bullington, James L; Scannevin, Robert H; Carroll, Karen; Lampron, Lisa; Westover, Lori; Russell, Ronald; Branum, Shawn; Wells, Kenneth; Damon, Sandra; Youells, Scott; Beauchamp, Derek; Li, Xun; Rhodes, Kenneth; Jackson, Paul F

    2010-05-01

    Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.

  13. [Simplified microdetermination of cerebral phospholipase A1, A2 and lysophopholipase].

    PubMed

    Hirashima, Y; Koshu, K; Kamiyama, K; Endo, S; Takaku, A; Honda, T; Takasaki, C

    1983-08-01

    The purpose of our study was to examine the ischemia induced enzymatic changes of decaylation-reacylation cycle of membrane phospholipids in dog brain. In this study, we developed new modified method for assay of phospholipase A1, A2 and lysophospholipase which is simpler and needs only a smaller amount of materials. For the first report, we introduced this new method and demonstrated some properties of phospholipase A1, A2 and lysophospholipase in dog brain. Crude enzyme solution for assays of phospholipase A1, A2 and lysophospholipase was gained from extraction of frozen brain with aceton, butanol and saline. The level of phosphorus in the enzyme extract was determined and only those extracts which had a level of phosphorus within a certain range were used. The substrates for assays were L-alpha-[beta-palmitoyl-1-14C] phosphatidylcholine, dipalmitoyl for phospholipase A1 and A2 and L-lysophosphatidylcholine-1-[1-14C] palmitoyl for lysophospolipase respectively. Each radioactive substrates was diluted with cold carrier lipid to give the proper specific activity. Reaction system including substrate, buffer [pH 7.0] and enzyme extract was incubated for 10 hours at 38 degrees C. But for the assay of phospholipase A1 and A2, enzyme solution was pre-incubated at 70 degrees C for 5 minutes. In our new method, reaction mixture was directly separated by TLC without extracting lipids. Enzyme activities were calculated from radio thin-layer chromatograms. Furthermore, we made a comparison between our method and the former one. The value of each enzyme activity was slightly higher in our method than in the former one. However, it was revealed that the results were reproducible in both methods.

  14. A continuous spectrophotometric assay that distinguishes between phospholipase A1 and A2 activities[S

    PubMed Central

    El Alaoui, Meddy; Soulère, Laurent; Noiriel, Alexandre; Popowycz, Florence; Khatib, Abdallah; Queneau, Yves; Abousalham, Abdelkarim

    2016-01-01

    A new spectrophotometric assay was developed to measure, continuously and specifically, phospholipase A1 (PLA1) or phospholipase A2 (PLA2) activities using synthetic glycerophosphatidylcholines (PCs) containing α-eleostearic acid, either at the sn-1 position [1-α-eleostearoyl-2-octadecyl-rac-glycero-3-phosphocholine (EOPC)] or at the sn-2 position [1-octadecyl-2-α-eleostearoyl-rac-glycero-3-phosphocholine (OEPC)]. The substrates were coated onto the wells of microtiter plates. A nonhydrolyzable ether bond, with a non-UV-absorbing alkyl chain, was introduced at the other sn position to prevent acyl chain migration during lipolysis. Upon enzyme action, α-eleostearic acid is liberated and then solubilized into the micellar phase. The PLA1 or PLA2 activity was measured by the increase in absorbance at 272 nm due to the transition of α-eleostearic acid from the adsorbed to the soluble state. EOPC and OEPC differentiate, with excellent accuracy, between PLA1 and PLA2 activity. Lecitase®, guinea pig pancreatic lipase-related protein 2 (known to be a PLA1 enzyme), bee venom PLA2, and porcine pancreatic PLA2 were all used to validate the assay. Compared with current assays used for continuously measuring PLA1 or PLA2 activities and/or their inhibitors, the development of this sensitive enzymatic method, using coated PC substrate analogs to natural lipids and based on the UV spectroscopic properties of α-eleostearic acid, is a significant improvement. PMID:27194811

  15. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  16. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  17. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  18. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  19. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  20. ATPase activity of Mycobacterium tuberculosis SecA1 and SecA2 proteins and its importance for SecA2 function in macrophages.

    PubMed

    Hou, Jie M; D'Lima, Nadia G; Rigel, Nathan W; Gibbons, Henry S; McCann, Jessica R; Braunstein, Miriam; Teschke, Carolyn M

    2008-07-01

    The Sec-dependent translocation pathway that involves the essential SecA protein and the membrane-bound SecYEG translocon is used to export many proteins across the cytoplasmic membrane. Recently, several pathogenic bacteria, including Mycobacterium tuberculosis, were shown to possess two SecA homologs, SecA1 and SecA2. SecA1 is essential for general protein export. SecA2 is specific for a subset of exported proteins and is important for M. tuberculosis virulence. The enzymatic activities of two SecA proteins from the same microorganism have not been defined for any bacteria. Here, M. tuberculosis SecA1 and SecA2 are shown to bind ATP with high affinity, though the affinity of SecA1 for ATP is weaker than that of SecA2 or Escherichia coli SecA. Amino acid substitution of arginine or alanine for the conserved lysine in the Walker A motif of SecA2 eliminated ATP binding. We used the SecA2(K115R) variant to show that ATP binding was necessary for the SecA2 function of promoting intracellular growth of M. tuberculosis in macrophages. These results are the first to show the importance of ATPase activity in the function of accessory SecA2 proteins.

  1. Qualitative Differences in the N-Acetyl-D-galactosaminyltransferases Produced by Human A1 and A2 Genes

    PubMed Central

    Schachter, H.; Michaels, M. A.; Tilley, Christine A.; Crookston, Marie C.; Crookston, J. H.

    1973-01-01

    This study describes the kinetic properties of N-acetyl-D-galactosaminyltransferase in serum from subjects with blood groups A1 and A2. When the A1 and A2 enzymes were compared, with lacto-N-fucopentaose I and 2′-fucosyllactose as acceptors, the enzymes differed in their cation requirements, pH optima, and Km values. The two acceptors competed for the same transferase. Mixing experiments showed that the lower activity of the A2 enzyme could not be attributed to a modifier or inhibitor in serum. It was concluded that the A1 and A2 enzymes differ qualitatively. PMID:4509655

  2. Genetic evidence that mutations in the COL1A1, COL1A2, COL3A1, or COL5A2 collagen genes are not responsible for mitral valve prolapse.

    PubMed Central

    Henney, A M; Tsipouras, P; Schwartz, R C; Child, A H; Devereux, R B; Leech, G J

    1989-01-01

    DNA markers were used to assess the segregation of genes encoding the collagen types that predominate in the mitral valve (types I, III, and V) in two family pedigrees that are phenotypically different but showed dominantly inherited mitral valve prolapse. The inheritance of these markers was compared with the segregation of the phenotype for mitral valve prolapse in both families. In one family it was shown that the COL1A1, COL1A2, COL3A1, and COL5A2 genes segregated independently of the phenotype; in the other family the results for COL1A1, COL1A2, and COL5A2 were similar but analysis at the COL3A1 locus was not possible. These data indicate that in these families mitral valve prolapse does not arise from a defect in one of these collagen genes. PMID:2930668

  3. Inhibition of phagocytosis by Haemophilus ducreyi requires expression of the LspA1 and LspA2 proteins.

    PubMed

    Vakevainen, Merja; Greenberg, Steven; Hansen, Eric J

    2003-10-01

    Haemophilus ducreyi previously has been shown to inhibit the phagocytosis of both secondary targets and itself by certain cells in vitro. Wild-type H. ducreyi strain 35000HP contains two genes, lspA1 and lspA2, whose encoded protein products are predicted to be 456 and 543 kDa, respectively. An isogenic mutant of H. ducreyi 35000HP with inactivated lspA1 and lspA2 genes has been shown to exhibit substantially decreased virulence in the temperature-dependent rabbit model for chancroid. This lspA1 lspA2 mutant was tested for its ability to inhibit phagocytosis of immunoglobulin G-opsonized particles by differentiated HL-60 and U-937 cells and by J774A.1 cells. The wild-type strain H. ducreyi 35000HP readily inhibited phagocytosis, whereas the lspA1 lspA2 mutant was unable to inhibit phagocytosis. Similarly, the wild-type strain was resistant to phagocytosis, whereas the lspA1 lspA2 mutant was readily engulfed by phagocytes. This inhibitory effect of wild-type H. ducreyi on phagocytic activity was primarily associated with live bacterial cells but could also be found, under certain conditions, in concentrated H. ducreyi culture supernatant fluids that lacked detectable outer membrane fragments. Both the wild-type strain and the lspA1 lspA2 mutant attached to phagocytes at similar levels. These results indicate that the LspA1 and LspA2 proteins of H. ducreyi are involved, directly or indirectly, in the antiphagocytic activity of this pathogen, and they provide a possible explanation for the greatly reduced virulence of the lspA1 lspA2 mutant.

  4. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  5. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  6. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  7. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  8. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  9. StyA1 and StyA2B from Rhodococcus opacus 1CP: a Multifunctional Styrene Monooxygenase System▿

    PubMed Central

    Tischler, Dirk; Kermer, René; Gröning, Janosch A. D.; Kaschabek, Stefan R.; van Berkel, Willem J. H.; Schlömann, Michael

    2010-01-01

    Two-component flavoprotein monooxygenases are emerging biocatalysts that generally consist of a monooxygenase and a reductase component. Here we show that Rhodococcus opacus 1CP encodes a multifunctional enantioselective flavoprotein monooxygenase system composed of a single styrene monooxygenase (SMO) (StyA1) and another styrene monooxygenase fused to an NADH-flavin oxidoreductase (StyA2B). StyA1 and StyA2B convert styrene and chemical analogues to the corresponding epoxides at the expense of FADH2 provided from StyA2B. The StyA1/StyA2B system presents the highest monooxygenase activity in an equimolar ratio of StyA1 and StyA2B, indicating (transient) protein complex formation. StyA1 is also active when FADH2 is supplied by StyB from Pseudomonas sp. VLB120 or PheA2 from Rhodococcus opacus 1CP. However, in both cases the reductase produces an excess of FADH2, resulting in a high waste of NADH. The epoxidation rate of StyA1 heavily depends on the type of reductase. This supports that the FADH2-induced activation of StyA1 requires interprotein communication. We conclude that the StyA1/StyA2B system represents a novel type of multifunctional flavoprotein monooxygenase. Its unique mechanism of cofactor utilization provides new opportunities for biotechnological applications and is highly relevant from a structural and evolutionary point of view. PMID:20675468

  10. Interaction of model class A1, class A2, and class Y amphipathic helical peptides with membranes.

    PubMed

    Mishra, V K; Palgunachari, M N

    1996-08-27

    To test the hypothesis that differences in the lipid affinity of exchangeable apolipoproteins are due to the presence of different classes of amphipathic alpha-helical motifs which differ primarily in the distribution of charged amino acid residues, we designed and synthesized model peptides mimicking class A1, class A2, and class Y amphipathic helices present in these apolipoproteins. Both class A1 and class A2 helices have positive residues at the polar-nonpolar interface and negative residues at the center of the polar face. However, clustering of positive and negative residues is less exact in class A1 compared to class A2 helices. The class Y helices have two negative residue clusters on the polar face separating the two arms and the base of the Y motif formed by three positive residue clusters. The lipid affinities of three 18 residue model peptides representing these classes, Ac-18A1-NH2 (Ac-ELLEKWAEKLAALKEALK-NH2), Ac-18A2-NH2 (Ac-ELLEKWKEALAALAEKLK-NH2), and Ac-18Y-NH2 (Ac-ELLKAWKEALEALKEKLA-NH2), were determined by right-angle light scattering, circular dichroism spectroscopy, differential scanning calorimetry, and fluorescence spectroscopy. The observed rank order of lipid affinity of these three peptides is: Ac-18A2-NH2 > Ac-18Y-NH2 > Ac-18A1-NH2. This order is consistent with the known lipid affinity of exchangeable apolipoproteins containing class A1, class A2, and class Y helices (class A2 > class Y > class A1). Results of this study illustrate the important role of interfacial lysine residues in modulating the lipid affinity of amphipathic helices and suggest that the effect of interfacial lysine residues in increasing lipid affinity is additive. We propose that interfacial lysine residues, in addition to widening the hydrophobic face because of snorkeling, also help anchor the amphipathic helix in the lipid bilayer.

  11. Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia.

    PubMed

    Vrzalová, Zuzana; Hrubá, Zuzana; Hrabincová, Eva Sťahlová; Vrábelová, Slávka; Votava, Felix; Koloušková, Stanislava; Fajkusová, Lenka

    2011-01-01

    Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders caused by an enzymatic deficiency which impairs the biosynthesis of cortisol and, in the majority of severe cases, also the biosynthesis of aldosterone. Approximately 95% of all CAH cases are caused by mutations in the steroid 21-hydroxylase gene (CYP21A2). The CYP21A2 gene and its inactive pseudogene (CYP21A1P) are located within the HLA class III region of the major histocompatibility complex (MHC) locus on chromosome 6p21.3. In this study, we describe chimeric CYP21A1P/CYP21A2 genes detected in our patients with 21-hydroxylase deficiency (21OHD). Chimeric CYP21A1P/CYP21A2 genes were present in 171 out of 508 mutated CYP21A2 alleles (33.8%). We detected four types of chimeric CYP21A1P/CYP21A2 genes: three of them have been described previously as CH-1, CH-3, CH-4, and one type is novel. The novel chimeric gene, termed CH-7, was detected in 21.4% of the mutant alleles. Possible causes of CYP21A1P/CYP21A2 formation are associated with 1) high recombination rate in the MHC locus, 2) high recombination rate between highly homologous genes and pseudogenes in the CYP21 gene area, and 3) the existence of chi-like sequences and repetitive minisatellite consensus sequences in CYP21A2 and CYP21A1P which play a role in promoting genetic recombination.

  12. Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?

    PubMed

    Zhang, Ke Wei; Tonna, Stephen; Wang, Yan Yan; Rana, Kesha; Padavarat, Smitha; Savige, Judy

    2007-05-01

    Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans (COL4A5) and mice (COL4A1). This study examined whether COL4A1/COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3/COL4A4, were examined for linkage to COL4A1/COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations (n=23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1/COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1/COL4A2 does not represent a further major genetic locus for TBMN.

  13. Rational design of D-A1-D-A2 conjugated polymers with superior spectral coverage.

    PubMed

    Hedström, Svante; Tao, Qiang; Wang, Ergang; Persson, Petter

    2015-10-28

    The spectral coverage of a light-harvesting polymer largely determines the maximum achievable photocurrent in organic photovoltaics, and therefore constitutes a crucial parameter for improving their performance. The D-A1-D-A2 copolymer motif is a new and promising design strategy for extending the absorption range by incorporating two acceptor units with complementary photoresponses. The fundamental factors that promote an extended absorption are here determined for three prototype D-A1-D-A2 systems through a combination of experimental and computational methods. Systematic quantum chemical calculations are then used to reveal the intrinsic optical properties of ten further D-A1-D-A2 polymer candidates. These investigated polymers are all predicted to exhibit intense primary absorption peaks at 615-954 nm, corresponding to charge-transfer (CT) transitions to the stronger acceptor, as well as secondary absorption features at 444-647 nm that originate from CT transitions to the weaker acceptors. Realization of D-A1-D-A2 polymers with superior spectral coverage is thereby found to depend critically on the spatial and energetic separation between the two distinct acceptor LUMOs. Two promising D-A1-D-A2 copolymer candidates were finally selected for further theoretical and experimental study, and demonstrate superior light-harvesting properties in terms of significantly extended spectral coverage. This demonstrates great potential for enhanced light-harvesting in D-A1-D-A2 polymers via multiple absorption features compared to traditional D-A polymers.

  14. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...×104 7.3×105 Po-210 Polonium (84) 4.0×101 1.1×103 2.0×10−2 5.4×10−1 1.7×102 4.5×103 Pr-142 Praseodymium... 7.0×10−1 1.9×101 7.0×10−1 1.9×101 1.9 5.2×101 Bi-210 1.0 2.7×101 6.0×10−1 1.6×101 4.6×103 1.2×105 Bi... Unlimited Unlimited 4.5×10−6 1.2×10−4 Pb-210 (a) 1.0 2.7×101 5.0×10−2 1.4 2.8 7.6×101 Pb-212 (a) 7.0×10−1...

  15. Local expression of CYP19A1 and CYP19A2 in developing and adult killifish (Fundulus heteroclitus)

    PubMed Central

    Dong, Wu; Willett, Kristine L.

    2008-01-01

    P450 aromatase (CYP19) is the terminal enzyme in the steroidogenic pathway and catalyzes the conversion of androgens to estrogens. Fundulus heteroclitus like other teleosts, express two CYP19 genes, CYP19A1 and CYP19A2. The expression of CYP19s in Fundulus was measured by in situ hybridization throughout development. In 90 dpf (day post-fertilization) fish and adult fish, CYP19A1 was expressed in the ooplasm of early stage I oocytes (primary growth stage). Expression of CYP19A1 was localized in the follicle cell layer of late stage I (previtellogenic stage) and stage II (vitellogenic stage) follicles, but by stage III (early maturational follicles) CYP19A1 expression was localized in the vitelline envelope. Overall, CYP19A1 oocyte membrane expression gradually declined from highest expression at late stage I to nondetectable levels by stage IV. Highest expression of CYP19A2 was detected in the brain including the hypothalamus from 4, 6, 8, 10, 14 dpf embryos, 90 dpf fry fish and adult fish brain. In females compared to males, there was higher CYP19A2 expression in olfactory bulb. In addition to the brain, there was strong CYP19A2 signal in adrenal/kidney cells in 6-14 dpf embryos. This work establishes the localization and constitutive expression of CYP19s in Fundulus which can then be compared with potential disruption of CYP19A1 and CYP19A2 expression and physiological consequences caused by environmental contaminants. PMID:17582409

  16. Genetic Complexity of the Human Innate Host Defense Molecules, Surfactant Protein A1 (SP-A1) and SP-A2—Impact on Function

    PubMed Central

    Floros, Joanna; Wang, Guirong; Mikerov, Anatoly N.

    2010-01-01

    Innate immunity mechanisms play a critical role in the primary response to invading pathogenic microorganisms and other insulting agents. The innate lung immune system includes lung surfactant, a lipoprotein complex that carries out a function essential for life, that is, reduction of the surface tension at the air–liquid interphase of the alveolar space. By means of this function, pulmonary surfactant prevents lung collapse, therefore ensuring normal lung function and lung health. Pulmonary surfactant contains a number of host-defense molecules that are involved in the elimination of pathogens, viruses, particles, allergens, and other insults, as well as in the control of inflammation. This review is concerned with one of the surfactant proteins, the human (h) surfactant protein A (hSP-A), which, in addition to its role in surfactant-related functions, plays an important role in the modulation of lung host defense. The hSP-A locus has been identified with extensive complexity that may have an impact on its function, structure, and regulation. In humans, two genes—SP-A1 (SFTPA1) and SP-A2 (SFTPA2)—encode SP-A, with SP-A2 gene products being more biologically active than SP-A1 in most of the in vitro assays investigated. Although the two hSP-A genes share a high level of sequence similarity, differences in the structure and function between SP-A1 and SP-A2 have been observed in recent studies. In this review, we discuss the human SP-A complexity and how this may affect SP-A function. PMID:19392648

  17. Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury

    PubMed Central

    Gazoni, Leo M.; Walters, Dustin M.; Unger, Eric B.; Linden, Joel; Kron, Irving L.; Laubach, Victor E.

    2010-01-01

    Objective Adenosine and the activation of specific adenosine receptors are implicated in the attenuation of inflammation and organ ischemia-reperfusion (IR) injury. We hypothesized that activation of A1, A2A, or A3 adenosine receptors would provide protection against lung IR injury. Methods Using an isolated, ventilated, blood-perfused rabbit lung model, lungs underwent 18 hours cold ischemia followed by 2 hours reperfusion. Lungs were administered either vehicle, adenosine, or selective A1, A2A, or A3 receptor agonists (CCPA, ATL-313, or IB-MECA, respectively) alone or with their respective antagonists (DPCPX, ZM241385, or MRS1191) during reperfusion. Results Compared to the vehicle-treated control group, treatment with A1, A2A, or A3 agonists significantly improved function (increased lung compliance and oxygenation and decreased pulmonary artery pressure), decreased neutrophil infiltration by myeloperoxidase activity, decreased edema, and reduced TNF-α production. Adenosine treatment was also protective but not to the level of the agonists. When each agonist was paired with its respective antagonist, all protective effects were blocked. The A2A agonist reduced pulmonary artery pressure and myeloperoxidase activity and increased oxygenation to a greater degree than the A1 or A3 agonists. Conclusions Selective activation of A1, A2A, or A3 adenosine receptors provides significant protection against lung IR injury. The decreased elaboration of the potent proinflammatory cytokine, TNF-α, and decreased neutrophil sequestration likely contribute to the overall improvement in pulmonary function. These results provide evidence for the therapeutic potential of specific adenosine receptor agonists in lung transplant recipients. PMID:20398911

  18. The Functions of the A1A2A3 Domains in Von Willebrand Factor Include Multimerin 1 Binding

    PubMed Central

    Parker, D’Andra N.; Tasneem, Subia; Farndale, Richard W.; Bihan, Dominique; Sadler, J. Evan; Sebastian, Silvie; De Groot, Philip G.

    2016-01-01

    Summary Multimerin 1 (MMRN1) is a massive, homopolymeric protein that is stored in platelets and endothelial cells for activation-induced release. In vitro, MMRN1 binds to the outer surfaces of activated platelets and endothelial cells, the extracellular matrix (including collagen) and von Willebrand factor (VWF) to support platelet adhesive functions. VWF associates with MMRN1 at high shear, not static conditions, suggesting that shear exposes cryptic sites within VWF that support MMRN1 binding. Modified ELISA and surface plasmon resonance were used to study the structural features of VWF that support MMRN1 binding, and determine the affinities for VWF-MMRN1 binding. High shear microfluidic platelet adhesion assays determined the functional consequences for VWF-MMRN1 binding. VWF binding to MMRN1 was enhanced by shear exposure and ristocetin, and required VWF A1A2A3 region, specifically the A1 and A3 domains. VWF A1A2A3 bound to MMRN1 with a physiologically relevant binding affinity (KD: 2.0 ± 0.4 nM), whereas the individual VWF A1 (KD: 39.3 ± 7.7 nM) and A3 domains (KD: 229 ± 114 nM) bound to MMRN1 with lower affinities. VWF A1A2A3 was also sufficient to support the adhesion of resting platelets to MMRN1 at high shear, by a mechanism dependent on VWF-GPIbα binding. Our study provides new information on the molecular basis of MMRN1 binding to VWF, and its role in supporting platelet adhesion at high shear. We propose that at sites of vessel injury, MMRN1 that is released following activation of platelets and endothelial cells, binds to VWF A1A2A3 region to support platelet adhesion at arterial shear rates. PMID:27052467

  19. Isolation and characterization of new onionins A2 and A3 from Allium cepa, and of onionins A1, A2, and A3 from Allium fistulosum.

    PubMed

    Nohara, Toshihiro; Fujiwara, Yukio; Kudo, Rino; Yamaguchi, Koki; Ikeda, Tsuyoshi; Murakami, Kotaro; Ono, Masateru; Kajimoto, Tetsuya; Takeya, Motohiro

    2014-01-01

    In this study, the new stable sulfur-containing compounds onionins A2 (1) and A3 (2) were isolated from the acetone extracts of the bulbs of Allium cepa L. and identified as the stereoisomers of onionin A1 discovered in our previous study. Their chemical structures, 3,4-dimethyl-5-(1E-propenyl)-tetrahydrothiophene-2-sulfenic acid-S-oxides, were characterized using various spectroscopic techniques. In addition, 1 and 2 together with onionin A1 were successfully isolated from the leaves of the Welsh onion, Allium fistulosum L. The onion-extracted fractions showed good potential to inhibit the polarization of M2 activated macrophages, indicating their possible ability to inhibit tumor cell proliferation.

  20. A1 and A2a receptors mediate inhibitory effects of adenosine on the motor activity of human colon.

    PubMed

    Fornai, M; Antonioli, L; Colucci, R; Ghisu, N; Buccianti, P; Marioni, A; Chiarugi, M; Tuccori, M; Blandizzi, C; Del Tacca, M

    2009-04-01

    Experimental evidence in animal models suggests that adenosine is involved in the regulation of digestive functions. This study examines the influence of adenosine on the contractile activity of human colon. Reverse transcription-polymerase chain reaction revealed A(1) and A(2a) receptor expression in colonic neuromuscular layers. Circular muscle preparations were connected to isotonic transducers to determine the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A(1) receptor antagonist), ZM 241385 (A(2a) receptor antagonist), CCPA (A(1) receptor agonist) and 2-[(p-2-carboxyethyl)-phenethylamino]-5'-N-ethyl-carboxamide-adenosine (CGS 21680; A(2a) receptor agonist) on motor responses evoked by electrical stimulation or carbachol. Electrically evoked contractions were enhanced by DPCPX and ZM 241385, and reduced by CCPA and CGS 21680. Similar effects were observed when colonic preparations were incubated with guanethidine (noradrenergic blocker), L-732,138, GR-159897 and SB-218795 (NK receptor antagonists). However, in the presence of guanethidine, NK receptor antagonists and N(omega)-propyl-L-arginine (NPA; neuronal nitric oxide synthase inhibitor), the effects of DPCPX and CCPA were still evident, while those of ZM 241385 and CGS 21680 no longer occurred. Carbachol-induced contractions were unaffected by A(2a) receptor ligands, but they were enhanced or reduced by DPCPX and CCPA, respectively. When colonic preparations were incubated with guanethidine, NK antagonists and atropine, electrically induced relaxations were partly reduced by ZM 241385 or NPA, but unaffected by DPCPX. Dipyridamole or application of exogenous adenosine reduced electrically and carbachol-evoked contractions, whereas adenosine deaminase enhanced such motor responses. In conclusion, adenosine exerts an inhibitory control on human colonic motility. A(1) receptors mediate direct modulating actions on smooth muscle, whereas A(2a) receptors operate through inhibitory nitrergic nerve pathways.

  1. Sequence variants in COL4A1 and COL4A2 genes in Ecuadorian families with keratoconus

    PubMed Central

    Karolak, Justyna A.; Kulinska, Karolina; Nowak, Dorota M.; Pitarque, Jose A.; Molinari, Andrea; Rydzanicz, Malgorzata; Bejjani, Bassem A.

    2011-01-01

    Purpose Keratoconus (KTCN) is a non-inflammatory, usually bilateral disorder of the eye which results in the conical shape and the progressive thinning of the cornea. Several studies have suggested that genetic factors play a role in the etiology of the disease. Several loci were previously described as possible candidate regions for familial KTCN; however, no causative mutations in any genes have been identified for any of these loci. The purpose of this study was to evaluate role of the collagen genes collagen type IV, alpha-1 (COL4A1) and collagen type IV, alpha-2 (COL4A2) in KTCN in Ecuadorian families. Methods COL4A1 and COL4A2 in 15 Ecuadorian KTCN families were examined with polymerase chain reaction amplification, and direct sequencing of all exons, promoter and intron-exon junctions was performed. Results Screening of COL4A1 and COL4A2 revealed numerous alterations in coding and non-coding regions of both genes. We detected three missense substitutions in COL4A1: c.19G>C (Val7Leu), c.1663A>C (Thr555Pro), and c.4002A>C (Gln1334His). Five non-synonymous variants were identified in COL4A2: c.574G>T (Val192Phe), c.1550G>A (Arg517Lys), c.2048G>C (Gly683Ala), c.2102A>G (Lys701Arg), and c.2152C>T (Pro718Ser). None of the identified sequence variants completely segregated with the affected phenotype. The Gln1334His variant was possibly damaging to protein function and structure. Conclusions This is the first mutation screening of COL4A1 and COL4A2 genes in families with KTCN and linkage to a locus close to these genes. Analysis of COL4A1 and COL4A2 revealed no mutations indicating that other genes are involved in KTCN causation in Ecuadorian families. PMID:21527998

  2. Immunoglobulin A1 and A2 subclass of salivary antibodies to Candida albicans in patients with oral candidosis.

    PubMed Central

    Jeganathan, S; Ufomata, D; Hobkirk, J A; Ivanyi, L

    1987-01-01

    Immunoglobulin A antibody titres to a cytoplasmic protein extract of Candida albicans were determined by ELISA in saliva from 20 patients with oral candidosis and 21 controls. Patients had significantly increased levels of salivary IgA anti-Candida antibodies when compared with controls (P less than 0.001). Antibody levels were associated with IgA1 subclass in 90% of the patients; in contrast, IgA2 subclass was predominant in 67% of the controls. Antifungal therapy resulted in significantly decreased IgA1 titres (P less than 0.05) whilst the mean IgA2 antibody titre remained unchanged. The results indicate that Candida infection may change the subclass pattern of salivary IgA antibodies. PMID:3322616

  3. Cloning and characterization of a novel CYP3A1 allelic variant: analysis of CYP3A1 and CYP3A2 sex-hormone-dependent expression reveals that the CYP3A2 gene is regulated by testosterone.

    PubMed

    Ribeiro, V; Lechner, M C

    1992-02-14

    A clone was isolated from a cDNA library constructed from phenobarbital-treated Wistar rat liver and proven to correspond to the full-length mRNA of a polymorphic variant of Sprague-Dawley CYP3A1. Eight nucleotide differences were detected in a single 76-nucleotide stretch and confirmed to be present in the genomic clone. They are seated in a region implicated in the definition of a substrate binding domain of the native P450. Three out of the eight nucleotide changes are nonconservative, implicating the replacement of Thr/Ala 207, Phe/Ile 213, and Ile/Val 232. This is the first report of an allelic variant of CYP3A1, a new example of interstrain P450 variability. The CYP3A subfamily is composed of several genes coding for active testosterone 6 beta-hydroxylases which are expressed in the liver. CYP3A genes are under strong and distinct developmental regulation. Conversely to CYP3A1, transiently expressed in immature animals, CYP3A2 is constitutively expressed in the liver early after birth and characterized by an extinction in the adult females. Castration of 90-day-old male rats causes a drastic reduction (80%) of CYP3A2 mRNA relative abundance. Administration of testosterone propionate restores the physiological levels of CYP3A2 mRNA characteristic of the male rat liver. Our results demonstrate the existence of a direct relationship between the male hormonal status and the constitutive expression of rat liver CYP3A2.

  4. A correlated ab initio study of the X2A1 and A2E states of MgCH3

    NASA Technical Reports Server (NTRS)

    Woon, D. E.

    1996-01-01

    The X2A1 and A2E states of the MgCH3 radical have been studied with correlation consistent basis sets and the coupled cluster method RCCSD(T) in order to compare with two recent experimental efforts [M. A. Anderson and L. M. Ziurys, Astrophys. J. 452, L157 (1995); R. Rubino, J. M. Williamson, and T. A. Miller, J. Chem. Phys. 103, 5964 (1995)]. The best computed values [RCCSD(T)/cc-pCVTZ] for the X2A1 state are (experimental results in parentheses): Ae = 160.433 GHz, Be = 10.948 GHz (B0 = 11.008 GHz), and Mue = 1.011 D. The Mg-CH3 bond is weak, 26.3 kcal/mol. Values for the A2E state are Ae = 154.648 GHz (A0 = 149.666 GHz), Be = 10.87 GHz (B0 = 10.932 GHz), and Mue = 1.022 D. The excitation energy (Te) for the A2E <-- X2A1 transition is 19 999 cm-1 (T00 = 20 030 cm-1). A brief discussion of bonding trends in Mg-containing radials is included.

  5. Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction

    PubMed Central

    Pu, Xiangyuan; Ren, Meixia; An, Weiwei; Zhang, Ruoxin; Yan, Shunying; Situ, Haiteng; He, Xinjie; Chen, Yequn; Tan, Xuerui; Xiao, Qingzhong; Tucker, Arthur T.; Caulfield, Mark J.; Ye, Shu

    2016-01-01

    Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD

  6. Serum Levels of ApoA1 and ApoA2 Are Associated with Cognitive Status in Older Men

    PubMed Central

    Ma, Cheng; Li, Jin; Bao, Zhijun; Ruan, Qingwei; Yu, Zhuowei

    2015-01-01

    Background. Advancing age, chronic inflammation, oxidative damage, and disorders of lipid metabolism are positively linked to the late-life cognitive impairment. Serum biomarkers may be associated with the cognitive status in older men. Methods. 440 old male subjects with different cognitive functions were recruited to investigate probable serum markers. Pearson Chi-Squared test, univariate analysis, and multivariate logistic regression analysis were performed to evaluate biomarkers which may be associated with cognitive status. Results. Levels of fundus atherosclerosis (AS) (P < 0.001), age (P < 0.001), serum biomarkers peroxidase (POD) (P = 0.026) and interleukin-6 (IL-6) (P = 0.001), serum levels of high-density lipoprotein cholesterol (HDL-C) (P < 0.001), apolipoprotein A2 (ApoA2) (P = 0.001), and ApoC2 (P = 0.005) showed significant differences. Compared to group 3, ApoA1 in group 1 (OR = 1.30, 95% CI 1.01–1.67) and group 2 (OR = 1.47, 95% CI 1.11–1.94) were higher, while ApoA2 were lower (group 1: OR = 0.43, 95% CI 0.18–1.02; group 2: OR = 0.21, 95% CI 0.08–0.54) after adjusting for control variables. Conclusion. The results demonstrated that age, AS levels, POD, IL-6, HDL-C, ApoA2, and ApoC2 were significantly related to cognitive status. Moreover, ApoA1 and ApoA2 were independently associated with cognitive impairment and late-life dementia. PMID:26682220

  7. Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

    PubMed Central

    Bethke, Lara; Webb, Emily; Sellick, Gabrielle; Rudd, Matthew; Penegar, Stephen; Withey, Laura; Qureshi, Mobshra; Houlston, Richard

    2007-01-01

    Background Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. Methods To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. Results There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03–1.80 and OR = 1.34, 95% CI: 1.00–1.79 respectively). Conclusion This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility. PMID:17615053

  8. Membrane isoforms of human immunoglobulins of the A1 and A2 isotypes: structural and functional study.

    PubMed Central

    Leduc, I; Drouet, M; Bodinier, M C; Helal, A; Cogné, M

    1997-01-01

    As for IgM, human IgA occurs either as soluble molecules in plasma and various other body fluids, or as membrane-bound molecules on differentiated B cells, where they are part of the B-cell receptor for antigen (BCR). We studied the structure of transcripts encoding the membrane-anchored alpha-chain of the human BCR alpha, which may be present in two different forms resulting from alternate splicing of the alpha-chain mRNA (type I or type II). The ratio of type I versus type II did not vary upon stimulation of a B-cell line with various cytokines. Rather, it differed strikingly in cells expressing either the IgA1 or IgA2 isotype of the BCR alpha, with virtually no type II alpha-chain in the latter. Co-modulation experiments also yielded different results for both isotypes, since they demonstrated a physical association of both membrane (m)IgA1 and mIgA2 with CD79b, the beta component of the BCR Ig alpha/Ig beta heterodimer, but only of mIgA1 with CD19. Whatever the isotype, the BCR of the IgA class was able to carry out signal transduction upon cross-linking by specific monoclonal antibodies but, in contrast to mIgM, it relied mainly on the entry of extracellular Ca2+ rather than on the release of intracellular stocks. Images Figure 2 PMID:9155637

  9. Activation of J77A.1 macrophages by three phospholipases A2 isolated from Bothrops atrox snake venom.

    PubMed

    Furtado, Juliana L; Oliveira, George A; Pontes, Adriana S; Setúbal, Sulamita da S; Xavier, Caroline V; Lacouth-Silva, Fabianne; Lima, Beatriz F; Zaqueo, Kayena D; Kayano, Anderson M; Calderon, Leonardo A; Stábeli, Rodrigo G; Soares, Andreimar M; Zuliani, Juliana P

    2014-01-01

    In the present study, we investigated the in vitro effects of two basic myotoxic phospholipases A2 (PLA2), BaTX-I, a catalytically inactive Lys-49 variant, and BaTX-II, a catalytically active Asp-49, and of one acidic myotoxic PLA2, BaPLA2, a catalytically active Asp-49, isolated from Bothrops atrox snake venom, on the activation of J774A.1 macrophages. At noncytotoxic concentrations, the toxins did not affect the adhesion of the macrophages, nor their ability to detach. The data obtained showed that only BaTX-I stimulated complement receptor-mediated phagocytosis. However, BaTX-I, BaTX-II, and BaPLA2 induced the release of the superoxide anion by J774A.1 macrophages. Additionally, only BaTX-I raised the lysosomal volume of macrophages after 15 min of incubation. After 30 min, all the phospholipases increased this parameter, which was not observed within 60 min. Moreover, BaTX-I, BaTX-II, and BaPLA2 increased the number of lipid bodies on macrophages submitted to phagocytosis and not submitted to phagocytosis. However, BaTX-II and BaPLA2 induced the release of TNF-α by J774A.1 macrophages. Taken together, the data show that, despite differences in enzymatic activity, the three toxins induced inflammatory events and whether the enzyme is acidic or basic does not seem to contribute to these effects.

  10. Dipyridamole attenuates ischemia reperfusion induced acute kidney injury through adenosinergic A1 and A2A receptor agonism in rats.

    PubMed

    Puri, Nikkita; Mohey, Vinita; Singh, Manjinder; Kaur, Tajpreet; Pathak, Devendra; Buttar, Harpal Singh; Singh, Amrit Pal

    2016-04-01

    Dipyridamole (DYP) is an anti-platelet agent with marked vasodilator, anti-oxidant, and anti-inflammatory activity. The present study investigated the role of adenosine receptors in DYP-mediated protection against ischemia reperfusion-induced acute kidney injury (AKI) in rats. The rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h. The renal damage induced by ischemia reperfusion injury (IRI) was assessed by measuring creatinine clearance, blood urea nitrogen, uric acid, plasma potassium, fractional excretion of sodium, and microproteinuria in rats. The oxidative stress in renal tissues was assessed by quantification of thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The hematoxylin-eosin staining was carried out to observe histopathological changes in renal tissues. DYP (10 and 30 mg/kg, intraperitoneal, i.p.) was administered 30 min before subjecting the rats to renal IRI. In separate groups, caffeine (50 mg/kg, i.p.), an adenosinergic A1 and A2A receptor antagonist was administered with and without DYP treatment before subjecting the rats to renal IRI. The ischemia reperfusion-induced AKI was demonstrated by significant changes in serum as well as urinary parameters, enhanced oxidative stress, and histopathological changes in renal tissues. The administration of DYP demonstrated protection against AKI. The prior treatment with caffeine abolished DYP-mediated reno-protection suggesting role of A1 and A2A adenosine receptors in DYP-mediated reno-protection in rats. It is concluded that adenosine receptors find their definite involvement in DYP-mediated anti-oxidative and reno-protective effect against ischemia reperfusion-induced AKI.

  11. Activation of J77A.1 Macrophages by Three Phospholipases A2 Isolated from Bothrops atrox Snake Venom

    PubMed Central

    Furtado, Juliana L.; Oliveira, George A.; Pontes, Adriana S.; Setúbal, Sulamita da S.; Xavier, Caroline V.; Lacouth-Silva, Fabianne; Lima, Beatriz F.; Zaqueo, Kayena D.; Kayano, Anderson M.; Calderon, Leonardo A.; Stábeli, Rodrigo G.; Soares, Andreimar M.; Zuliani, Juliana P.

    2014-01-01

    In the present study, we investigated the in vitro effects of two basic myotoxic phospholipases A2 (PLA2), BaTX-I, a catalytically inactive Lys-49 variant, and BaTX-II, a catalytically active Asp-49, and of one acidic myotoxic PLA2, BaPLA2, a catalytically active Asp-49, isolated from Bothrops atrox snake venom, on the activation of J774A.1 macrophages. At noncytotoxic concentrations, the toxins did not affect the adhesion of the macrophages, nor their ability to detach. The data obtained showed that only BaTX-I stimulated complement receptor-mediated phagocytosis. However, BaTX-I, BaTX-II, and BaPLA2 induced the release of the superoxide anion by J774A.1 macrophages. Additionally, only BaTX-I raised the lysosomal volume of macrophages after 15 min of incubation. After 30 min, all the phospholipases increased this parameter, which was not observed within 60 min. Moreover, BaTX-I, BaTX-II, and BaPLA2 increased the number of lipid bodies on macrophages submitted to phagocytosis and not submitted to phagocytosis. However, BaTX-II and BaPLA2 induced the release of TNF-α by J774A.1 macrophages. Taken together, the data show that, despite differences in enzymatic activity, the three toxins induced inflammatory events and whether the enzyme is acidic or basic does not seem to contribute to these effects. PMID:24592395

  12. Site-specific Arylation of Rat Glutathione S-Transferase A1 and A2 by Bromobenzene Metabolites in vivo

    PubMed Central

    Koen, Yakov M.; Yue, Weimin; Galeva, Nadezhda A.; Williams, Todd D.; Hanzlik, Robert P.

    2006-01-01

    The hepatotoxicity of bromobenzene (BB) derives from its reactive metabolites (epoxides and quinones) which arylate cellular proteins. Application of proteomic methods to liver proteins from rats treated with an hepatotoxic dose of [14C]-BB has identified more than 40 target proteins, but no adducted peptides have yet been observed. Because such proteins are known to contain bromophenyl- and bromodihydroxyphenyl derivatives of cysteine, histidine and lysine, the failure to observe modified peptides has been attributed to the low level of total covalent binding and to the “dilution” effect of multiple metabolites reacting at multiple sites on multiple proteins. In this work glutathione transferase, a well known and abundant BB-target protein, was isolated from liver cytosol of rats treated with 14C-BB using a GSH-agarose affinity column and further resolved by reverse phase HPLC into subunits M1, M2, A1, A2 and A3. The subunits were identified by a combination of SDS-PAGE, whole-molecule mass spectrometry and peptide mass mapping and found to contain radioactivity corresponding to 0.01 - 0.05 adduct per molecule of protein. Examination of tryptic digests of these subunits by MALDI-TOF and ESI-MS again failed to reveal any apparent adducted peptides despite observed sequence coverages up to 87%. However, using HPLC-LTQ-FTMS to search for predicted modified tryptic peptides revealed peaks corresponding, with a high degree of mass accuracy, to a bromobenzoquinone adduct of peptide 89-119 in both GSTA1 and A2. The identity of these adducts and their location at Cys-111 was confirmed by MS-MS. No evidence for the presence of any putative BB-adducts in GST M1, M2 or A3 was obtained. This work highlights the challenges involved in the unambiguous identification of reactive metabolite adducts formed in vivo. PMID:17112229

  13. Study of proton conductivity of a 2D flexible MOF and a 1D coordination polymer at higher temperature.

    PubMed

    Sanda, Suresh; Biswas, Soumava; Konar, Sanjit

    2015-02-16

    We report the proton conduction properties of a 2D flexible MOF and a 1D coordination polymer having the molecular formulas {[Zn(C10H2O8)0.5(C10S2N2H8)]·5H2O]}n (1) and {[Zn(C10H2O8)0.5(C10S2N2H8)]·2H2O]}n (2), respectively. Compounds 1 and 2 show high conductivity values of 2.55 × 10(-7) and 4.39 × 10(-4) S cm(-1) at 80 °C and 95% RH. The conductivity value of compound 1 is in the range of those for previously reported flexible MOFs, and compound 2 shows the highest proton conductivity among the carboxylate-based 1D CPs. The dimensionality and the internal hydrogen bonding connectivity play a vital role in the resultant conductivity. Variable-temperature experiments of both compounds at high humidity reveal that the conductivity values increase with increasing temperature, whereas the variable humidity studies signify the influence of relative humidity on high-temperature proton conductivity. The time-dependent measurements for both compounds demonstrate their ability to retain conductivity up to 10 h.

  14. Purification and characterization of pepsins A1 and A2 from the Antarctic rock cod Trematomus bernacchii

    PubMed Central

    Brier, Sébastien; Maria, Giovanna; Carginale, Vincenzo; Capasso, Antonio; Wu, Yan; Taylor, Robert M.; Borotto, Nicholas B.; Capasso, Clemente; Engen, John R.

    2008-01-01

    SUMMARY The Antarctic notothenioid Trematomus bernacchii (rock cod) lives at a constant mean temperature of −1.9 °C. Gastric digestion under these conditions relies on the proteolytic activity of aspartic proteases such as pepsin. To understand the molecular mechanisms of Antarctic fish pepsins, T. bernacchii pepsins A1 and A2 were cloned, overexpressed in E. coli, purified and characterized with a number of biochemical and biophysical methods. The properties of these two Antarctic isoenzymes were compared to porcine pepsin and found to be unique in a number of ways. Fish pepsins were found to be more temperature sensitive, generally less active at lower pH and more sensitive to inhibition by pepstatin than the mesophilic counterpart. The specificity of Antarctic fish pepsins was similar but not identical to pig pepsin, likely owing to changes in the sequence of fish enzymes near the active site. Gene duplication of Antarctic rock cod pepsins is the likely mechanism for adaptation to the harsh temperature environment in which these enzymes must function. PMID:17976195

  15. HsfA1d and HsfA1e involved in the transcriptional regulation of HsfA2 function as key regulators for the Hsf signaling network in response to environmental stress.

    PubMed

    Nishizawa-Yokoi, Ayako; Nosaka, Ryota; Hayashi, Hideki; Tainaka, Hitoshi; Maruta, Takanori; Tamoi, Masahiro; Ikeda, Miho; Ohme-Takagi, Masaru; Yoshimura, Kazuya; Yabuta, Yukinori; Shigeoka, Shigeru

    2011-05-01

    Heat shock transcription factor A2 (HsfA2) acts as a key component of the Hsf signaling network involved in cellular responses to various types of environmental stress. However, the mechanism governing the regulation of HsfA2 expression is still largely unknown. We demonstrated here that a heat shock element (HSE) cluster in the 5'-flanking region of the HsfA2 gene is involved in high light (HL)-inducible HsfA2 expression. Accordingly, to identify the Hsf regulating the expression of HsfA2, we analyzed the effect of loss-of-function mutations of class A Hsfs on the expression of HsfA2 in response to HL stress. Overexpression of an HsfA1d or HsfA1e chimeric repressor and double knockout of HsfA1d and HsfA1e Arabidopsis mutants (KO-HsfA1d/A1e) significantly suppressed the induction of HsfA2 expression in response to HL and heat shock (HS) stress. Transient reporter assays showed that HsfA1d and HsfA1e activate HsfA2 transcription through the HSEs in the 5'-flanking region of HsfA2. In the KO-HsfA1d/A1e mutants, 560 genes, including a number of stress-related genes and several Hsf genes, HsfA7a, HsfA7b, HsfB1 and HsfB2a, were down-regulated compared with those in the wild-type plants under HL stress. The PSII activity of KO-HsfA1d/A1e mutants decreased under HL stress, while the activity of wild-type plants remained high. Furthermore, double knockout of HsfA1d and HsfA1e impaired tolerance to HS stress. These findings indicated that HsfA1d and HsfA1e not only regulate HsfA2 expression but also function as key regulators of the Hsf signaling network in response to environmental stress.

  16. Differential Roles for "Nr4a1" and "Nr4a2" in Object Location vs. Object Recognition Long-Term Memory

    ERIC Educational Resources Information Center

    McNulty, Susan E.; Barrett, Ruth M.; Vogel-Ciernia, Annie; Malvaez, Melissa; Hernandez, Nicole; Davatolhagh, M. Felicia; Matheos, Dina P.; Schiffman, Aaron; Wood, Marcelo A.

    2012-01-01

    "Nr4a1" and "Nr4a2" are transcription factors and immediate early genes belonging to the nuclear receptor Nr4a family. In this study, we examine their role in long-term memory formation for object location and object recognition. Using siRNA to block expression of either "Nr4a1" or "Nr4a2", we found that "Nr4a2" is necessary for both long-term…

  17. Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine.

    PubMed

    Yang, Jiang-Ning; Chen, Jiang-Fan; Fredholm, Bertil B

    2009-04-01

    Heart rate (HR), body temperature (Temp), locomotor activity (LA), and oxygen consumption (O(2)C) were studied in awake mice lacking one or both of the adenosine A(1) or A(2A) receptors (A(1)R or A(2A)R, respectively) using telemetry and respirometry, before and after caffeine administration. All parameters were lower during day than night and higher in females than males. When compared with wild-type (WT) littermates, HR was higher in male A(1)R knockout (A(1)RKO) mice but lower in A(2A)RKO mice and intermediate in A(1)-A(2A)R double KO mice. A single dose of an unselective beta-blocker (timolol; 1 mg/kg) abolished the HR differences between these genotypes. Deletion of A(1)Rs had little effect on Temp, whereas deletion of A(2A)Rs increased it in females and decreased it in males. A(1)-A(2A)RKO mice had lower Temp than WT mice. LA was unaltered in A(1)RKO mice and lower in A(2A)RKO and A(1)-A(2A)RKO mice than in WT mice. Caffeine injection increased LA but only in mice expressing A(2A)R. Caffeine ingestion also increased LA in an A(2A)R-dependent manner in male mice. Caffeine ingestion significantly increased O(2)C in WT mice, but less in the different KO mice. Injection of 30 mg/kg caffeine decreased Temp, especially in KO mice, and hence in a manner unrelated to A(1)R or A(2A)R blockade. Selective A(2B) antagonism had little or no effect. Thus A(1)R and A(2A)R influence HR, Temp, LA, and O(2)C in mice in a sex-dependent manner, indicating effects of endogenous adenosine. The A(2A)R plays an important role in the modulation of O(2)C and LA by acute and chronic caffeine administration. There is also evidence for effects of higher doses of caffeine being independent of both A(1)R and A(2A)R.

  18. Omeprazole transactivates human CYP1A1 and CYP1A2 expression through the common regulatory region containing multiple xenobiotic-responsive elements.

    PubMed

    Yoshinari, Kouichi; Ueda, Rika; Kusano, Kazutomi; Yoshimura, Tsutomu; Nagata, Kiyoshi; Yamazoe, Yasushi

    2008-07-01

    Omeprazole induces human CYP1A1 and CYP1A2 in human hepatoma cells and human liver. Aryl hydrocarbon receptor (AHR) is shown to be involved in this induction. However, its precise molecular mechanism remains unknown because the chemical activates AHR without its direct binding in contrast to typical AHR ligands such as 3-methylcholanthrene (3MC) and beta-naphthoflavone (BNF). Human CYP1A1 and CYP1A2 genes are located in a head-to-head orientation sharing about 23 kb 5'-flanking region. Recently, we succeeded to measure CYP1A1 and CYP1A2 transcriptional activities simultaneously using dual reporter gene constructs containing the 23 kb sequence. In this study, transient transfection assays have been performed using numbers of single and dual reporter constructs to identify omeprazole-responsive region for CYP1A1 and CYP1A2 induction. Reporter assays with deletion constructs have demonstrated that the omeprazole-induced expression of both CYP1A1 and CYP1A2 is mediated via the common regulatory region containing multiple AHR-binding motifs (the nucleotides from -464 to -1829 of human CYP1A1), which is identical with the region for BNF and 3MC induction. Interestingly, omeprazole activated the transcription of CYP1A1 and CYP1A2 to similar extents while BNF and 3MC preferred CYP1A1 expression. We have also found that primaquine is an omeprazole-like CYP1A inducer, while lansoprazole and albendazole are 3MC/BNF-like in terms of the CYP1A1/CYP1A2 preference. The present results suggest that omeprazole as well as BNF and 3MC activates both human CYP1A1 and CYP1A2 expression through the common regulatory region despite that omeprazole may involve a different cellular signal(s) from BNF and 3MC.

  19. The Nonplanar Secretory IgA2 and Near Planar Secretory IgA1 Solution Structures Rationalize Their Different Mucosal Immune Responses*S⃞

    PubMed Central

    Bonner, Alexandra; Almogren, Adel; Furtado, Patricia B.; Kerr, Michael A.; Perkins, Stephen J.

    2009-01-01

    Secretory IgA (SIgA) is the most prevalent human antibody and is central to mucosal immunity. It exists as two subclasses, SIgA1 and SIgA2, where SIgA2 has a shorter hinge joining the Fab and Fc regions. Both forms of SIgA are predominantly dimeric and contain an additional protein called the secretory component (SC) that is attached during the secretory process and is believed to protect SIgA in harsh mucosal conditions. Here we locate the five SC domains relative to dimeric IgA2 within SIgA2 using constrained scattering modeling. The x-ray and sedimentation parameters showed that SIgA2 has an extended solution structure. The constrained modeling of SIgA2 was initiated using two IgA2 monomers that were positioned according to our best fit solution structure for dimeric IgA1. SC was best located along the convex edge of the Fc-Fc region. The best fit models showed that SIgA2 is significantly nonplanar in its structure, in distinction to our previous near planar SIgA1 structure. Both the shorter IgA2 hinges and the presence of SC appear to displace the four Fab regions out of the Fc plane in SIgA2. This may explain the noncovalent binding of SC in some SIgA2 molecules. This nonplanar structure is predicted to result in specific immune properties for SIgA2 and SIgA1. It may explain differences observed between the SIgA1 and SIgA2 subclasses in terms of their interactions with antigens, susceptibility to proteases, effects on receptors, and distribution in different tissues. The different structures account for the prevalence of both forms in mucosal secretions. PMID:19109255

  20. Enzymatic characterization of in vitro-expressed Baikal seal cytochrome P450 (CYP) 1A1, 1A2, and 1B1: implication of low metabolic potential of CYP1A2 uniquely evolved in aquatic mammals.

    PubMed

    Iwata, Hisato; Yamaguchi, Keisuke; Takeshita, Yoko; Kubota, Akira; Hirakawa, Shusaku; Isobe, Tomohiko; Hirano, Masashi; Kim, Eun-Young

    2015-05-01

    This study aimed to elucidate the catalytic function of cytochrome P450 (CYP) 1 enzymes in aquatic mammals. Alkoxyresorufin O-dealkylation (AROD) activities including methoxy- (MROD), ethoxy- (EROD), pentoxy- (PROD), and benzyloxyresorufin O-dealkylation (BROD), and 2- and 4-hydroxylation activities of 17β-estradiol (E2) were measured by using yeast-expressed Baikal seal (Pusa sibirica) CYP1A1, 1A2, and 1B1 proteins. Heterologous protein expression of the Baikal seal CYP1s (bsCYP1s) in yeast microsomes was confirmed by reduced CO-difference spectra and immunoblotting. Heterologously expressed human CYP1 enzyme (hCYP1) activities were simultaneously measured and compared with those of bsCYP1 isozymes. Recombinant bsCYP1A1 protein showed the highest Vmax of EROD, followed by MROD, PROD, and BROD, similar to that of hCYP1A1. Vmax/Km ratios of all AROD activities catalyzed by bsCYP1A1 were lower than those catalyzed by hCYP1A1, suggesting less potential for AROD by bsCYP1A1. Enzymatic assays for bsCYP1A2 showed no or minimal AROD activities, while hCYP1A2 displayed MROD and EROD activities. bsCYP1B1 showed an AROD profile (EROD>BROD>MROD>PROD) similar to that of hCYP1B1; however, Vmax/Km ratios of all AROD activities by bsCYP1B1 were higher. Yeast microsomes containing bsCYP1A1 and 1B1 and hCYP1A1, 1A2, and 1B1 metabolized E2 to 2-OHE2 and 4-OHE2, whereas bsCYP1A2 showed no such activity. Comparison of 4- and 2-hydroxylations of E2 by CYP1As suggests that bsCYP1A1, hCYP1A1, and 1A2 preferentially catalyze 2- rather than 4-hydroxylation. As for CYP1B1, the Vmax/Km ratios suggest that both Baikal seal and human CYPs catalyze 4- rather than 2-hydroxylation. Interspecies comparison showed that bsCYP1B1 has higher metabolic potencies for both E2 hydroxylations than does hCYP1B1, whereas the activity of bsCYP1A1 was lower than that of hCYP1A1. Messenger RNA expression levels of bsCYP1s in the liver of Baikal seals indicated that bsCYP1A1 and 1A2 enzymes contributed to 16

  1. Physiological Evaluation of A1 (Extreme-Cold-Weather) and A2 (Buoyant, Intermediate-Cold-Weather) Jackets.

    DTIC Science & Technology

    1983-08-01

    the resting metabolic heat will be dissipated through the clothing with the remaining 25% lost through the respiratory tract and insensible sweating...AD-A258 410 PHYSIOLOGICAL EVALUATION OF Al (EXTREME-COLD-WEATHER) AND A2 (BUOYANT, INTERMEDIATE-COLD-WEATHER) JACKETS NAVY CLOTHING AND TEXTILE...Navy Clothing and Textile Research Facility 523-003-30-06 21 Strathmore Road 523-003-30-08 Natick, MA 01760 11. CONTROLLING OFFICE NAME AND ADDRESS

  2. Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus)

    PubMed Central

    Feng, Ruijuan; Fang, Lingling; Cheng, Yunying; He, Xue; Jiang, Wentao; Dong, Ranran; Shi, Hongjuan; Jiang, Dongneng; Sun, Lina; Wang, Deshou

    2015-01-01

    Meiosis is a process unique to the differentiation of germ cells. Retinoic acid (RA) is the key factor controlling the sex-specific timing of meiotic initiation in tetrapods; however, the role of RA in meiotic initiation in teleosts has remained unclear. In this study, the genes encoding RA synthase aldh1a2, and catabolic enzyme cyp26a1 were isolated from Nile tilapia (Oreochromis niloticus), a species without stra8. The expression of aldh1a2 was up-regulated and expression of cyp26a1 was down-regulated before the meiotic initiation in ovaries and in testes. Treatment with RA synthase inhibitor or disruption of Aldh1a2 by CRISPR/Cas9 resulted in delayed meiotic initiation, with simultaneous down-regulation of cyp26a1 and up-regulation of sycp3. By contrast, treatment with an inhibitor of RA catabolic enzyme and disruption of cyp26a1 resulted in earlier meiotic initiation, with increased expression of aldh1a2 and sycp3. Additionally, treatment of XY fish with estrogen (E2) and XX fish with fadrozole led to sex reversal and reversion of meiotic initiation. These results indicate that RA is indispensable for meiotic initiation in teleosts via a stra8 independent signaling pathway where both aldh1a2 and cyp26a1 are critical. In contrast to mammals, E2 is a major regulator of sex determination and meiotic initiation in teleosts. PMID:25976364

  3. Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory.

    PubMed

    McNulty, Susan E; Barrett, Ruth M; Vogel-Ciernia, Annie; Malvaez, Melissa; Hernandez, Nicole; Davatolhagh, M Felicia; Matheos, Dina P; Schiffman, Aaron; Wood, Marcelo A

    2012-11-16

    Nr4a1 and Nr4a2 are transcription factors and immediate early genes belonging to the nuclear receptor Nr4a family. In this study, we examine their role in long-term memory formation for object location and object recognition. Using siRNA to block expression of either Nr4a1 or Nr4a2, we found that Nr4a2 is necessary for both long-term memory for object location and object recognition. In contrast, Nr4a1 appears to be necessary only for object location. Indeed, their roles in these different types of long-term memory may be dependent on their expression in the brain, as NR4A2 was found to be expressed in hippocampal neurons (associated with object location memory) as well as in the insular and perirhinal cortex (associated with object recognition memory), whereas NR4A1 showed minimal neuronal expression in these cortical areas. These results begin to elucidate how NR4A1 and NR4A2 differentially contribute to object location versus object recognition memory.

  4. Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus).

    PubMed

    Feng, Ruijuan; Fang, Lingling; Cheng, Yunying; He, Xue; Jiang, Wentao; Dong, Ranran; Shi, Hongjuan; Jiang, Dongneng; Sun, Lina; Wang, Deshou

    2015-05-15

    Meiosis is a process unique to the differentiation of germ cells. Retinoic acid (RA) is the key factor controlling the sex-specific timing of meiotic initiation in tetrapods; however, the role of RA in meiotic initiation in teleosts has remained unclear. In this study, the genes encoding RA synthase aldh1a2, and catabolic enzyme cyp26a1 were isolated from Nile tilapia (Oreochromis niloticus), a species without stra8. The expression of aldh1a2 was up-regulated and expression of cyp26a1 was down-regulated before the meiotic initiation in ovaries and in testes. Treatment with RA synthase inhibitor or disruption of Aldh1a2 by CRISPR/Cas9 resulted in delayed meiotic initiation, with simultaneous down-regulation of cyp26a1 and up-regulation of sycp3. By contrast, treatment with an inhibitor of RA catabolic enzyme and disruption of cyp26a1 resulted in earlier meiotic initiation, with increased expression of aldh1a2 and sycp3. Additionally, treatment of XY fish with estrogen (E2) and XX fish with fadrozole led to sex reversal and reversion of meiotic initiation. These results indicate that RA is indispensable for meiotic initiation in teleosts via a stra8 independent signaling pathway where both aldh1a2 and cyp26a1 are critical. In contrast to mammals, E2 is a major regulator of sex determination and meiotic initiation in teleosts.

  5. Bacillus anthracis acetyltransferases PatA1 and PatA2 modify the secondary cell wall polysaccharide and affect the assembly of S-layer proteins.

    PubMed

    Lunderberg, J Mark; Nguyen-Mau, Sao-Mai; Richter, G Stefan; Wang, Ya-Ting; Dworkin, Jonathan; Missiakas, Dominique M; Schneewind, Olaf

    2013-03-01

    The envelope of Bacillus anthracis encompasses a proteinaceous S-layer with two S-layer proteins (Sap and EA1). Protein assembly in the envelope of B. anthracis requires S-layer homology domains (SLH) within S-layer proteins and S-layer-associated proteins (BSLs), which associate with the secondary cell wall polysaccharide (SCWP), an acetylated carbohydrate that is tethered to peptidoglycan. Here, we investigated the contributions of two putative acetyltransferases, PatA1 and PatA2, on SCWP acetylation and S-layer assembly. We show that mutations in patA1 and patA2 affect the chain lengths of B. anthracis vegetative forms and perturb the deposition of the BslO murein hydrolase at cell division septa. The patA1 and patA2 mutants are defective for the assembly of EA1 in the envelope but retain the ability of S-layer formation with Sap. SCWP isolated from the patA1 patA2 mutant lacked acetyl moieties identified in wild-type polysaccharide and failed to associate with the SLH domains of EA1. A model is discussed whereby patA1- and patA2-mediated acetylation of SCWP enables the deposition of EA1 as well as BslO near the septal region of the B. anthracis envelope.

  6. SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in Streptococcus pyogenes

    PubMed Central

    Port, Gary C.; Cusumano, Zachary T.; Tumminello, Paul R.

    2017-01-01

    ABSTRACT SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen Streptococcus pyogenes, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1− mutants were defective for growth under aerobic conditions, while SpxA2− mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1− mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2− mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1− mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2− mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1− attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2− hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of speB. These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2− hypervirulence also shows that stress resistance is not always essential for S. pyogenes pathogenesis in soft tissue. PMID:28351920

  7. Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5'-flanking region.

    PubMed

    Yoshinari, Kouichi; Yoda, Noriaki; Toriyabe, Takayoshi; Yamazoe, Yasushi

    2010-01-15

    Phenobarbital has long been known to increase cellular levels of CYP1A1 and CYP1A2 possibly through a pathway(s) independent of aryl hydrocarbon receptor. We have investigated the role of constitutive androstane receptor (CAR), a xenobiotic-responsive nuclear receptor, in the transactivation of human CYP1A1 and CYP1A2. These genes are located in a head-to-head orientation, sharing a 5'-flanking region. Reporter assays were thus performed with dual-reporter constructs, containing the whole or partially deleted human CYP1A promoter between two different reporter genes. In this system, human CAR (hCAR) enhanced the transcription of both genes through common promoter regions from -461 to -554 and from -18089 to -21975 of CYP1A1. With reporter assays using additional deleted and mutated constructs, electrophoresis mobility shift assays and chromatin immunoprecipitation assays, an ER8 motif (everted repeat separated by eight nucleotides), located at around -520 of CYP1A1, was identified as an hCAR-responsive element and a binding motif of hCAR/human retinoid X receptor alpha heterodimer. hCAR enhanced the transcription of both genes also in the presence of an aryl hydrocarbon receptor ligand. Finally, hCAR activation increased CYP1A1 and CYP1A2 mRNA levels in cultured human hepatocytes. Our results indicate that CAR transactivates human CYP1A1 and CYP1A2 in human hepatocytes through the common cis-element ER8. Interestingly, the ER8 motif is highly conserved in the CYP1A1 proximal promoter sequences of various species, suggesting a fundamental role of CAR in the xenobiotic-induced expression of CYP1A1 and CYP1A2 independent of aryl hydrocarbon receptor.

  8. Involvement of cAMP-PKA pathway in adenosine A1 and A2A receptor-mediated regulation of acetaldehyde-induced activation of HSCs.

    PubMed

    Yang, Yaru; Wang, He; Lv, Xiongwen; Wang, Qi; Zhao, Han; Yang, Feng; Yang, Yan; Li, Jun

    2015-08-01

    The present study was undertaken to investigate the mechanism by which adenosine receptors (ARs)-mediated the cAMP/PKA/CREB signal pathway regulates the activation of acetaldehyde-induced hepatic stellate cells (HSCs). Primary HSCs were isolated from SD rats, cultured in vitro, and activated with different concentrations of acetaldehyde at different time points. Quantitative real-time PCR and Western blotting were used to quantify both protein and mRNA levels of the four AR (A1R, A2AR, A2BR, and A3R) in rat HSCs. Selective inhibitors of PDEs and the Gi/o protein pathway, general AR agonists, and AR subtype specific agents were used to study the AR signaling. The level of cAMP was measured by radio-immunoassay, and the expression of α-SMA, collagen type I and III, PKA and p-CREB were also detected by Western blotting. Acetaldehyde could significantly promote HSC proliferation, with a maximum stimulatory effect observed at 48 h after exposure to 200 μM acetaldehyde. All four AR subtypes could be present in rat HSCs, and the mRNA and protein expression levels for A2AR and A1R in much greater abundance than those for A2BR and A3R. The expression of A2AR and A1R was significantly increased in acetaldehyde-induced HSCs as compared with that of control group, whereas the expression of A2BR and A3R remained unaffected by the addition of acetaldehyde. Curiously, there is coupling of A2AR to the Gs-AC signaling, as well as coupling of A1R to the Gi/o-AC signaling pathway in acetaldehyde-induced HSCs. Both the A2AR and A1R antagonists could suppress the activation of HSC, although they have opposing effects on cAMP signal transduction. These results suggested that a combination of cAMP/PKA/CREB signals via A2AR and A1R likely mediate the activation of acetaldehyde-induced HSCs, and A1R coupled to the Gi/o-AC signaling pathway may be masked by the more predominant A2AR that coupled to the Gs-AC signaling pathway.

  9. Triple-Singlet Mixing in Si_3: the 1^3A_{1}^{''} - {a}{^3}A{^{'}_2} Transition

    NASA Astrophysics Data System (ADS)

    Zhang, Ruohan; Steimle, Timothy C.

    2013-06-01

    The electronic spectrum of the triplet states of the D_{3h} isomer of Si_3 recorded using both mass selected REMPI and LIF spectroscopy was recently reported. In that same study the dispersed laser induced fluorescence (DLIF) spectra resulting from excitation of various bands in the visible range were recorded. The DLIF spectra exhibited a progression with a 505 cm^{-1} spacing, which was assign to the breathing mode of the D_{3h}, equilateral triangle, Si_{3} molecule. In addition, and quite unexpectedly, the DLIF spectra exhibited a progression having a spacing of 173 cm^{-1}. This progression was tentatively assigned to transition involving the bending mode of the ^1A_1 state of the C_{2v} isomer. A possible explanation for the observation of transitions in the singlet manifold is that upon laser excitation in the D_{3h} triplet manifold there is rapid intersystem crossing to the singlet manifold followed by fluorescence to the ground state of C_{2v} isomer. Here we address the issue of possible intersystem crossing by recording the excitation on DLIF spectra in the present of a static magnetic field. Magnetic fields are known to enhance the singlet-triple mixing. Si_{3} was produced using a supersonic pulsed discharge source (900 V, 20 μs, 6kΩ) with a 1% SiH_{4} in argon mixture. Magnetic fields of approximately 500 and 950 Gauss were applied. We will report the interpretation of the magnetic field induced changes to the LIF and DLIF spectra and the implications for the singlet-triple mixing process. N. J. Reilly, X. Zhuang, V. Gupta, R. Nagarajan, R. C. Fortenberry, J. P. Maier, T. C. Steimle, J. F. Stanton, M. C. McCarthy; {J. Chem. Phys., {136(19)}, 194307, (2004). V. I. Makarov, I. V. Khmelinskii; {Advances in Chemical Phisics, {Volume 118}, 45-98, (2001). thanks

  10. EphrinA1-EphA2 interaction-mediated apoptosis and Flt3L-induced immunotherapy inhibits tumor growth in a breast cancer mouse model

    PubMed Central

    Tandon, Manish; Vemula, Sai V.; Sharma, Anurag; Ahi, Yadvinder S.; Mittal, Shalini; Bangari, Dinesh S.; Mittal, Suresh K.

    2014-01-01

    Background The receptor tyrosine kinase EphA2 is overexpressed in several types of cancers and is currently being pursued as a target for breast cancer therapeutics. The EphA2 ligand EphrinA1 induces EphA2 phosphorylation and intracellular internalization and degradation, thus inhibiting tumor progression. The hematopoietic growth factor, FMS-like tyrosine kinase receptor ligand (Flt3L), promotes expansion and mobilization of functional dendritic cells. Methods We tested the EphrinA1-EphA2 interaction in MDA-MB-231 breast cancer cells focusing on the receptor-ligand-mediated apoptosis of breast cancer cells. In order to determine whether the EphrinA1-EphA2 interaction-associated apoptosis and Flt3L-mediated immunotherapy would have an additive effect in inhibiting tumor growth, we used an immunocompetent mouse model of breast cancer to evaluate intratumoral (i.t.) inoculation strategies with human adenovirus (HAd) vectors expressing either EphrinA1 (HAd-EphrinA1-Fc), Flt3L (HAd-Flt3L) or a combination of EphrinA1-Fc + Flt3L (HAd-EphrinA1-Fc + HAd-Flt3L). Results In vitro analysis demonstrated that an EphrinA1-EphA2 interaction led to apoptosis-related changes in breast cancer cells. In vivo, three i.t. inoculations of HAd-EphrinA1-Fc showed potent inhibition of tumor growth. Furthermore, increased inhibition in tumor growth was observed with the combination of HAd-EphrinA1-Fc and HAd-Flt3L accompanied by the generation of an anti-tumor adaptive immune response. Conclusions The results indicating induction of apoptosis and inhibition of mammary tumor growth show the potential therapeutic benefits of HAd-EphrinA1-Fc. In combination with HAd-Flt3L, this represents a promising strategy to effectively induce mammary tumor regression by HAd vector-based therapy. PMID:22228563

  11. Conversion of Bacillus subtilis OhrR from a 1-Cys to a 2-Cys Peroxide Sensor▿

    PubMed Central

    Soonsanga, Sumarin; Lee, Jin-Won; Helmann, John D.

    2008-01-01

    OhrR proteins can be divided into two groups based on their inactivation mechanism: 1-Cys (represented by Bacillus subtilis OhrR) and 2-Cys (represented by Xanthomonas campestris OhrR). A conserved cysteine residue near the amino terminus is present in both groups of proteins and is initially oxidized to the sulfenic acid. The B. subtilis 1-Cys OhrR protein is subsequently inactivated by formation of a mixed-disulfide bond with low-molecular-weight thiols or by cysteine overoxidation to sulfinic and sulfonic acids. In contrast, the X. campestris 2-Cys OhrR is inactivated when the initially oxidized cysteine sulfenate forms an intersubunit disulfide bond with a second Cys residue from the other subunit of the protein dimer. Here, we demonstrate that the 1-Cys B. subtilis OhrR can be converted into a 2-Cys OhrR by introducing another cysteine residue in either position 120 or position 124. Like the X. campestris OhrR protein, these mutants (G120C and Q124C) are inactivated by intermolecular disulfide bond formation. Analysis of oxidized 2-Cys variants both in vivo and in vitro indicates that intersubunit disulfide bond formation can occur simultaneously at both active sites in the protein dimer. Rapid formation of intersubunit disulfide bonds protects OhrR against irreversible overoxidation in the presence of strong oxidants much more efficiently than do the endogenous low-molecular-weight thiols. PMID:18586944

  12. Apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine for adenosine A1 and A2 receptors in isolated tissues from guinea-pigs.

    PubMed Central

    Collis, M. G.; Stoggall, S. M.; Martin, F. M.

    1989-01-01

    1. The classification of adenosine receptor subtypes (A1 and A2) in intact tissues has been based on the order of agonist potency. In this study the apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine (CPX), an antagonist which has been reported to be A1 selective, and the non-selective antagonist 1,3-dimethyl-8-phenylxanthine (8PT) has been evaluated on isolated tissues from the guinea-pig. 2. The isolated tissues used were atria (bradycardic response, proposed A1 sub-type), aorta and trachea (relaxant response, proposed A2 sub-type). 3. Both the xanthines antagonized responses to adenosine in the three tissues but had little or no effect on responses to carbachol (atria), sodium nitrite (aorta) or isoprenaline (trachea). 4. pA2 values for 8PT were similar on the three tissues (6.3-6.7), however, the pA2 value for CPX on the atria (7.9-8.4) was greater than that on the aorta (6.6) or trachea (6.6). 5. These results support the suggestion that the adenosine receptors which mediate bradycardia in the atrium are of the A1 sub-type and that those which mediate relaxation in the aorta and trachea are of the A2 type. PMID:2790383

  13. Selected C8 two-chain linkers enhance the adenosine A1/A2A receptor affinity and selectivity of caffeine.

    PubMed

    van der Walt, M M; Terre'Blanche, G

    2017-01-05

    Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker (1e A1Ki = 1.52 μM) displayed the highest affinity for the A1 adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A2AKi = 1.33 μM) linker the best A2A adenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A1 adenosine receptor selectivity over the benzyloxy linker and, by introducing a para-chloro substituent, A2A adenosine receptor selectivity was obtained. Selected compounds (1c, 1e) behaved as A1 adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A1 and A2A adenosine receptor antagonists that may have potential for treating neurological disorders.

  14. Hyperthermia-induced seizures alter adenosine A1 and A2A receptors and 5'-nucleotidase activity in rat cerebral cortex.

    PubMed

    León-Navarro, David Agustín; Albasanz, José L; Martín, Mairena

    2015-08-01

    Febrile seizure is one of the most common convulsive disorders in children. The neuromodulator adenosine exerts anticonvulsant actions through binding adenosine receptors. Here, the impact of hyperthermia-induced seizures on adenosine A1 and A2A receptors and 5'-nucleotidase activity has been studied at different periods in the cerebral cortical area by using radioligand binding, real-time PCR, and 5'-nucleotidase activity assays. Hyperthermic seizures were induced in 13-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. A significant increase in A1 receptor density was observed using [(3) H]DPCPX as radioligand, and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density was detected, using [(3) H]ZM241385 as radioligand, 48 h after hyperthermia-evoked convulsions. These short-term changes in A1 and A2A receptors were also accompanied by a loss of 5'-nucleotidase activity. No significant variations either in A1 or A2A receptor density or 5'-nucleotidase were observed 5 and 20 days after hyperthermic seizures. Taken together, both regulation of A1 and A2A receptors and loss of 5'-nucleotidase in the cerebral cortex suggest the existence of a neuroprotective mechanism against seizures. Febrile seizure is one of the most common convulsive disorders in children. The consequences of hyperthermia-induced seizures (animal model of febrile seizures) on adenosine A1 and A2A receptors and 5'-nucleotidase activity have been studied at different periods in cerebral cortical area. A significant increase in A1 receptor density and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density and 5'-nucleotidase activity was detected 48 h after convulsions evoked by hyperthermia

  15. Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness

    PubMed Central

    Desronvil, T.; Logan-Wyatt, D.; Abdrabou, W.; Triana, M.; Jones, R.; Taheri, S.; Del Bono, E.; Pasquale, L.R.; Olivier, M.; Haines, J.L.; Fan, B.J.

    2010-01-01

    Purpose One approach to identify genes that contribute to common complex ocular disorders such as primary open angle glaucoma (POAG) is to study the genetic determinates of endophenotypes that are defined by underlying pre-disposing heritable quantitative traits such as central corneal thickness (CCT). Collagen VIII is a major component of Descemet’s membrane and studies in mice have indicated that targeted inactivation of the genes encoding the collagen type 8 alpha1 (Col8a1) and collagen type 8 alpha2 (Col8a2) subunits (COL8A1 and COL8A2) results in thinning of the corneal stroma and of Descemet’s membrane. The purpose of this study is to evaluate COL8A1 and COL8A2 as candidate genes for thin CCT in human POAG patients. Methods 100 Caucasian POAG patients were enrolled in this study. The entire COL8A1 and COL8A2 coding sequence was determined in 8 patients with CCT<513 µm (one standard deviation (36 microns) below the mean (550 microns) and 8 patients with CCT>586 µm (one standard deviation above the mean). Selected COL8A2 exons containing variants of interest were sequenced in the full POAG cohort. Association and quantitative trait analyses were performed. Results Three patients with CCT less than 513 µm and advanced POAG were found to have missense changes in COL8A2; two patients had a previously identified mutation, R155Q and one had a novel change, P678L (p=0.0035, Fisher’s exact test). Missense changes were not found in any of the patients with CCT>513 µm and missense changes in the COL8A1 gene were not found in any patient. One common COL8A2 SNP, rs274754 was also statistically associated with CCT (p=0.018). Conclusions In this study we have identified COL8A2 missense changes in a group of Caucasian patients with very thin CCT and advanced POAG. These results suggest that DNA sequence variants in the COL8A2 gene may be associated with thin corneas in some glaucoma patients. Further study of COL8A2 variants in other patient populations, especially

  16. Crystal structures of SULT1A2 and SULT1A1 *3: insights into the substrate inhibition and the role of Tyr149 in SULT1A2.

    PubMed

    Lu, Jinghua; Li, Haitao; Zhang, Jiping; Li, Mei; Liu, Ming-Yih; An, Xiaomin; Liu, Ming-Cheh; Chang, Wenrui

    2010-05-28

    The cytosolic sulfotransferases (SULTs) in vertebrates catalyze the sulfonation of endogenous thyroid/steroid hormones and catecholamine neurotransmitters, as well as a variety of xenobiotics, using 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as the sulfonate donor. In this study, we determined the structures of SULT1A2 and an allozyme of SULT1A1, SULT1A1 *3, bound with 3'-phosphoadenosine 5'-phosphate (PAP), at 2.4 and 2.3A resolution, respectively. The conformational differences between the two structures revealed a plastic substrate-binding pocket with two channels and a switch-like substrate selectivity residue Phe247, providing clearly a structural basis for the substrate inhibition. In SULT1A2, Tyr149 extends approximately 2.1A further to the inside of the substrate-binding pocket, compared with the corresponding His149 residue in SULT1A1 *3. Site-directed mutagenesis study showed that, compared with the wild-type SULT1A2, mutant Tyr149Phe SULT1A2 exhibited a 40 times higher K(m) and two times lower V(max) with p-nitrophenol as substrate. These latter data imply a significant role of Tyr149 in the catalytic mechanism of SULT1A2.

  17. Extraction and Inhibition of Enzymatic Activity of Botulinum Neurotoxins/A1, /A2, and /A3 by a Panel of Monoclonal Anti-BoNT/A Antibodies

    DTIC Science & Technology

    2009-04-01

    a disease that is contracted by ingestion of food containing the toxin [1,2], colonization of the bacteria in the gastrointestinal tract of infants...In addition, commer- cially purified BoNT/A1 (strain Hall) and BoNT/A2 (strain FRI- honey ) complex toxins from Metabiologics (Madison, WI) were used

  18. PapA1 and PapA2 are acyltransferases essential for the biosynthesis of the Mycobacterium tuberculosis virulence factor sulfolipid-1.

    PubMed

    Kumar, Pawan; Schelle, Michael W; Jain, Madhulika; Lin, Fiona L; Petzold, Christopher J; Leavell, Michael D; Leary, Julie A; Cox, Jeffery S; Bertozzi, Carolyn R

    2007-07-03

    Mycobacterium tuberculosis produces numerous exotic lipids that have been implicated as virulence determinants. One such glycolipid, Sulfolipid-1 (SL-1), consists of a trehalose-2-sulfate (T2S) core acylated with four lipid moieties. A diacylated intermediate in SL-1 biosynthesis, SL(1278), has been shown to activate the adaptive immune response in human patients. Although several proteins involved in SL-1 biosynthesis have been identified, the enzymes that acylate the T2S core to form SL(1278) and SL-1, and the biosynthetic order of these acylation reactions, are unknown. Here we demonstrate that PapA2 and PapA1 are responsible for the sequential acylation of T2S to form SL(1278) and are essential for SL-1 biosynthesis. In vitro, recombinant PapA2 converts T2S to 2'-palmitoyl T2S, and PapA1 further elaborates this newly identified SL-1 intermediate to an analog of SL(1278). Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. The loss of SL-1 (and SL(1278)) did not appear to affect bacterial replication or trafficking, suggesting that the functions of SL-1 are specific to human infection.

  19. Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A1 and A2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats.

    PubMed

    Iglesias, Inmaculada; Albasanz, Jose Luis; Martín, Mairena

    2014-12-01

    Background: Caffeine is the most widely consumed psychoactive substance in the world, even during pregnancy. Its stimulatory effects are mainly due to antagonism of adenosine actions by blocking adenosine A1 and A2A receptors. Previous studies have shown that caffeine can cross the placenta and therefore modulate these receptors not only in the fetal brain but also in the heart. Methods: In the present work, the effect of caffeine chronically consumed during pregnancy on A1 and A2A receptors in Wistar rat heart, from both mothers and their fetuses, were studied using radioligand binding, Western-blotting, and adenylyl cyclase activity assays, as well as reverse transcription polymerase chain reaction. Results: Caffeine did not significantly alter A1R neither at protein nor at gene expression level in both the maternal and fetal heart. On the contrary, A2AR significantly decreased in the maternal heart, although mRNA was not affected. Gi and Gs proteins were also preserved. Finally, A1R-mediated inhibition of adenylyl cyclase activity did not change in the maternal heart, but A2AR mediated stimulation of this enzymatic activity significantly decreased according to the detected loss of this receptor. Conclusions: Opposite to the downregulation and desensitization of the A1R/AC pathway previously reported in the brain, these results show that this pathway is not affected in rat heart after caffeine exposure during pregnancy. In addition, A2AR is downregulated and desensitized in the maternal heart, suggesting a differential modulation of these receptor-mediated pathways by caffeine.

  20. Differential Expression of Adenosine A1 and A2A Receptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

    PubMed Central

    Petrov, Theodor; Kreipke, Christian; Alilain, Warren; Nantwi, Kwaku D

    2007-01-01

    Background: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated via adenosine receptors to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although spinal phrenic motoneurons immunopositive for adenosine receptors have been demonstrated (C3–C5), it is unclear if adenosine receptor protein levels are altered after C2 hemisection and theophylline administration. Objective: To assess the effects of C2 spinal cord hemisection and theophylline administration on the expression of adenosine receptor proteins. Methods: Adenosine A1 and A2A receptor protein levels were assessed in adult rats classified as (a) noninjured and theophylline treated, (b) C2 hemisected, (c) C2 hemisected and administered theophylline orally (3× daily) for 3 days only, and (d) C2 hemisected and administered theophylline (3× daily for 3 days) and assessed 12 days after drug administration. Assessment of A1 protein levels was carried out via immunohistochemistry and A2A protein levels by densitometry. Results: Adenosine A1 protein levels decreased significantly (both ipsilateral and contralateral to injury) after C2 hemisection; however, the decrease was attenuated in hemisected and theophylline-treated animals. Attenuation in adenosine A1 receptor protein levels persisted when theophylline administration was stopped for 12 days prior to assessment. Adenosine A2A protein levels were unchanged by C2 hemisection; however, theophylline reduced the levels within the phrenic motoneurons. Furthermore, the decrease in A2A levels persisted 12 days after theophylline was withdrawn. Conclusion: Our findings suggest that theophylline mitigates the effects of C2 hemisection by attenuating the C2 hemisection–induced decrease in A1 protein levels. Furthermore, A2A protein levels are unaltered by C2 hemisection but decrease after continuous or interrupted theophylline

  1. Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A1 and A2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats

    PubMed Central

    Iglesias, Inmaculada; Albasanz, Jose Luis

    2014-01-01

    Background: Caffeine is the most widely consumed psychoactive substance in the world, even during pregnancy. Its stimulatory effects are mainly due to antagonism of adenosine actions by blocking adenosine A1 and A2A receptors. Previous studies have shown that caffeine can cross the placenta and therefore modulate these receptors not only in the fetal brain but also in the heart. Methods: In the present work, the effect of caffeine chronically consumed during pregnancy on A1 and A2A receptors in Wistar rat heart, from both mothers and their fetuses, were studied using radioligand binding, Western-blotting, and adenylyl cyclase activity assays, as well as reverse transcription polymerase chain reaction. Results: Caffeine did not significantly alter A1R neither at protein nor at gene expression level in both the maternal and fetal heart. On the contrary, A2AR significantly decreased in the maternal heart, although mRNA was not affected. Gi and Gs proteins were also preserved. Finally, A1R-mediated inhibition of adenylyl cyclase activity did not change in the maternal heart, but A2AR mediated stimulation of this enzymatic activity significantly decreased according to the detected loss of this receptor. Conclusions: Opposite to the downregulation and desensitization of the A1R/AC pathway previously reported in the brain, these results show that this pathway is not affected in rat heart after caffeine exposure during pregnancy. In addition, A2AR is downregulated and desensitized in the maternal heart, suggesting a differential modulation of these receptor-mediated pathways by caffeine. PMID:25538864

  2. Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss.

    PubMed

    Saijo, Y; Sata, F; Yamada, H; Suzuki, K; Sasaki, S; Kondo, T; Gong, Y Y; Kato, E H; Shimada, S; Morikawa, M; Minakami, H; Kishi, R

    2004-10-01

    The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40-1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53-1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71-1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68-2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.

  3. Induction of cytochromes P450 1A1 and 1A2 by tanshinones in human HepG2 hepatoma cell line

    SciTech Connect

    Zhang Rong; Sun Jianguo; Ma Liping; Wu Xiaolan; Pan Guoyu; Hao Haiping; Zhou Fang; Jiye, A; Liu Changhui; Ai Hua; Shang Lili; Gao Haiyan; Peng Ying; Wan Ping; Wu Hui; Wang Guangji

    2011-04-01

    Diterpenoid tanshinones including tanshinone IIA (TIIA), cryptotanshinone (CTS), tanshinone I (TI) and dihydrotanshinone I (DHTI) are the major bioactive components from Danshen. The major aim of our present study was to investigate the induction potential of these four main components of tanshinones (TIIA, CTS, TI, and DHTI) on the expression of CYP1A1 and CYP1A2 in HepG2 cells. Our results showed that all of these four tanshinones caused a significant time- and concentration-dependent increase in the amount of CYP1A1/2 expression in HepG2 cells. These induction effects were further characterized through transcriptional regulation: the induction of CYP1A1/2 mRNA level by tanshinones was completely blocked by the transcription inhibitor actinomycin D; the expression of CYP1A1/2 heterogeneous nuclear RNA was induced by tanshinone treatment; and CYP1A1 mRNA stability was not influenced by these tanshinones. Interestingly, tanshinones plus B[a]P produced additive/synergistic effect on CYP1A1/2 induction. In addition, the tanshinone-induced CYP1A1/2 expression was abolished by the aryl hydrocarbon receptor (AhR) antagonist resveratrol, suggesting an AhR dependent transcription mechanism. In the reporter gene assay, while TI and DHTI significantly induced AhR-dependent luciferase activity, TIIA and CTS failed to induce this activity. Collectively, the tanshinones could induce CYP1A1 and CYP1A2 expression through transcriptional activation mechanism and exert differential effects on activating AhR in HepG2 cells. Our findings suggest that rational administration of tanshinones should be considered with respect to their effect on AhR and CYP1A1/2 expression.

  4. Modulation of CYP1A1 and CYP1A2 hepatic enzymes after oral administration of Chios mastic gum to male Wistar rats.

    PubMed

    Katsanou, Efrosini S; Kyriakopoulou, Katerina; Emmanouil, Christina; Fokialakis, Nikolas; Skaltsounis, Alexios-Leandros; Machera, Kyriaki

    2014-01-01

    Chios mastic gum (CMG), a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE), at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well-known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD). The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE.

  5. Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A 2A receptors in striatal projection neurons.

    PubMed

    Hernández-González, O; Hernández-Flores, T; Prieto, G A; Pérez-Burgos, A; Arias-García, M A; Galarraga, E; Bargas, J

    2014-01-01

    D(1)- and D(2)-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A(1)-type receptors are located in both neuron classes, and adenosine A(2A)-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca(2+)-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D(1)-type receptors increase, while D(2)-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, CaV1 Ca(2+)-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A(1)- and A(2A)-receptors have not been compared observing their actions on Ca(2+)-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca(2+)-currents by A(1)-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A(1)- and A2A-receptors. We demonstrate that A(1)-type receptors reduced Ca(2+)-currents in all SPNs tested. However, A(2A)-type receptors enhanced Ca(2+)-currents only in half tested neurons. Intriguingly, to observe the actions of A(2A)-type receptors, occupation of A(1)-type receptors had to occur first. However, A(1)-receptors decreased Ca(V)2 Ca(2+)-currents, while A(2A)-type receptors enhanced current through Ca(V)1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability.

  6. Inheritance and molecular mapping of Rf6 locus with pollen fertility restoration ability on A1 and A2 cytoplasms in sorghum.

    PubMed

    Praveen, M; Anurag Uttam, G; Suneetha, N; Umakanth, Av; Patil, J V; Madhusudhana, R

    2015-09-01

    Of the several male sterility cytoplasms available as an alternative to the widely exploited A1 (milo) cytoplasm in sorghum, A2 is more suitable for commercial exploitation. Diversification of genetic and cytoplasmic base of hybrids involving A2 cytoplasm necessitates mapping of fertility restorer (Rf) genes for use in marker-assisted restorer development. We mapped a major male fertility restoration locus on sorghum chromosome 4 tightly linked with SSR markers, SB2387 and SB2388. This new fertility locus, Rf6, was able to restore male fertility on both A1 and A2 cytoplasms. Analysis of the genomic region around the Rf6 locus identified six genes including a pentatricopeptide repeat (PPR) gene, Sobic.004G004100. With its similar restoration ability to Rf1, Rf2 and Rf5 loci in sorghum, it is most likely that the Rf6 is a member of the PPR gene family, and the PPR gene Sobic.004G004100 could be a candidate for fertility restoration on A1 and A2 cytoplasms.

  7. The a 1Δg(a2 g)→X 3Σ-g(X 21 g) transition of Se 2

    NASA Astrophysics Data System (ADS)

    Setzer, K. D.; Dorn, A.; Lorenz, M.; Fink, E. H.

    2003-09-01

    Emission spectra of the 0-0 and 1-1 bands of the a 1Δg(a2 g)→X 3Σ-g(X 21 g) magnetic dipole transition of Se 2 have been observed in the near-infrared spectral region near 3780 cm -1. The Se 2 molecules were generated in a fast-flow system by passing Se x vapor in Ar carrier gas through a microwave discharge and were excited by electronic-to-electronic energy transfer from metastable singlet oxygen O2(a 1Δg) . Medium-resolution spectra of the b 1Σ+g(b0 +g)→X 3Σ-g(X 21 g) and a 1Δg(a2 g)→X 3Σ-g(X 21 g) transitions were measured with a Fourier-transform spectrometer. By comparing the band shape of the 0-0 band of the a→ X2 system with computer simulations, the following spectroscopic constants of the a 1Δg(a2 g) state of 80Se 2 were derived (cm -1): Te=4303.7(1), B0=0.08888(5), and Δ G1/2=369.6(2), where the numbers in parentheses are estimated error limits of the parameters in units of the last digit.

  8. Downregulation of A(1) and A(2B) adenosine receptors in human trisomy 21 mesenchymal cells from first-trimester chorionic villi.

    PubMed

    Gessi, Stefania; Merighi, Stefania; Stefanelli, Angela; Mirandola, Prisco; Bonfatti, Alessandra; Fini, Sergio; Sensi, Alberto; Marci, Roberto; Varani, Katia; Borea, Pier Andrea; Vesce, Fortunato

    2012-11-01

    Human reproduction is complex and prone to failure. Though causes of miscarriage remain unclear, adenosine, a proangiogenic nucleoside, may help determine pregnancy outcome. Although adenosine receptor (AR) expression has been characterized in euploid pregnancies, no information is available for aneuploidies, which, as prone to spontaneous abortion (SA), are a potential model for shedding light on the mechanism regulating this event. AR expression was investigated in 71 first-trimester chorionic villi (CV) samples and cultured mesenchymal cells (MC) from euploid and TR21 pregnancies, one of the most frequent autosomal aneuploidy, with a view to elucidating their potential role in the modulation of vascular endothelial growth factor (VEGF) and nitric oxide (NO). Compared to euploid cells, reduced A(1) and A(2B) expression was revealed in TR21 CV and MCs. The non-selective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased NO, by activating, predominantly, A(1)AR and A(2A)AR through a molecular pathway involving hypoxia-inducible-factor-1 (HIF-1α), and increased VEGF, mainly through A(2B). In conclusion the adenosine transduction cascade appears to be disturbed in TR21 through reduced expression of A(2B) and A(1)ARs. These anomalies may be implicated in complications such as fetal growth restriction, malformation and/or SA, well known features of aneuploid pregnancies. Therefore A(1) and A(2B)ARs could be potential biomarkers able to provide an early indication of SA risk and their stimulation may turn out to improve fetoplacental perfusion by increasing NO and VEGF.

  9. The Human UDP-glucuronosyltransferase UGT2A1 and UGT2A2 enzymes are highly active in bile acid glucuronidation.

    PubMed

    Perreault, Martin; Gauthier-Landry, Louis; Trottier, Jocelyn; Verreault, Mélanie; Caron, Patrick; Finel, Moshe; Barbier, Olivier

    2013-09-01

    Bile acids (BA) are essential modulators of lipid, glucose, and cholesterol homeostasis, but they exert cytotoxic effects in the cholestatic liver. Glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT) enzymes is a pharmacologically relevant BA detoxification process. The present study characterized the BA-conjugating activity of the little-studied human UGTs of subfamily 2A: UGT2A1, 2A2, and 2A3. Recombinant UGT2As, expressed in baculovirus-infected insect cells, were assayed for the glucuronidation of six major bile acids: chenodeoxycholic acid (CDCA), cholic acid (CA), lithocholic acid (LCA), deoxycholic acid (DCA), hyocholic acid (HCA) and hyodeoxycholic acid (HDCA). UGT2A3 exhibited detectable but very low activity with all the tested BA substrates. UGT2A1 was highly efficient in forming LCA-3 and LCA-24G, CDCA-24, DCA-24, HCA-24, and HDCA-24G, whereas UGT2A2 was the most active enzyme for CA-24G and CDCA-24G formation and also was able to generate HDCA-6G, HDCA-24G, LCA-24G, and HCA-24G. The Km values of UGT2A1 varied between 102.2 ± 14.3 µM and 2.4 ± 1.2 mM. With the exception of CA-24G, a low affinity substrate for UGT2A2, all the Km values for UGT2A2 were in the 100 to 400 µM range. We demonstrate the high reactivity of the human UGT2A1 and UGT2A2 for bile acid glucuronidation. The physiologic importance of these reactions to BA disposition remains, however, to be clarified in vivo.

  10. The human UDP-glucuronosyltransferase UGT2A1 and UGT2A2 enzymes are highly active in bile acid glucuronidation

    PubMed Central

    Perreault, Martin; Gauthier-Landry, Louis; Trottier, Jocelyn; Verreault, Mélanie; Caron, Patrick; Finel, Moshe; Barbier, Olivier

    2013-01-01

    Bile acids (BA) are essential modulators of lipid, glucose and cholesterol homeostasis, but exert cytotoxic effects in the cholestatic liver. Glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT) enzymes is a pharmacologically-relevant BA detoxification process. The present study aimed at characterizing the BA-conjugating activity of the little-studied human UGTs of subfamily 2A, UGT2A1, 2A2 and 2A3. Recombinant UGT2As, expressed in baculovirus-infected insect cells, were assayed for the glucuronidation of 6 major bile acids, chenodeoxycholic (CDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA), hyocholic (HCA) and hyodeoxycholic (HDCA) acids. UGT2A3 exhibited detectable, but very low, activity with all the tested BAs substrates. UGT2A1 was highly efficient in forming LCA-3 and -24G, CDCA-24, DCA-24, HCA-24 and HDCA-24G, while UGT2A2 was the most active enzyme for CA-24G and CDCA-24G formation, and was also able to generate HDCA-6G, HDCA-24G, LCA-24G and HCA-24G. The Km values of UGT2A1 varied between 102.2 ± 14.3 μM and 2.4 ± 1.2 mM. With the exception of CA-24G, a low affinity substrate for UGT2A2, all the Km values for UGT2A2 were in the 100 to 400 μM range. In conclusion, the present study demonstrates the high reactivity of the human UGT2A1 and UGT2A2 for bile acid glucuronidation. The physiological importance of these reactions to BA disposition remains, however, to be clarified in vivo. PMID:23756265

  11. Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats.

    PubMed

    Justinova, Zuzana; Ferre, Sergi; Segal, Pavan N; Antoniou, Katerina; Solinas, Marcello; Pappas, Lara A; Highkin, Jena L; Hockemeyer, Jorg; Munzar, Patrik; Goldberg, Steven R

    2003-12-01

    Adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission. We have recently reported that nonselective adenosine receptor antagonists (caffeine and 3,7-dimethyl-1-propargylxanthine) can partially substitute for the discriminative-stimulus effects of methamphetamine. In the present study, by using more selective compounds, we investigated the involvement of A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of both cocaine and methamphetamine. The effects of the A1 receptor agonist N6-cyclopentyladenosine (CPA; 0.01-0.1 mg/kg) and antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.3-23.7 mg/kg) and the A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; 0.03-0.18 mg/kg) and antagonist 3-(3-hydroxypropyl)-8-(3-methoxystyryl)-7-methyl-1-propargylxanthin phosphate disodium salt (MSX-3; 1-56 mg/kg) were evaluated in rats trained to discriminate either 1 mg/kg methamphetamine or 10 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. The A1 and A2A receptor antagonists (CPT and MSX-3) both produced high levels of drug-lever selection when substituted for either methamphetamine or cocaine and significantly shifted dose-response curves of both psychostimulants to the left. Unexpectedly, the A2A receptor agonist CGS 21680 also produced drug-appropriate responding (although at lower levels) when substituted for the cocaine-training stimulus, and both CGS 21680 and the A1 receptor agonist CPA significantly shifted the cocaine dose-response curve to the left. In contrast, both agonists did not produce significant levels of drug-lever selection when substituted for the methamphetamine-training stimulus and failed to shift the methamphetamine dose-response curve. Therefore, adenosine A1 and A2A receptors appear to play important but differential roles in the modulation of the

  12. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Performance Verification Report: EOS AMSU-A1 and AMSU-A2 Receiver Assemblies

    NASA Technical Reports Server (NTRS)

    Ma, Y.

    1995-01-01

    The AMSU-A receiver subsystem comprises two separated receiver assemblies; AMSU-A1 and AMSU-A2 (P/N 1356441-1). The AMSU-A1 receiver contains 13 channels and the AMSU-A2 receiver 2 channels. The AMSU-A1 receiver assembly is further divided into two parts; AMSU-A1-1 (P/N 1356429-1) and AMSU-A1-2 (P/N 1356409-1), which contain 9 and 4 channels, respectively. The receiver assemblies are highlighted and illustrate the functional block diagrams of the AMSU-A1 and AMSU-A2 systems. The AMSU-A receiver subsystem stands in between the antenna and signal processing subsystems of the AMSU-A instrument and comprises the RF and IF components from isolators to attenuators. It receives the RF signals from the antenna subsystem, down-converts the RF signals to IF signals, amplifies and defines the IF signals to proper power level and frequency bandwidth as specified for each channel, and inputs the IF signals to the signal processing subsystem. This test report presents the test data of the EOS AMSU-A Flight Model No. 1 (FM-1) receiver subsystem. The tests are performed per the Acceptance Test Procedure for the AMSU-A Receiver Subsystem, AE-26002/6A. The functional performance tests are conducted either at the component or subsystem level. While the component-level tests are performed over the entire operating temperature range predicted by thermal analysis, the subsystem-level tests are conducted at ambient temperature only.

  13. Vitamin-D receptor agonist calcitriol reduces calcification in vitro through selective upregulation of SLC20A2 but not SLC20A1 or XPR1

    PubMed Central

    Keasey, M. P.; Lemos, R. R.; Hagg, T.; Oliveira, J. R. M.

    2016-01-01

    Vitamin D deficiency (hypovitaminosis D) causes osteomalacia and poor long bone mineralization. In apparent contrast, hypovitaminosis D has been reported in patients with primary brain calcifications (“Fahr’s disease”). We evaluated the expression of two phosphate transporters which we have found to be associated with primary brain calcification (SLC20A2, whose promoter has a predicted vitamin D receptor binding site, and XPR1), and one unassociated (SLC20A1), in an in vitro model of calcification. Expression of all three genes was significantly decreased in calcifying human bone osteosarcoma (SaOs-2) cells. Further, we confirmed that vitamin D (calcitriol) reduced calcification as measured by Alizarin Red staining. Cells incubated with calcitriol under calcifying conditions specifically maintained expression of the phosphate transporter SLC20A2 at higher levels relative to controls, by RT-qPCR. Neither SLC20A1 nor XPR1 were affected by calcitriol treatment and remained suppressed. Critically, knockdown of SLC20A2 gene and protein with CRISPR technology in SaOs2 cells significantly ablated vitamin D mediated inhibition of calcification. This study elucidates the mechanistic importance of SLC20A2 in suppressing the calcification process. It also suggests that vitamin D might be used to regulate SLC20A2 gene expression, as well as reduce brain calcification which occurs in Fahr’s disease and normal aging. PMID:27184385

  14. Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

    PubMed Central

    Meienberg, Janine; Rohrbach, Marianne; Neuenschwander, Stefan; Spanaus, Katharina; Giunta, Cecilia; Alonso, Sira; Arnold, Eliane; Henggeler, Caroline; Regenass, Stephan; Patrignani, Andrea; Azzarello-Burri, Silvia; Steiner, Bernhard; Nygren, Anders OH; Carrel, Thierry; Steinmann, Beat; Mátyás, Gábor

    2010-01-01

    Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys–Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers–Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3 408 306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene. PMID:20648054

  15. CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines

    SciTech Connect

    Uno, Shigeyuki; Endo, Kaori; Ishida, Yuji; Tateno, Chise; Makishima, Makoto; Yoshizato, Katsutoshi; Nebert, Daniel W.

    2009-05-15

    Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1{sub C}YP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+){sub s}evere-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

  16. Downregulation of let-7b promotes COL1A1 and COL1A2 expression in dermis and skin fibroblasts during heat wound repair.

    PubMed

    Liu, Jinyan; Luo, Chengqun; Yin, Zhaoqi; Li, Ping; Wang, Shaohua; Chen, Jia; He, Quanyong; Zhou, Jianda

    2016-03-01

    MicroRNAs (miRs), a class of non‑coding RNAs 18‑25 nucleotides in length, generally serve suppressive role in the regulation of gene expression via directly binding to the 3'‑untranslated region (UTR) of their target mRNA. Previous studies have identified several miRs to be involved in thermal injury repair. However, the role of miR let‑7b during the recovery of thermal injury, in addition to the underlying mechanisms, has not previously been studied. In the present study, the expression of let‑7b was observed to be significantly increased in skin tissue shortly following thermal injury, however, gradually reduced during the recovery of thermal injury. Notably, similar findings were observed in heat‑denatured skin fibroblasts. Furthermore, collagen, type I, alpha 1 (COL1A1) and collagen, type I, alpha 2 (COL1A2), which are associated with the synthesis of type I collagen, were identified as two targets of let‑7b in skin fibroblasts. The overexpression of let‑7b was observed to upregulate the protein expression levels of COL1A1 and COL1A2, while knockdown of let‑7b reduced the levels of COL1A1 and COL1A2 in skin fibroblasts. Furthermore, COL1A1 and COL1A2 were significantly downregulated shortly following thermal injury, while gradually upregulated during healing, in heat‑damaged skin tissue and skin fibroblasts, with the expression profiles opposite to that of let‑7b. Taken together, this suggests that the downregulation of let‑7b in heat‑damaged dermis promotes the synthesis of type I collagen and thus aids in burn wound repair.

  17. Expression of the LspA1 and LspA2 proteins by Haemophilus ducreyi is required for virulence in human volunteers.

    PubMed

    Janowicz, Diane M; Fortney, Kate R; Katz, Barry P; Latimer, Jo L; Deng, Kaiping; Hansen, Eric J; Spinola, Stanley M

    2004-08-01

    Haemophilus ducreyi colocalizes with polymorphonuclear leukocytes and macrophages and evades phagocytosis during experimental infection of human volunteers. H. ducreyi contains two genes, lspA1 and lspA2, which encode predicted proteins of 456 and 543 kDa, respectively. Compared to its wild-type parent, an lspA1 lspA2 double mutant does not inhibit phagocytosis by macrophage and myelocytic cell lines in vitro and is attenuated in an experimental rabbit model of chancroid. To test whether expression of LspA1 and LspA2 was necessary for virulence in humans, six volunteers were experimentally infected. Each volunteer was inoculated with three doses (ranging from 85 to 112 CFU) of the parent (35000HP) in one arm and three doses (ranging from 60 to 822 CFU) of the mutant (35000HP Omega 12) in the other arm. The papule formation rates were 88% (95% confidence interval [95% CI], 76.8 to 99.9%) at 18 parent sites and 72% (95% CI, 44.4 to 99.9%) at 18 mutant sites (P = 0.19). However, papules were significantly smaller at mutant sites (mean size, 24.8 mm(2)) than at parent sites (mean size, 39.1 mm(2)) 24 h after inoculation (P = 0.0002). The pustule formation rates were 44% (95% CI, 5.8 to 77.6%) at parent sites and 0% (95% CI, 0 to 39.4%) at mutant sites (P = 0.009). With the caveat that biosafety regulations preclude testing of a complemented mutant in human subjects, these results indicate that expression of LspA1 and LspA2 facilitates the ability of H. ducreyi to initiate disease and to progress to pustule formation in humans.

  18. Phenotype of the Cyp1a1/1a2/1b1(−/−) Triple-Knockout Mouse*

    PubMed Central

    Dragin, Nadine; Shi, Zhanquan; Madan, Rajat; Karp, Christopher L.; Sartor, Maureen A.; Chen, Chi; Gonzalez, Frank J.; Nebert, Daniel W.

    2009-01-01

    Crossing the Cyp1a1/1a2(−/−) double-knockout mouse with the Cyp1b1(−/−) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(−/−) triple-knockout mouse. In this triple-knockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(−/−) produced the same degree of marked immunosuppression as seen in the Cyp1a1(−/−) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(−/−) mice showed the same “rescued” response as that seen in the Cyp1a1/1b1(−/−) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up- and 62 genes down-regulated (P-value ≤0.00086). Gene Ontology “classes of genes” most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect down-regulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and

  19. Common and distinct functions of Arabidopsis class A1 and A2 heat shock factors in diverse abiotic stress responses and development.

    PubMed

    Liu, Hsiang-chin; Charng, Yee-yung

    2013-09-01

    There are 21 heat shock factor (HSF) homologs in Arabidopsis (Arabidopsis thaliana), of which members of class A1 (HSFA1a/HSFA1b/HSFA1d/HSFA1e) play the major role in activating the transcription of heat-induced genes, including HSFA2. Once induced, HSFA2 becomes the dominant HSF and is able to form heterooligomeric complexes with HSFA1. However, whether HSFA2 could function independently as a transcription regulator in the absence of the HSFA1s was undetermined. To address this question, we introduced a Cauliflower mosaic virus 35S promoter:HSFA2 construct into hsfa1a/hsfa1b/hsfa1d/hsfa1e quadruple knockout (QK) and wild-type (Wt) backgrounds to yield transgenic lines A2QK and A2Wt, respectively. Constitutive expression of HSFA2 rescued the developmental defects of the QK mutant and promoted callus formation in A2QK, but not in A2Wt, after heat treatment. Transcriptome analysis showed that heat stress response genes are differentially regulated by the HSFA1s and HSFA2; the genes involved in metabolism and redox homeostasis are preferentially regulated by HSFA2, while HSFA1-preferring genes are enriched in transcription function. Ectopic expression of HSFA2 complemented the defects of QK in tolerance to different heat stress regimes, and to hydrogen peroxide, but not to salt and osmotic stresses. Furthermore, we showed that HSFA1a/HSFA1b/HSFA1d are involved in thermotolerance to mild heat stress at temperatures as low as 27°C. We also noticed subfunctionalization of the four Arabidopsis A1-type HSFs in diverse abiotic stress responses. Overall, this study reveals the overlapping and distinct functions of class A1 and A2 HSFs and may enable more precise use of HSFs in engineering stress tolerance in the future.

  20. Comparison of CYP106A1 and CYP106A2 from Bacillus megaterium - identification of a novel 11-oxidase activity.

    PubMed

    Kiss, Flora Marta; Schmitz, Daniela; Zapp, Josef; Dier, Tobias K F; Volmer, Dietrich A; Bernhardt, Rita

    2015-10-01

    The CYP106A subfamily hydroxylates steroids, diterpenes, and triterpenes in a regioselective and stereoselective manner, which is a challenging task for synthetic chemistry. The well-studied CYP106A2 enzyme, from the Bacillus megaterium strain ATCC 13368, is a highly promising candidate for the pharmaceutical industry. It shares 63 % amino acid sequence identity with CYP106A1 from B. megaterium DSM319, which was recently characterized. A focused steroid library was screened with both CYP106A1 and CYP106A2. Out of the 23 tested steroids, 19 were successfully converted by both enzymes during in vitro and in vivo reactions. Thirteen new substrates were identified for CYP106A1, while the substrate spectrum of CYP106A2 was extended by seven new members. Finally, six chosen steroids were further studied on a preparative scale employing a recombinant B. megaterium MS941 whole-cell system, yielding sufficient amounts of product for structure characterization by nuclear magnetic resonance. The hydroxylase activity was confirmed at positons 6β, 7β, 9α, and 15β. In addition, the CYP106A subfamily showed unprecedented 11-oxidase activity, converting 11β-hydroxysteroids to their 11-keto derivatives. This novel reaction and the diverse hydroxylation positions on pharmaceutically relevant compounds underline the role of the CYP106A subfamily in drug development and production.

  1. Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex.

    PubMed

    Toyoda, Hiroki; Zhao, Ming-Gao; Ulzhöfer, Bettina; Wu, Long-Jun; Xu, Hui; Seeburg, Peter H; Sprengel, Rolf; Kuner, Rohini; Zhuo, Min

    2009-08-10

    Cortical areas including the anterior cingulate cortex (ACC) are important for pain and pleasure. Recent studies using genetic and physiological approaches have demonstrated that the investigation of basic mechanism for long-term potentiation (LTP) in the ACC may reveal key cellular and molecular mechanisms for chronic pain in the cortex. Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits. However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated. Here, we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluA1 but not GluA2 contributes to LTP in the ACC using genetic manipulated mice lacking GluA1 or GluA2 gene. Furthermore, GluA1 knockout mice showed decreased extracellular signal-regulated kinase (ERK) phosphorylation in the ACC in inflammatory pain models in vivo. Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.

  2. The effect of knockout of sulfotransferases 1a1 and 1d1 and of transgenic human sulfotransferases 1A1/1A2 on the formation of DNA adducts from furfuryl alcohol in mouse models.

    PubMed

    Sachse, Benjamin; Meinl, Walter; Glatt, Hansruedi; Monien, Bernhard H

    2014-10-01

    Furfuryl alcohol is a rodent carcinogen present in numerous foodstuffs. Sulfotransferases (SULTs) convert furfuryl alcohol into the DNA reactive and mutagenic 2-sulfoxymethylfuran. Sensitive techniques for the isotope-dilution ultra performance liquid chromatography-tandem mass spectrometry quantification of resulting DNA adducts, e.g. N (2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N (2)-MF-dG), were developed. To better understand the contribution of specific SULT forms to the genotoxicity of furfuryl alcohol in vivo, we studied the tissue distribution of N (2)-MF-dG in different mouse models. Earlier mutagenicity studies with Salmonella typhimurium strains expressing different human and murine SULT forms indicated that human SULT1A1 and murine Sult1a1 and 1d1 catalyze furfuryl alcohol sulfo conjugation most effectively. Here, we used three mouse lines to study the bioactivation of furfuryl alcohol by murine SULTs, FVB/N wild-type (wt) mice and two genetically modified models lacking either murine Sult1a1 or Sult1d1. The animals received a single dose of furfuryl alcohol, and the levels of the DNA adducts were determined in liver, kidney, lung, colon and small intestine. The effect of Sult1d1 gene disruption on the genotoxicity of furfuryl alcohol was moderate and limited to kidney and small intestine. In contrast, the absence of functional Sult1a1 had a massive influence on the adduct levels, which were lowered by 33-73% in all tissues of the female Sult1a1 null mice compared with the wt animals. The detection of high N (2)-MF-dG levels in a humanized mouse line expressing hSULT1A1/1A2 instead of endogeneous Sult1a1 and Sult1d1 supports the hypothesis that furfuryl alcohol is converted to the mutagenic 2-sulfoxymethylfuran also in humans.

  3. Differential regulation of baboon SP-A1 and SP-A2 genes: structural and functional analysis of 5'-flanking DNA.

    PubMed

    Li, J; Gao, E; Seidner, S R; Mendelson, C R

    1998-12-01

    Surfactant protein (SP) A gene transcription is developmentally regulated and stimulated by hormones and factors that increase intracellular cAMP. The baboon (b) genome contains two highly similar SP-A genes, bSP-A1 and bSP-A2. With the use of a ribonuclease protection assay with gene-specific probes, the two bSP-A genes were found to be differentially regulated during baboon fetal lung development in that expression of the bSP-A2 gene appeared to be induced to a high level at a later time in gestation than that of the bSP-A1 gene. Both the bSP-A1 and bSP-A2 genes were found to be highly responsive to the inductive effects of cAMP in baboon fetal lung explants in culture. By DNase I footprinting and electrophoretic mobility shift assays with bacterially expressed thyroid transcription factor-1 (TTF-1) and type II cell nuclear extracts, three TTF-1 binding elements were identified within the 255-bp region flanking the 5'-end of each bSP-A gene; however, these differed in position and spacing for the two bSP-A genes. To functionally define the genomic regions that are required for cAMP regulation of bSP-A gene expression in type II cells, fusion genes composed of various amounts of 5'-flanking DNA from the bSP-A1 and bSP-A2 genes linked to the human growth hormone structural gene as a reporter were transfected into type II cells in primary culture. We found that 255 bp of 5'-flanking DNA, which contain three TTF-1 binding elements, from bSP-A1 and bSP-A2 genes were sufficient to mediate high basal and cAMP-inducible expression in type II cells. We also observed that there were no obvious differences in the magnitude of the responses of these fusion genes to cAMP treatment.

  4. The LspB protein is involved in the secretion of the LspA1 and LspA2 proteins by Haemophilus ducreyi.

    PubMed

    Ward, Christine K; Mock, Jason R; Hansen, Eric J

    2004-04-01

    The LspA1 and LspA2 proteins of Haemophilus ducreyi 35000 are two very large macromolecules that can be detected in concentrated culture supernatant fluid. Both of these proteins exhibit homology with the N-terminal region of the Bordetella pertussis filamentous hemagglutinin (FHA), which is involved in secretion of the latter macromolecule. The lspA2 open reading frame is flanked upstream by a gene, lspB, that encodes a predicted protein with homology to the B. pertussis FhaC outer membrane protein that is involved in secretion of FHA across the outer membrane. The H. ducreyi lspB gene encodes a protein with a predicted molecular mass of 66,573 Da. Reverse transcription-PCR analysis suggested that the lspB gene was transcribed together with the lspA2 gene on a single mRNA transcript. Polyclonal H. ducreyi LspB antiserum reacted with a 64-kDa antigen present in the Sarkosyl-insoluble cell envelope fraction of H. ducreyi 35000, which indicated that the LspB protein is likely an outer membrane protein. Concentrated culture supernatant fluids from H. ducreyi lspB and lspA1 lspB mutants did not contain detectable LspA1 and detectable LspA2, respectively. However, complementation of the lspB mutant with the wild-type lspB gene on a plasmid restored LspB protein expression and resulted in release of detectable amounts of the LspA1 protein into culture supernatant fluid. When evaluated in the temperature-dependent rabbit model of infection, the lspB mutant was attenuated in the ability to cause lesions and was never recovered in a viable form from lesions. These results indicated that the H. ducreyi LspB protein is involved in secretion of the LspA1 and LspA2 proteins across the outer membrane.

  5. Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations

    PubMed Central

    2013-01-01

    Background Classic Ehlers–Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect. Methods This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the COL5A1 gene and, if no mutation was detected, COL5A2 analysis. In the negative patients the presence of large genomic rearrangements in COL5A1 was investigated using MLPA, and positive results were confirmed via SNP-array analysis. Results We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, COL5A1 or COL5A2 mutations were detected. Twenty-one mutations were in the COL5A1 gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel COL5A2 splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the COL1A1 gene was identified in one patient with vascular-like cEDS. Conclusions Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical

  6. Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1.

    PubMed

    Uehara, Shotaro; Uno, Yasuhiro; Inoue, Takashi; Sasaki, Erika; Yamazaki, Hiroshi

    2016-01-01

    The common marmoset (Callithrix jacchus), a New World monkey, has potential to be an animal model for drug metabolism studies. In this study, we identified and characterized cytochrome P450 (P450) 1A1 and 1B1 in addition to the known P450 1A2 in marmosets. Marmoset P450 1A1 and 1B1 cDNA contained open reading frames encoding 512 and 543 amino acids, respectively, with high sequence identities (90%-93%) to other primate P450 1A1s and 1B1s. A phylogenetic tree based on amino acid sequences showed close evolutionary relationships among marmoset, macaque, and human P450 1A and 1B enzymes. By mRNA quantification and immunoblot analyses in five marmoset tissues, P450 1A1 was mainly expressed in lungs and small intestines, and P450 1A2 was expressed predominantly in livers. In contrast, P450 1B1 was expressed in all tissues tested. Marmoset P450 1A1, 1A2, and 1B1 heterologously expressed in Escherichia coli catalyzed 7-ethoxyresorufin O-deethylation, 7-ethoxycoumarin O-deethylation, and phenacetin O-deethylation, similar to those of humans and cynomolgus monkeys. Notably, marmoset P450 1A1 and 1A2 more efficiently catalyzed 7-ethoxyresorufin O-deethylation than those of the human homologs, but were comparable to those of the cynomolgus monkey homologs. Additionally, marmoset P450 1B1 preferentially catalyzed estradiol 4-hydroxylation; however, rat P450 1B1 more favorably catalyzed estradiol 2-hydroxylation, indicating that the estradiol hydroxylation specificity of marmoset P450 1B1 was similar to those of human and cynomolgus monkey P450 1B1. These results indicated that marmoset P450 1A and 1B enzymes had functional characteristics similar to those of humans and cynomolgus monkeys, suggesting that P450 1A and 1B-dependent metabolism was similar among marmosets, cynomolgus monkeys, and humans.

  7. Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats

    PubMed Central

    O’Neill, Casey E.; Hobson, Benjamin D.; Levis, Sophia C.; Bachtell, Ryan K.

    2014-01-01

    Rationale Adenosine receptor stimulation and blockade has been shown to modulate a variety of cocaine related behaviors. Objectives These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking. Methods Rats self-administered cocaine on a fixed-ratio 1 schedule in daily sessions over 3 weeks. Following 1 week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A1 receptor agonist, CPA (0.03 mg/kg and 0.1 mg/kg), the adenosine A2A agonist, CGS 21680 (0.03 mg/kg and 0.1 mg/kg), the presynaptic adenosine A2A receptor antagonist, SCH 442416 (0.3 mg/kg, 1 mg/kg, and 3 mg/kg), or vehicle prior to each of 6 daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D2 receptor agonist, quinpirole. Results All doses of CPA and CGS 21680 impaired initial extinction responding, however only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding, but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking. Conclusions These findings demonstrate that adenosine A1 or A2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A1 receptor stimulation or presynaptic adenosine A2A receptor blockade during extinction produces lasting changes in relapse susceptibility. PMID:24562064

  8. Dual blockade of the A1 and A2A adenosine receptor prevents amyloid beta toxicity in neuroblastoma cells exposed to aluminum chloride.

    PubMed

    Giunta, Salvatore; Andriolo, Violetta; Castorina, Alessandro

    2014-09-01

    In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl3) enhanced the neurotoxicity of the amyloid beta(25-35) fragment (Abeta(25-35)) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A2A adenosine receptors (A2AR), although it also inhibits A1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta(25-35)+AlCl3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta(25-35)+AlCl3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A1R and A2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl3 treatment exacerbated Abeta(25-35) toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta(25-35) only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta(25-35)+AlCl3-induced damage, suggesting that A1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A1R inhibition in the setting of combined Abeta(25-35)+AlCl3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum.

  9. A2 Milk Enhances Dynamic Muscle Function Following Repeated Sprint Exercise, a Possible Ergogenic Aid for A1-Protein Intolerant Athletes?

    PubMed Central

    Kirk, Ben; Mitchell, Jade; Jackson, Matthew; Amirabdollahian, Farzad; Alizadehkhaiyat, Omid; Clifford, Tom

    2017-01-01

    Hyperaminoacidemia following ingestion of cows-milk may stimulate muscle anabolism and attenuate exercise-induced muscle damage (EIMD). However, as dairy-intolerant athletes do not obtain the reported benefits from milk-based products, A2 milk may offer a suitable alternative as it lacks the A1-protein. This study aimed to determine the effect of A2 milk on recovery from a sports-specific muscle damage model. Twenty-one male team sport players were allocated to three independent groups: A2 milk (n = 7), regular milk (n = 7), and placebo (PLA) (n = 7). Immediately following muscle-damaging exercise, participants consumed either A2 milk, regular milk or PLA (500 mL each). Visual analogue scale (muscle soreness), maximal voluntary isometric contraction (MVIC), countermovement jump (CMJ) and 20-m sprint were measured prior to and 24, 48, and 72 h post EIMD. At 48 h post-EIMD, CMJ and 20-m sprint recovered quicker in A2 (33.4 ± 6.6 and 3.3 ± 0.1, respectively) and regular milk (33.1 ± 7.1 and 3.3 ± 0.3, respectively) vs. PLA (29.2 ± 3.6 and 3.6 ± 0.3, respectively) (p < 0.05). Relative to baseline, decrements in 48 h CMJ and 20-m sprint were minimised in A2 (by 7.2 and 5.1%, respectively) and regular milk (by 6.3 and 5.2%, respectively) vs. PLA. There was a trend for milk treatments to attenuate decrements in MVIC, however statistical significance was not reached (p = 0.069). Milk treatments had no apparent effect on muscle soreness (p = 0.152). Following muscle-damaging exercise, ingestion of 500 mL of A2 or regular milk can limit decrements in dynamic muscle function in male athletes, thus hastening recovery and improving subsequent performance. The findings propose A2 milk as an ergogenic aid following EIMD, and may offer an alternative to athletes intolerant to the A1 protein. PMID:28134840

  10. Ethanol and Caffeine Effects on Social Interaction and Recognition in Mice: Involvement of Adenosine A2A and A1 Receptors.

    PubMed

    López-Cruz, Laura; San-Miguel, Noemí; Bayarri, Pilar; Baqi, Younis; Müller, Christa E; Salamone, John D; Correa, Mercé

    2016-01-01

    Ethanol and caffeine are frequently consumed in combination and have opposite effects on the adenosine system: ethanol metabolism leads to an increase in adenosine levels, while caffeine is a non-selective adenosine A1/A2A receptor antagonist. These receptors are highly expressed in striatum and olfactory tubercle, brain areas involved in exploration and social interaction in rodents. Ethanol modulates social interaction processes, but the role of adenosine in social behavior is still poorly understood. The present work was undertaken to study the impact of ethanol, caffeine and their combination on social behavior, and to explore the involvement of A1 and A2A receptors on those actions. Male CD1 mice were evaluated in a social interaction three-chamber paradigm, for preference of conspecific vs. object, and also for long-term recognition memory of familiar vs. novel conspecific. Ethanol showed a biphasic effect, with low doses (0.25 g/kg) increasing social contact and higher doses (1.0-1.5 g/kg) reducing social interaction. However, no dose changed social preference; mice always spent more time sniffing the conspecific than the object, independently of the ethanol dose. Ethanol, even at doses that did not change social exploration, produced amnestic effects on social recognition the following day. Caffeine reduced social contact (15.0-60.0 mg/kg), and even blocked social preference at higher doses (30.0-60.0 mg/kg). The A1 antagonist Cyclopentyltheophylline (CPT; 3-9 mg/kg) did not modify social contact or preference on its own, and the A2A antagonist MSX-3 (1.5-6 mg/kg) increased social interaction at all doses. Ethanol at intermediate doses (0.5-1.0 g/kg) was able to reverse the reduction in social exploration induced by caffeine (15.0-30.0 mg/kg). Although there was no interaction between ethanol and CPT or MSX-3 on social exploration in the first day, MSX-3 blocked the amnestic effects of ethanol observed on the following day. Thus, ethanol impairs the

  11. Ethanol and Caffeine Effects on Social Interaction and Recognition in Mice: Involvement of Adenosine A2A and A1 Receptors

    PubMed Central

    López-Cruz, Laura; San-Miguel, Noemí; Bayarri, Pilar; Baqi, Younis; Müller, Christa E.; Salamone, John D.; Correa, Mercé

    2016-01-01

    Ethanol and caffeine are frequently consumed in combination and have opposite effects on the adenosine system: ethanol metabolism leads to an increase in adenosine levels, while caffeine is a non-selective adenosine A1/A2A receptor antagonist. These receptors are highly expressed in striatum and olfactory tubercle, brain areas involved in exploration and social interaction in rodents. Ethanol modulates social interaction processes, but the role of adenosine in social behavior is still poorly understood. The present work was undertaken to study the impact of ethanol, caffeine and their combination on social behavior, and to explore the involvement of A1 and A2A receptors on those actions. Male CD1 mice were evaluated in a social interaction three-chamber paradigm, for preference of conspecific vs. object, and also for long-term recognition memory of familiar vs. novel conspecific. Ethanol showed a biphasic effect, with low doses (0.25 g/kg) increasing social contact and higher doses (1.0–1.5 g/kg) reducing social interaction. However, no dose changed social preference; mice always spent more time sniffing the conspecific than the object, independently of the ethanol dose. Ethanol, even at doses that did not change social exploration, produced amnestic effects on social recognition the following day. Caffeine reduced social contact (15.0–60.0 mg/kg), and even blocked social preference at higher doses (30.0–60.0 mg/kg). The A1 antagonist Cyclopentyltheophylline (CPT; 3–9 mg/kg) did not modify social contact or preference on its own, and the A2A antagonist MSX-3 (1.5–6 mg/kg) increased social interaction at all doses. Ethanol at intermediate doses (0.5–1.0 g/kg) was able to reverse the reduction in social exploration induced by caffeine (15.0–30.0 mg/kg). Although there was no interaction between ethanol and CPT or MSX-3 on social exploration in the first day, MSX-3 blocked the amnestic effects of ethanol observed on the following day. Thus, ethanol

  12. Basal adenosine modulates the functional properties of AMPA receptors in mouse hippocampal neurons through the activation of A1R A2AR and A3R

    PubMed Central

    Di Angelantonio, Silvia; Bertollini, Cristina; Piccinin, Sonia; Rosito, Maria; Trettel, Flavia; Pagani, Francesca; Limatola, Cristina; Ragozzino, Davide

    2015-01-01

    Adenosine is a widespread neuromodulator within the CNS and its extracellular level is increased during hypoxia or intense synaptic activity, modulating pre- and postsynaptic sites. We studied the neuromodulatory action of adenosine on glutamatergic currents in the hippocampus, showing that activation of multiple adenosine receptors (ARs) by basal adenosine impacts postsynaptic site. Specifically, the stimulation of both A1R and A3R reduces AMPA currents, while A2AR has an opposite potentiating effect. The effect of ARs stimulation on glutamatergic currents in hippocampal cultures was investigated using pharmacological and genetic approaches. A3R inhibition by MRS1523 increased GluR1-Ser845 phosphorylation and potentiated AMPA current amplitude, increasing the apparent affinity for the agonist. A similar effect was observed blocking A1R with DPCPX or by genetic deletion of either A3R or A1R. Conversely, impairment of A2AR reduced AMPA currents, and decreased agonist sensitivity. Consistently, in hippocampal slices, ARs activation by AR agonist NECA modulated glutamatergic current amplitude evoked by AMPA application or afferent fiber stimulation. Opposite effects of AR subtypes stimulation are likely associated to changes in GluR1 phosphorylation and represent a novel mechanism of physiological modulation of glutamatergic transmission by adenosine, likely acting in normal conditions in the brain, depending on the level of extracellular adenosine and the distribution of AR subtypes. PMID:26528137

  13. Identification, characterization and genetic mapping of TLR7, TLR8a1 and TLR8a2 genes in rainbow trout (Oncorhynchus mykiss)

    USGS Publications Warehouse

    Palti, Yniv; Gahr, Scott A.; Purcell, Maureen K.; Hadidi, Sima; Rexroad, Caird E.; Wiens, Gregory A.

    2010-01-01

    Induction of the innate immune pathways is critical for early anti-viral defense but there is limited understanding of how teleost fish recognize viral molecules and activate these pathways. In mammals, Toll-like receptors (TLR) 7 and 8 bind single-stranded RNA of viral origin and are activated by synthetic anti-viral imidazoquinoline compounds. Herein, we identify and describe the rainbow trout (Oncorhynchus mykiss) TLR7 and TLR8 gene orthologs and their mRNA expression. Two TLR7/8 loci were identified from a rainbow trout bacterial artificial chromosome (BAC) library using DNA fingerprinting and genetic linkage analyses. Direct sequencing of two representative BACs revealed intact omTLR7 and omTLR8a1 open reading frames (ORFs) located on chromosome 3 and a second locus on chromosome 22 that contains an omTLR8a2 ORF and a putative TLR7 pseudogene. We used the omTLR8a1/2 nomenclature for the two trout TLR8 genes as phylogenetic analysis revealed that they and all the other teleost TLR8 genes sequenced to date are similar to the zebrafish TLR8a, but are distinct from the zebrafish TLR8b. The duplicated trout loci exhibit conserved synteny with other fish genomes extending beyond the tandem of TLR7/8 genes. The trout TLR7 and 8a1/2 genes are composed of a single large exon similar to all other described TLR7/8 genes. The omTLR7 ORF is predicted to encode a 1049 amino acid (aa) protein with 84% similarity to the Fugu TLR7 and a conserved pattern of predicted leucine-rich repeats (LRR). The omTLR8a1 and omTLR8a2 are predicted to encode 1035- and 1034-aa proteins, respectively, and have 86% similarity to each other. omTLR8a1 is likely the ortholog of the only Atlantic salmon TLR8 gene described to date as they have 95% aa sequence similarity. The tissue expression profiles of omTLR7, omTLR8a1 and omTLR8a2 in healthy trout were highest in spleen tissue followed by anterior and then posterior kidney tissues. Rainbow trout anterior kidney leukocytes produced elevated

  14. Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart.

    PubMed

    Lee, Yong-Cheol; Jung, Jiyoon; Park, Sang-Jin

    2016-01-01

    The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs) and adenosine receptors (ADRs) in remifentanil preconditioning (R-Pre) and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP),velocity of contraction (+dP/dtmax), and coronary flow (CF) were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax,and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia). These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross-talk.

  15. The role of adenosine A1 and A2A receptors in the caffeine effect on MDMA-induced DA and 5-HT release in the mouse striatum.

    PubMed

    Górska, A M; Gołembiowska, K

    2015-04-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") popular as a designer drug is often used with caffeine to gain a stronger stimulant effect. MDMA induces 5-HT and DA release by interaction with monoamine transporters. Co-administration of caffeine and MDMA may aggravate MDMA-induced toxic effects on DA and 5-HT terminals. In the present study, we determined whether caffeine influences DA and 5-HT release induced by MDMA. We also tried to find out if adenosine A1 and A2A receptors play a role in the effect of caffeine by investigating the effect of the selective adenosine A1 and A2A receptor antagonists, DPCPX and KW 6002 on DA and 5-HT release induced by MDMA. Mice were treated with caffeine (10 mg/kg) and MDMA (20 or 40 mg/kg) alone or in combination. DA and 5-HT release in the mouse striatum was measured using in vivo microdialysis. Caffeine exacerbated the effect of MDMA on DA and 5-HT release. DPCPX or KW 6002 co-administered with MDMA had similar influence as caffeine, but KW 6002 was more potent than caffeine or DPCPX. To exclude the contribution of MAO inhibition by caffeine in the caffeine effect on MDMA-induced increase in DA and 5-HT, we also tested the effect of the nonxanthine adenosine receptor antagonist CGS 15943A lacking properties of MAO activity modification. Our findings indicate that adenosine A1 and A2A receptor blockade may account for the caffeine-induced exacerbation of the MDMA effect on DA and 5-HT release and may aggravate MDMA toxicity.

  16. Increased annexin A1 and A2 levels in bronchoalveolar lavage fluid are associated with resistance to respiratory disease in beef calves

    PubMed Central

    2013-01-01

    Strategies to control bovine respiratory disease depend on accurate classification of disease risk. An objective method to refine the risk classification of beef calves could be economically beneficial, improve welfare by preventing unexpected disease occurrences, refine and reduce the use of antibiotics in beef production, and facilitate alternative methods of disease control. The objective of this study was to identify proteins in bronchoalveolar lavage fluid (BALF) of stressed healthy calves that predict later disease outcome, serve as biomarkers of susceptibility to pneumonia, and play a role in pathogenesis. BALF was collected from 162 healthy beef calves 1–2 days after weaning and transportation. Difference in gel electrophoresis (DIGE) and mass spectrometry were used to compare proteins in samples from 7 calves that later developed respiratory disease compared to 7 calves that remained healthy. Calves that later developed pneumonia had significantly lower levels of annexin A1, annexin A2, peroxiredoxin I, calcyphosin, superoxide dismutase, macrophage capping protein and dihydrodiol dehydrogenase 3. Differences in annexin levels were partially confirmed by western blot analysis. Thus, lower levels of annexins A1 and A2 are potential biomarkers of increased susceptibility to pneumonia in recently weaned and transported feedlot cattle. Since annexins are regulated by glucocorticoids, this finding may reflect individual differences in the stress response that predispose to pneumonia. These findings also have implications in pathogenesis. Annexins A1 and A2 are known to prevent neutrophil influx and fibrin deposition respectively, and may thus act to minimize the harmful effects of the inflammatory response during development of pneumonia. PMID:23565988

  17. Hypervelocity Impact (HVI). Volume 2; WLE Small-Scale Fiberglass Panel Flat Multi-Layer Targets A-1, A-2, and B-1

    NASA Technical Reports Server (NTRS)

    Gorman, Michael R.; Ziola, Steven M.

    2007-01-01

    During 2003 and 2004, the Johnson Space Center's White Sands Testing Facility in Las Cruces, New Mexico conducted hypervelocity impact tests on the space shuttle wing leading edge. Hypervelocity impact tests were conducted to determine if Micro-Meteoroid/Orbital Debris impacts could be reliably detected and located using simple passive ultrasonic methods. The objective of Targets A-1, A-2, and B-2 was to study hypervelocity impacts through multi-layered panels simulating Whipple shields on spacecraft. Impact damage was detected using lightweight, low power instrumentation capable of being used in flight.

  18. Postsynaptic VAMP/Synaptobrevin Facilitates Differential Vesicle Trafficking of GluA1 and GluA2 AMPA Receptor Subunits

    PubMed Central

    Hussain, Suleman; Davanger, Svend

    2015-01-01

    Vertebrate organisms adapt to a continuously changing environment by regulating the strength of synaptic connections between brain cells. Excitatory synapses are believed to increase their strength by vesicular insertion of transmitter glutamate receptors into the postsynaptic plasma membrane. These vesicles, however, have never been demonstrated or characterized. For the first time, we show the presence of small vesicles in postsynaptic spines, often closely adjacent to the plasma membrane and PSD (postsynaptic density). We demonstrate that they harbor vesicle-associated membrane protein 2 (VAMP2/synaptobrevin-2) and glutamate receptor subunit 1 (GluA1). Disrupting VAMP2 by tetanus toxin treatment reduces the concentration of GluA1 in the postsynaptic plasma membrane. GluA1/VAMP2-containing vesicles, but not GluA2/VAMP2-vesicles, are concentrated in postsynaptic spines relative to dendrites. Our results indicate that small postsynaptic vesicles containing GluA1 are inserted directly into the spine plasma membrane through a VAMP2-dependent mechanism. PMID:26488171

  19. Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice

    PubMed Central

    Alshahrani, Saeed; Almutairi, Mohammed Mashari; Kursan, Shams; Dias-Junior, Eduardo; Almiahuob, Mohamed Mahmoud; Aguilar-Bryan, Lydia; Di Fulvio, Mauricio

    2015-01-01

    The products of the Slc12a1 and Slc12a2 genes, commonly known as Na+-dependent K+2Cl− co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl−]i) in pancreatic β-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl− transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele of Slc12a2 exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15–30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence of Slc12a2 associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl− uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a single Slc12a2 allele may protect β-cells from failure due to increased homeostatic expression of Slc12a1. PMID:26400961

  20. A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1

    PubMed Central

    Geissler, Rene; Simkin, Alfred; Floss, Doreen; Patel, Ravi; Fogarty, Elizabeth A.; Scheller, Jürgen; Grimson, Andrew

    2016-01-01

    3′-untranslated regions (UTRs) specify post-transcriptional fates of mammalian messenger RNAs (mRNAs), yet knowledge of the underlying sequences and mechanisms is largely incomplete. Here, we identify two related novel 3′ UTR motifs in mammals that specify transcript degradation. These motifs are interchangeable and active only within 3′ UTRs, where they are often preferentially conserved; furthermore, they are found in hundreds of transcripts, many encoding regulatory proteins. We found that degradation occurs via mRNA deadenylation, mediated by the CCR4–NOT complex. We purified trans factors that recognize the motifs and identified heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2/B1, which are required for transcript degradation, acting in a previously unknown manner. We used RNA sequencing (RNA-seq) to confirm hnRNP A1 and A2/B1 motif-dependent roles genome-wide, profiling cells depleted of these factors singly and in combination. Interestingly, the motifs are most active within the distal portion of 3′ UTRs, suggesting that their role in gene regulation can be modulated by alternative processing, resulting in shorter 3′ UTRs. PMID:27151978

  1. Gene sequences for cytochromes p450 1A1 and 1A2: the need for biomarker development in sea otters (Enhydra lutris).

    PubMed

    Hook, Sharon E; Cobb, Michael E; Oris, James T; Anderson, Jack W

    2008-11-01

    There has been recent public concern regarding the impacts of environmental pollution on populations of otters. Population level impacts have been seen with otter (Lutra lutra) populations in Europe due to polychlorinated biphenyls, and with some segments of the Prince William Sound, AK, sea otter (Enhydra lutris) population following the Exxon Valdez oil spill. Despite public interest in these animals and their ecological significance, there are few tools that allow for the study of otter's response to contaminant exposure. Cytochrome p450 1A (CYP1A) performs the first step in metabolizing many xenobiotics, including many polychlorinated biphenyls and polycyclic aromatic hydrocarbons. CYP1A induction is a frequently used biomarker of exposure to these compounds. Despite the potential importance of this gene in ecological risk assessment, the complete coding sequence has not been published for any otter species. This study's objective was to isolate the gene for CYP1A1 and CYP1A2 in sea otters using a series of PCR-based approaches. The coding sequences from CYP1A1 and CYP1A2 from sea otters were identified and published in GenBank. Both CYP1A sequences are homologous to those obtained from marine mammals and other carnivores. These sequences will be useful as tools for researchers assessing contaminant exposure in mustelid populations.

  2. The antidepressant-like effect of inosine in the FST is associated with both adenosine A1 and A 2A receptors.

    PubMed

    Kaster, Manuella P; Budni, Josiane; Gazal, Marta; Cunha, Mauricio P; Santos, Adair R S; Rodrigues, Ana Lúcia S

    2013-09-01

    Inosine is an endogenous purine nucleoside, which is formed during the breakdown of adenosine. The adenosinergic system was already described as capable of modulating mood in preclinical models; we now explored the effects of inosine in two predictive models of depression: the forced swim test (FST) and tail suspension test (TST). Mice treated with inosine displayed higher anti-immobility in the FST (5 and 50 mg/kg, intraperitoneal route (i.p.)) and in the TST (1 and 10 mg/kg, i.p.) when compared to vehicle-treated groups. These antidepressant-like effects started 30 min and lasted for 2 h after intraperitoneal administration of inosine and were not accompanied by any changes in the ambulatory activity in the open-field test. Both adenosine A1 and A2A receptor antagonists prevented the antidepressant-like effect of inosine in the FST. In addition, the administration of an adenosine deaminase inhibitor (1 and 10 mg/kg, i.p.) also caused an antidepressant-like effect in the FST. These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.

  3. A D-π-A1-π-A2 push-pull small molecule donor for solution processed bulk heterojunction organic solar cells.

    PubMed

    Gautam, Prabhat; Misra, Rajneesh; Biswas, Subhayan; Sharma, Ganesh D

    2016-05-18

    Herein, benzothiadiazole (BTD), as an acceptor A1, has been used as a backbone to link triphenylamine (TPA) as donor and naphthalimide (NPI) as acceptor (A2) moieties through ethylene linkers to design a small molecule. The donor-π-acceptor-π-acceptor (D-π-A1-π-A2) type small molecule denoted as was synthesized. In order to use it as an electron donor for solution processed bulk heterojunction small molecule solar cells its photonic and electronic properties were explored. The small molecule organic solar cells based on the optimized blend of with PC71BM processed in chloroform showed a power conversion efficiency (PCE) of 2.21%, which was significantly improved up to 6.67%, when a two-step annealing (TSA) treated blend was used as an active layer. The increase in the PCE was due to the enhancement in both Jsc and FF. The improvement in Jsc was related to the enhancement in the light harvesting efficiency of a TSA treated active layer relative to the as-cast layer, which is reflected in a better IPCE and better charge collection. The TSA treatment also leads to better nanoscale morphology for exciton dissociation into free charge carriers and improved crystallinity for balanced charge transport.

  4. Two families with Leber's hereditary optic neuropathy carrying G11778A and T14502C mutations with haplogroup H2a2a1 in mitochondrial DNA.

    PubMed

    Qiao, Chen; Wei, Tanwei; Hu, Bo; Peng, Chunyan; Qiu, Xueping; Wei, Li; Yan, Ming

    2015-08-01

    The mitochondrial haplogroup has been reported to affect the clinical expression of Leber's hereditary optic neuropathy (LHON). The present study aimed to investigate the interaction between mutations and the haplogroup of mitochondrial DNA (mtDNA) in families. Two unrelated families with LHON were enrolled in the study, and clinical, genetic and molecular characterizations were determined in the affected and unaffected family members. Polymerase chain reaction direct sequencing was performed using 24 pairs of overlapping primers for whole mtDNA to screen for mutations and haplogroup. Bioinformatics analysis was performed to evaluate the pathogenic effect of these mtDNA mutations and the haplogroup. The G11778A mutation was identified in the two families. In addition, the members of family 2 exhibited the T14502C mutation and those in family 1 exhibited the T3394C and T14502C mutations, which were regarded as secondary mutations. The penetrance of visual loss in families 1 and 2 were 30.8 and 33.3%, respectively. In addition, the two families were found to be in the H2a2a1 haplogroup. In this limited sample size, it was demonstrated that the H2a2a1 haplogroup had a possible protective effect against LHON. Additional modifying factors, including environmental factors, lifestyle, estrogen levels and nuclear genes may also be important in LHON.

  5. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

    PubMed Central

    Amin, N; Byrne, E; Johnson, J; Chenevix-Trench, G; Walter, S; Nolte, I M; Vink, J M; Rawal, R; Mangino, M; Teumer, A; Keers, J C; Verwoert, G; Baumeister, S; Biffar, R; Petersmann, A; Dahmen, N; Doering, A; Isaacs, A; Broer, L; Wray, N R; Montgomery, G W; Levy, D; Psaty, B M; Gudnason, V; Chakravarti, A; Sulem, P; Gudbjartsson, D F; Kiemeney, L A; Thorsteinsdottir, U; Stefansson, K; van Rooij, F J A; Aulchenko, Y S; Hottenga, J J; Rivadeneira, F R; Hofman, A; Uitterlinden, A G; Hammond, C J; Shin, S-Y; Ikram, A; Witteman, J C M; Janssens, A C J W; Snieder, H; Tiemeier, H; Wolfenbuttel, B H R; Oostra, B A; Heath, A C; Wichmann, E; Spector, T D; Grabe, H J; Boomsma, D I; Martin, N G; van Duijn, C M

    2012-01-01

    Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10−11 and 2.7 × 10−11), which were also in strong linkage disequilibrium (r2=0.7) with each other, lie in the 23-kb long commonly shared 5′ flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10−09) near NRCAM—a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10−09)—an SNP associated with blood pressure—in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10−05) and Parkinson's disease pathways (P-value=3.6 × 10−05). PMID:21876539

  6. Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody-inhibited β-adrenergic mucin secretion response

    PubMed Central

    Pereira, M M C; Lloyd Mills, C; Dormer, R L; McPherson, M A

    1998-01-01

    The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated β-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β-adrenergic response and whether excessive cyclic AMP rise is required.CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured.The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion.DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion.CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism.DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not.Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis. PMID:9831904

  7. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    PubMed

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type.

  8. Down-regulation of adenosine A1 and A2A receptors in peripheral cells from idiopathic normal-pressure hydrocephalus patients.

    PubMed

    Casati, Martina; Arosio, Beatrice; Gussago, Cristina; Ferri, Evelyn; Magni, Lorenzo; Assolari, Lara; Scortichini, Valeria; Nani, Carolina; Rossi, Paolo Dionigi; Mari, Daniela

    2016-02-15

    Idiopathic normal-pressure hydrocephalus (iNPH) is a neurological disease that usually develops in the elderly. Natural history of iNPH is still unknown. It has been hypothesized that cerebrovascular diseases could have a role in etiology of chronic hydrocephalus and studies show an increased prevalence of cardiovascular diseases in iNPH patients. Moreover, evidences show a possible alteration of immune system in iNPH patients. Adenosine (Ado) is a metabolite produced in response to metabolic stress and injury. Adenosine and its receptors play an important role in vascular protection and in the modulation of inflammatory reactions and neuroinflammation. Our aim is to evaluate gene and protein expression of A1R and A2AR in the peripheral blood mononuclear cells (PBMCs) from iNPH patients compared to control subjects. We investigate if Ado system, that plays an important role in central nervous system, in vascular system, and also in inflammation, is involved in pathophysiology of iNPH disease. Our analysis showed that A1R mRNA levels and A1R density in PBMCs from iNPH patients were significantly lower than CT subjects (0.84 ± 0.12 and 2.42 ± 0.42, p<0.001 and 0.31 ± 0.02 and 0.42 ± 0.04, p=0.043; respectively). About A2AR, the gene expression in PBMCs was significantly lower in iNPH than CT (0.65 ± 0.09 and 1.5 ± 0.14, p<0.001) as well as there was a trend in protein expression: iNPH and CT (0.51 ± 0.05 and 0.62 ± 0.03; p=0.172). This preliminary study underlines the involvement of Ado system in iNPH disease whose pathophysiology is still unclear.

  9. Opposite modulation of 4-aminopyridine and hypoxic hyperexcitability by A1 and A2 adenosine receptor ligands in rat hippocampal slices.

    PubMed

    Longo, R; Zeng, Y C; Sagratella, S

    1995-11-10

    The effects of the adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), and of the adenosine agonists N6-cyclopentyladenosine (CPA), N6-(2-phenylisopropyl)adenosine (R-PIA), and 2-[p-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) were investigated on the hyperexcitability induced in the CA1 area of rat hippocampal slices by hypoxia or the epileptogenic agent 4-aminopiridine. Slice perfusion with the mixed adenosine receptor agonist R-PIA (0.2 microM) significantly (P < 0.05) decreased: (i) the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period; (ii) the duration of the hypoxia-induced epileptiform bursting. Conversely, slice perfusion with the selective A1 adenosine receptor antagonists DPCPX (0.2 microM) or with the selective A2 adenosine receptor agonist CGS 21680 significantly (P < 0.05) increased the number of slices showing a transient CA1 epileptiform bursting during the hypoxic period but did not affect the duration of the hypoxia-induced epileptiform bursting. Neither drug significantly affected the number of slices showing functional recovery after hypoxia. Slice perfusion with DPCPX (0.2 microM) also significantly increased (P < 0.05) the number of slices showing a persistent CA1 epileptiform bursting during the reoxygenation period, while the other drugs failed to affect it. Slice perfusion with the selective A1 adenosine receptor agonist CPA (2 microM) or R-PIA (5 microM) significantly (P < 0.05) decreased the duration of the CA1 epileptiform bursting induced by 100 microM 4-aminopyridine. CGS 21680 (5 microM) perfused together with CPA (2 microM) significantly (P < 0.05) counteracted the inhibitory effects of the A1 adenosine receptor agonist on 4-aminopyridine epileptiform bursting, while it failed by itself to directly affect the 4-aminopyridine epileptiform bursting duration. The results produce evidence for a selective opposite modulation by A1 and A2 adenosine

  10. Oxidation of the flavonoids galangin and kaempferide by human liver microsomes and CYP1A1, CYP1A2, and CYP2C9.

    PubMed

    Otake, Yoko; Walle, Thomas

    2002-02-01

    There is very limited information on cytochrome P450 (P450)-mediated oxidative metabolism of dietary flavonoids in humans. In this study, we used human liver microsomes and recombinant P450 isoforms to examine the metabolism of two flavonols, galangin and kaempferide, and one flavone, chrysin. Both galangin and kaempferide, but not chrysin, were oxidized by human liver microsomes to kaempferol, with K(m) values of 9.5 and 17.8 microM, respectively. These oxidations were catalyzed mainly by CYP1A2 but also by CYP2C9. Consistent with these observations, the human liver microsomal metabolism of galangin and kaempferide were inhibited by the P450 inhibitors furafylline and sulfaphenazole. In addition, CYP1A1, although less efficient, was also able to oxidize the two flavonols. Thus, dietary flavonols are likely to undergo oxidative metabolism mainly in the liver but also extrahepatically.

  11. Dynamic hip screw versus proximal femur locking compression plate in intertrochanteric femur fractures (AO 31A1 and 31A2): A prospective randomized study

    PubMed Central

    Agrawal, Prabhat; Gaba, Sahil; Das, Saubhik; Singh, Ranjit; Kumar, Arvind; Yadav, Gajanand

    2017-01-01

    Introduction: Intertrochanteric fractures are common in elderly population and pose a significant financial burden to the society. Anatomically contoured proximal femur locking compression plate (PFLCP) is the latest addition in the surgeons’ armamentarium to deal with these fractures. It creates an angular stable construct, which will theoretically lessen the risk of failure by screw cut-out and varus collapse, the common mode of DHS failure. We compared DHS with PFLCP in AO type 31A1 and 31A2 intertrochanteric fractures. Materials and Methods: A randomized prospective study was carried out between June 2011 and June 2013. 26 cases each of DHS and PFLCP were included. Results: Functional and radiological outcome was similar in both groups. Conclusion: Both DHS and PFLCP are good choices for stable intertrochanteric fractures, and both lead to excellent functional outcomes, but non-union might be more common with PFLCP.

  12. Pulmonary surfactant synthesis in miRNA-26a-1/miRNA-26a-2 double knockout mice generated using the CRISPR/Cas9 system

    PubMed Central

    Zhang, Ying-Hui; Wu, Li-Zhi; Liang, Hong-Lu; Yang, Yang; Qiu, Jie; Kan, Qing; Zhu, Wen; Ma, Cheng-Ling; Zhou, Xiao-Yu

    2017-01-01

    Pulmonary surfactant (PS), which is synthesized by type II alveolar epithelial cells (AECIIs), maintains alveolar integrity by reducing surface tension. Many premature neonates who lack adequate PS are predisposed to developing respiratory distress syndrome (RDS), one of the leading causes of neonatal morbidity and mortality. PS synthesis is influenced and regulated by various factors, including microRNAs. Previous in vitro studies have shown that PS synthesis is regulated by miR-26a in fetal rat AECIIs. This study aimed to investigate the role of miR-26a in PS synthesis in vivo. To obtain a miR-26a-1/miR-26a-2 double knockout mouse model, we used the clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9 (CRISPR/Cas9) system, an important genome editing technology. Real-time PCR was performed to determine the miR-26a levels in various organs, as well as the mRNA levels of surfactant-associated proteins. Moreover, AECIIs and surfactant-associated proteins in lung tissues were analyzed by hematoxylin-eosin staining and immunohistochemistry. Homozygous offspring of miR-26a-1/miR-26a-2 double knockout mice generated using the CRISPR/Cas9 system were successfully obtained, and PS synthesis and the number of AECIIs were significantly increased in the miR-26a knockout mice. These results indicate that miR-26a plays an important role in PS synthesis in AECIIs. PMID:28337265

  13. Pharmacokinetic and pharmacodynamic consequences of inhibition of terazosin metabolism via CYP3A1 and/or 3A2 by DA-8159, an erectogenic, in rats

    PubMed Central

    Oh, E Y; Bae, S K; Kwon, J W; You, M; Lee, D C; Lee, M G

    2007-01-01

    Background and purpose: Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting alpha blocker). Therefore, this study was performed with DA-8159 (a long acting PDE 5 inhibitor) and terazosin in rats to find whether or not pharmacokinetic and pharmacodynamic interactions between the two drugs were observed. Experimental approach: Pharmacokinetic and pharmacodynamic (changes in blood pressure) interactions between DA-8159 and terazosin were evaluated after simultaneous i.v. and p.o. administration of DA-8159 (30 mg kg−1) and terazosin (5 mg kg−1) to male Sprague–Dawley rats. Key results: After simultaneous i.v. and p.o. administration of terazosin and DA-8159, the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of terazosin became significantly greater (57.4 and 75.4% increase for i.v. and p.o. administration, respectively) than those of without DA-8159. The blood pressure dropping effect was considerable after simultaneous p.o. administration of DA-8159 and terazosin compared with each drug alone. Conclusions and implications: The significantly greater AUC of terazosin after both simultaneous i.v. and p.o. administration of both drugs could be due to the hepatic (both i.v. and p.o.) and intestinal (p.o.) inhibition of the metabolism of terazosin via CYP3A1 and/or 3A2 by DA-8159, since both DA-8159 and terazosin are metabolized via CYP3A1 and/or 3A2 in rats. The blood pressure lowering effect after simultaneous p.o. administration of both drugs could be due to significant increase in plasma concentrations of terazosin. PMID:17351661

  14. Cloning and structural analysis of two highly divergent IgA isotypes, IgA1 and IgA2 from the duck billed platypus, Ornithorhynchus anatinus.

    PubMed

    Vernersson, M; Belov, K; Aveskogh, M; Hellman, L

    2010-01-01

    To trace the emergence of modern IgA isotypes during vertebrate evolution we have studied the immunoglobulin repertoire of a model monotreme, the platypus. Two highly divergent IgA-like isotypes (IgA1 and IgA2) were identified and their primary structures were determined from full-length cDNAs. A comparative analysis of the amino acid sequences for IgA from various animal species showed that the two platypus IgA isotypes form a branch clearly separated from their eutherian (placental) counterparts. However, they still conform to the general structure of eutherian IgA, with a hinge region and three constant domains. This indicates that the deletion of the second domain and the formation of a hinge region in IgA did occur very early during mammalian evolution, more than 166 million years ago. The two IgA isotypes in platypus differ in primary structure and appear to have arisen from a very early gene duplication, possibly preceding the metatherian eutherian split. Interestingly, one of these isotypes, IgA1, appears to be expressed in only the platypus, but is present in the echidna based on Southern blot analysis. The platypus may require a more effective mucosal immunity, with two highly divergent IgA forms, than the terrestrial echidna, due to its lifestyle, where it is exposed to pathogens both on land and in the water.

  15. Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation

    PubMed Central

    Corley, Susan M.; Wilkins, Marc R.; Shannon Weickert, Cynthia

    2016-01-01

    Many genes are differentially expressed in the cortex of people with schizophrenia, implicating factors that control transcription more generally. Hormone nuclear receptors dimerize to coordinate context-dependent changes in gene expression. We hypothesized that members of two families of nuclear receptors (NR4As), and retinoid receptors (RARs and RXRs), are altered in the dorsal lateral prefrontal cortex (DLPFC) of people with schizophrenia. We used next generation sequencing and then qPCR analysis to test for changes in mRNA levels for transcripts encoding nuclear receptors: orphan nuclear receptors (3 in the NR4A, 3 in the RAR, 3 in the RXR families and KLF4) in total RNA extracted from the DLPFC from people with schizophrenia compared to controls (n = 74). We also correlated mRNA levels with demographic factors and with estimates of antipsychotic drug exposure (schizophrenia group only). We tested for correlations between levels of transcription factor family members and levels of genes putatively regulated by these transcription factors. We found significantly down regulated expression of NR4A1 (Nurr 77) and KLF4 mRNAs in people with schizophrenia compared to controls, by both NGS and qPCR (p = or <0.01). We also detected decreases in NR4A2 (Nurr1) and RXRB mRNAs by using qPCR in the larger cohort (p<0.05 and p<0.01, respectively). We detected decreased expression of RARG and NR4A2 mRNAs in females with schizophrenia (p<0.05). The mRNA levels of NR4A1, NR4A2 and NR4A3 were all negative correlated with lifetime estimates of antipsychotic exposure. These novel findings, which may be influenced by antipsychotic drug exposure, implicate the orphan and retinoid nuclear receptors in the cortical pathology found in schizophrenia. Genes down stream of these receptors can be dysregulated as well, but the direction of change is not immediately predictable based on the putative transcription factor changes. PMID:27992436

  16. Analysis of the Rotationally Resolved, Non-Degenerate (a''_1) and Degenerate (e') Vibronic Bands in the tilde{A}^2E'' ← tilde{X}^2A'_2 Transition of NO_3.

    NASA Astrophysics Data System (ADS)

    Tran, Henry; Miller, Terry A.

    2016-06-01

    The magnitude of the Jahn-Teller (JT) effect in NO_3 has been the subject of considerable research in our group and other groups around the world. The rotational contour of the 4^1_0 vibronic band was first described by Hirota and coworkers using an oblate symmetric top. Near-infrared band of the nitrate radical NO_3 observed by diode laser spectroscopy. J. Chem. Phys., 107:2829, 1997.} Deev et al. argued that an asymmetric top was required to describe the 2^1_0 band, although their spectrum was not completely rotationally resolved. These discrepancies suggest that a rotational analysis will provide considerable experimental information on the geometry of NO_3. Our group has collected high-resolution, rotationally resolved spectra of the vibronic tilde{A}^2E'' ← tilde{X}^2A'_2 transitions. We have completed analysis of the 3^1_0 and 3^1_04^1_0 parallel bands with a_1'' symmetry by using an oblate symmetric top with spin-rotation and centrifugal distortions. Several other parallel bands are now also reasonably understood. This analysis is consistent with a D3h geometry for NO_3. In order to analyze the perpendicular bands with e' symmetry, we have adapted the oblate symmetric top Hamiltonian from the previous analysis to include spin-orbit coupling, coriolis coupling, and Watson Terms (JT distortions) that allow the oblate symmetric top Hamiltonian to transition continuously to the distorted limit of C2v symmetry. Preliminary analysis of the 2^1_0 and 2^1_04^2_0 bands has shown generally good agreement between model and experimental spectra. Our results indicate only modest JT distortions, although we do find evidence of multiple perturbations between these bands and high vibrational levels of the tilde{X} state. We will present our adapted Hamiltonian and the analysis of the 3^1_0, 3^1_04^1_0, 2^1_0, and 2^1_04^2_0 bands. E. Hirota, T. Ishiwata, K. Kawaguchi, M. Fujitake, N. Ohashi, and I. Tanaka. Near-infrared band of the nitrate radical NO_3 observed by diode

  17. Formation of DNA adducts in wild-type and transgenic mice expressing human sulfotransferases 1A1 and 1A2 after oral exposure to furfuryl alcohol

    PubMed Central

    Høie, Anja Hortemo; Monien, Bernhard Hans; Sakhi, Amrit Kaur; Glatt, Hansruedi; Hjertholm, Hege; Husøy, Trine

    2015-01-01

    Furfuryl alcohol (FFA) is present in many heat-treated foods as a result of its formation via dehydration of pentoses. It is also used legally as a flavouring agent. In an inhalation study conducted in the National Toxicology Program, FFA showed some evidence of carcinogenic activity in rats and mice. FFA was generally negative in conventional genotoxicity assays, which suggests that it may be a non-genotoxic carcinogen. However, it was recently found that FFA is mutagenic in Salmonella strains expressing appropriate sulfotransferases (SULTs), such as human or mouse SULT1A1. The same DNA adducts that were formed by FFA in these strains, mainly N 2-((furan-2-yl)methyl)-2′-deoxyguanosine (N 2-MF-dG), were also detected in tissues of FFA-exposed mice and even in human lung specimens. In the present study, a single oral dose of FFA (250mg/kg body weight) or saline was administered to FVB/N mice and transgenic mice expressing human SULT1A1/1A2 on the FVB/N background. The transgenic mice were used, since human and mouse SULT1A1 substantially differ in substrate specificity and tissue distribution. DNA adducts were studied in liver, kidney, proximal and distal small intestine as well as colon, using isotope-dilution ultra performance liquid chromatography (UPLC–MS/MS). Surprisingly, low levels of adducts that may represent N 2-MF-dG were detected even in tissues of untreated mice. FFA exposure enhanced the adduct levels in colon and liver, but not in the remaining investigated tissues of wild-type (wt) mice. The situation was similar in transgenic mice, except that N 2-MF-dG levels were also strongly enhanced in the proximal small intestine. These different results between wt and transgenic mice may be attributed to the fact that human SULT1A1, but not the orthologous mouse enzyme, is strongly expressed in the small intestine. PMID:25904584

  18. Formation of DNA adducts in wild-type and transgenic mice expressing human sulfotransferases 1A1 and 1A2 after oral exposure to furfuryl alcohol.

    PubMed

    Høie, Anja Hortemo; Monien, Bernhard Hans; Sakhi, Amrit Kaur; Glatt, Hansruedi; Hjertholm, Hege; Husøy, Trine

    2015-09-01

    Furfuryl alcohol (FFA) is present in many heat-treated foods as a result of its formation via dehydration of pentoses. It is also used legally as a flavouring agent. In an inhalation study conducted in the National Toxicology Program, FFA showed some evidence of carcinogenic activity in rats and mice. FFA was generally negative in conventional genotoxicity assays, which suggests that it may be a non-genotoxic carcinogen. However, it was recently found that FFA is mutagenic in Salmonella strains expressing appropriate sulfotransferases (SULTs), such as human or mouse SULT1A1. The same DNA adducts that were formed by FFA in these strains, mainly N (2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N (2)-MF-dG), were also detected in tissues of FFA-exposed mice and even in human lung specimens. In the present study, a single oral dose of FFA (250 mg/kg body weight) or saline was administered to FVB/N mice and transgenic mice expressing human SULT1A1/1A2 on the FVB/N background. The transgenic mice were used, since human and mouse SULT1A1 substantially differ in substrate specificity and tissue distribution. DNA adducts were studied in liver, kidney, proximal and distal small intestine as well as colon, using isotope-dilution ultra performance liquid chromatography (UPLC-MS/MS). Surprisingly, low levels of adducts that may represent N (2)-MF-dG were detected even in tissues of untreated mice. FFA exposure enhanced the adduct levels in colon and liver, but not in the remaining investigated tissues of wild-type (wt) mice. The situation was similar in transgenic mice, except that N (2)-MF-dG levels were also strongly enhanced in the proximal small intestine. These different results between wt and transgenic mice may be attributed to the fact that human SULT1A1, but not the orthologous mouse enzyme, is strongly expressed in the small intestine.

  19. Energetics and kinetics of phase transition between a 2H and a 1T MoS2 monolayer-a theoretical study.

    PubMed

    Zhao, Wen; Ding, Feng

    2017-02-09

    Phase transitions between semiconducting 2H and metallic 1T (or 1T') molybdenum disulphides (MoS2) are explored comprehensively by first-principles calculations. The nucleation of a 1T (or 1T') nucleus in a 2H MoS2 lattice, the formation of the 2H-1T (1T') interfaces and the kinetics of interface propagation during phase transition were thoroughly investigated in this study. It was found that, among various potential interface structures between the two phases, Mo-rich and two S-rich zigzag (ZZ) boundaries are energetically more preferable than others. Therefore, triangular or hexagonal 1T MoS2 domains with the three types of ZZ boundaries are expected to be the equilibrium structures of the 1T nucleus in a 2H lattice. Further exploration reveals a very high nucleation energy of the 1T phase which suggests that the nucleation may start from a defect site or the edge of the 2H phase. Besides, the kinetics of 2H-1T (1T') boundary propagation show that the growth rate of the ZZ boundaries is significantly slower than the armchair (AC) ones'. Therefore, the ZZ-boundary dominated domains are expected to be observed during the growth of the 1T phase while the rounded domains with various high-index edges are expected to be seen throughout shrinkage. This study reveals both the energetics and the kinetics of the phase transition of transition metal dichalcogenide materials and also sheds light on other 2D materials.

  20. Human Organic Cation Transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as Disposition Pathways for Fluoroquinolone Antimicrobials

    PubMed Central

    Mulgaonkar, Aditi; Venitz, Jürgen; Gründemann, Dirk

    2013-01-01

    Fluoroquinolones (FQs) are important antimicrobials that exhibit activity against a wide range of bacterial pathogens and excellent tissue permeation. They exist as charged molecules in biological fluids, and thus, their disposition depends heavily on active transport and facilitative diffusion. A recent review of the clinical literature indicated that tubular secretion and reabsorption are major determinants of their half-life in plasma, efficacy, and drug-drug interactions. In particular, reported in vivo interactions between FQs and cationic drugs affecting renal clearance implicated organic cation transporters (OCTs). In this study, 13 FQs, ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, and sparfloxacin, were screened for their ability to inhibit transport activity of human OCT1 (hOCT1) (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). All, with the exception of enoxacin, significantly inhibited hOCT1-mediated uptake under initial test conditions. None of the FQs inhibited hOCT2, and only moxifloxacin inhibited hOCT3 (∼30%), even at a 1,000-fold excess. Gatifloxacin, moxifloxacin, prulifloxacin, and sparfloxacin were determined to be competitive inhibitors of hOCT1. Inhibition constants (Ki) were estimated to be 250 ± 18 μM, 161 ± 19 μM, 136 ± 33 μM, and 94 ± 8 μM, respectively. Moxifloxacin competitively inhibited hOCT3-mediated uptake, with a Ki value of 1,598 ± 146 μM. Despite expression in enterocytes (luminal), hepatocytes (sinusoidal), and proximal tubule cells (basolateral), hOCT3 does not appear to contribute significantly to FQ disposition. However, hOCT1 in the sinusoidal membrane of hepatocytes, and potentially the basolateral membrane of proximal tubule cells, is likely to play a role in the disposition of these antimicrobial agents. PMID:23545524

  1. Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye.

    PubMed

    Hopfer, Ulrike; Fukai, Naomi; Hopfer, Helmut; Wolf, Gunter; Joyce, Nancy; Li, En; Olsen, Bjorn R

    2005-08-01

    Collagen VIII is localized in subendothelial and subepithelial extracellular matrices. It is a major component of Descemet's membrane, a thick basement membrane under the corneal endothelium, where it forms a hexagonal lattice structure; a similar structure, albeit less extensive, may be formed in other basement membranes. We have examined the function of collagen VIII in mice by targeted inactivation of the genes encoding the two polypeptide subunits, Col8a1 and Col8a2. Analysis of these mice reveals no major structural defects in most organs, but demonstrates that type VIII collagen is required for normal anterior eye development, particularly the formation of a corneal stroma with the appropriate number of fibroblastic cell layers and Descemet's membrane of appropriate thickness. Complete lack of type VIII collagen leads to dysgenesis of the anterior segment of the eye: a globoid, keratoglobus-like protrusion of the anterior chamber with a thin corneal stroma. Descemet's membrane is markedly thinned. The corneal endothelial cells are enlarged and reduced in number, and show a decreased ability to proliferate in response to different growth factors in vitro. An important function of collagen VIII may therefore be to generate a peri- or subcellular matrix environment that permits or stimulates cell proliferation.

  2. Identification and Quantification of Fumonisin A1, A2, and A3 in Corn by High-Resolution Liquid Chromatography-Orbitrap Mass Spectrometry

    PubMed Central

    Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Harayama, Koichi; Toriba, Akira; Hayakawa, Kazuichi

    2015-01-01

    Three compounds, hypothesized as fumonisin A1 (FA1), fumonisin A2 (FA2), and fumonisin A3 (FA3), were detected in a corn sample contaminated with mycotoxins by high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS). One of them has been identified as FA1 synthesized by the acetylation of fumonisin B1 (FB1), and established a method for its quantification. Herein, we identified the two remaining compounds as FA2 and FA3, which were acetylated fumonisin B2 (FB2) and fumonisin B3 (FB3), respectively. Moreover, we examined a method for the simultaneous analysis of FA1, FA2, FA3, FB1, FB2, and FB3. The corn samples were prepared by extraction using a QuEChERS kit and purification using a multifunctional cartridge. The linearity, recovery, repeatability, limit of detection, and limit of quantification of the method were >0.99, 82.9%–104.6%, 3.7%–9.5%, 0.02–0.60 μg/kg, and 0.05–1.98 μg/kg, respectively. The simultaneous analysis of the six fumonisins revealed that FA1, FA2, and FA3 were present in all corn samples contaminated with FB1, FB2, and FB3. The results suggested that corn marketed for consumption can be considered as being contaminated with both the fumonisin B-series and with fumonisin A-series. This report presents the first identification and quantification of FA1, FA2, and FA3 in corn samples. PMID:25690692

  3. Cloning and expression analysis of two ROR-γ homologues (ROR-γa1 and ROR-γa2) in rainbow trout Oncorhynchus mykiss.

    PubMed

    Monte, Milena M; Wang, Tiehui; Costa, Maria M; Harun, Nor Omaima; Secombes, Chris J

    2012-08-01

    This paper describes the cloning and characterisation of two retinoid-related orphan receptor (ROR)-γ homologues (ROR-γa1 and -γa2) in rainbow trout (Oncorhynchus mykiss). The coding region predicted for both homologues consists of 1410 base pairs (bp), which translate into two 469 amino acid (aa) proteins. The trout ROR-γs revealed a high conservation of both DNA- and ligand-binding domains (functional regions of the nuclear receptor family), and shared a high homology to mammalian ROR-γt. A phylogenetic tree containing ROR family members confirmed that both trout homologues clustered within the ROR-γ group. Both results suggested that these molecules are likely to be ROR-γ homologues, more similar to the mammalian splice variant ROR-γt than the full length ROR-γ. Expression analysis of tissues obtained from healthy fish revealed highest constitutive expression of trout ROR-γ in muscle, followed by the brain, heart and skin. This suggests that these genes may play an important role in such tissues. In vitro studies, using trout cell lines, demonstrated that ROR-γ is induced significantly by LPS and down-regulated by the presence of PolyI:C and recombinant interferon (IFN)-γ. Moreover, analysis of this gene in head kidney macrophages and mixed primary leucocyte cultures indicated that differences were apparent between the different cell types/sources used, indicating that its expression may be cell-type dependent. Additional studies to investigate the regulation of this gene in vivo demonstrated that its expression was significantly higher in vaccinated vs unvaccinated fish following bacterial (Yersinia ruckeri) challenge but it was down-regulated after a viral (VHSV) infection. This suggests a potential role of trout ROR-γ, a putative T(H)17 transcription factor, in protection against extracellular bacteria.

  4. In vitro digestion of purified β-casein variants A(1), A(2), B, and I: effects on antioxidant and angiotensin-converting enzyme inhibitory capacity.

    PubMed

    Petrat-Melin, B; Andersen, P; Rasmussen, J T; Poulsen, N A; Larsen, L B; Young, J F

    2015-01-01

    Genetic polymorphisms of bovine milk proteins affect the protein profile of the milk and, hence, certain technological properties, such as casein (CN) number and cheese yield. However, reports show that such polymorphisms may also affect the health-related properties of milk. Therefore, to gain insight into their digestion pattern and bioactive potential, β-CN was purified from bovine milk originating from cows homozygous for the variants A(1), A(2), B, and I by a combination of cold storage, ultracentrifugation, and acid precipitation. The purity of the isolated β-CN was determined by HPLC, variants were verified by mass spectrometry, and molar extinction coefficients at λ=280nm were determined. β-Casein from each of the variants was subjected to in vitro digestion using pepsin and pancreatic enzymes. Antioxidant and angiotensin-converting enzyme (ACE) inhibitory capacities of the hydrolysates were assessed at 3 stages of digestion and related to that of the undigested samples. Neither molar extinction coefficients nor overall digestibility varied significantly between these 4 variants; however, clear differences in digestion pattern were indicated by gel electrophoresis. In particular, after 60min of pepsin followed by 5min of pancreatic enzyme digestion, one ≈4kDa peptide with the N-terminal sequence (106)H-K-E-M-P-F-P-K- was absent from β-CN variant B. This is likely a result of the (122)Ser to (122)Arg substitution in variant B introducing a novel trypsin cleavage site, leading to the changed digestion pattern. All investigated β-CN variants exhibited a significant increase in antioxidant capacity upon digestion, as measured by the Trolox-equivalent antioxidant capacity assay. After 60min of pepsin + 120min of pancreatic enzyme digestion, the accumulated increase in antioxidant capacity was ≈1.7-fold for the 4 β-CN variants. The ACE inhibitory capacity was also significantly increased by digestion, with the B variant reaching the highest inhibitory

  5. Structural investigation of the A-site vacancy in scheelites and the luminescence behavior of two continuous solid solutions A(1-1.5x)Eu(x)□(0.5x)WO₄ and A(0.64-0.5y)Eu(0.24)Li(y)□(0.12-0.5y)WO₄ (A = Ca, Sr; □ = vacancy).

    PubMed

    Jiang, Pengfei; Gao, Wenliang; Cong, Rihong; Yang, Tao

    2015-04-07

    Scheelite compounds with Eu(3+) substitution are well-known red-phosphors. We prepared and performed a detailed structural characterization of A(1-1.5x)Eu(x)□(0.5x)WO4 and A(0.64-0.5y)Eu(0.24)Li(y)□(0.12-0.5y)WO4 (A = Ca, Sr; □ = vacancy) to confirm the A-site vacancy mechanism for charge balance when bivalent A cations were substituted by Eu(3+). All compounds crystallize in I4₁/a with a disordered arrangement of A(2+), Eu(3+), □ at the A-site. The title compounds are all good red phosphors with a high R/O ratio (∼10), indicating that Eu(3+) is located at a significantly distorted cavity. A(1-1.5x)Eu(x)□(0.5x)WO4 shows a saturation phenomenon at a high doping level, x = 0.20. With the incorporation of Li(+), the emission intensity was generally enhanced compared to the Li(+)-free samples, moreover, an increase of the Li(+) content reduces the content of vacancies, resulting in further increase of the luminescence intensity.

  6. Maternal protein restriction during lactation modulated the expression and activity of rat offspring hepatic CYP1A1, CYP1A2, CYP2B1, CYP2B2, and CYP2E1 during development

    PubMed Central

    Da Costa, N. Meireles; Visoni, S.B.C.; Dos Santos, I.L.; Barja-Fidalgo, T.C.; Ribeiro-Pinto, L.F.

    2016-01-01

    Early nutrition plays a long-term role in the predisposition to chronic diseases and influences the metabolism of several drugs. This may happen through cytochromes P450 (CYPs) regulation, which are the main enzymes responsible for the metabolism of xenobiotics. Here, we analyzed the effects of maternal protein restriction (MPR) on the expression and activity of hepatic offspring’s CYPs during 90 days after birth, using Wistar rats as a mammal model. Hepatic CYP1A1, CYP1A2, CYP2B1, CYP2B2 and CYP2E1 mRNA and protein expression, and associated catalytic activities (ECOD, EROD, MROD, BROD, PROD and PNPH) were evaluated in 15-, 30-, 60-, and 90-day-old offspring from dams fed with either a 0% protein (MPR groups) or a standard diet (C groups) during the 10 first days of lactation. Results showed that most CYP genes were induced in 60- and 90-day-old MPR offspring. The inductions detected in MPR60 and MPR90 were of 5.0- and 2.0-fold (CYP1A2), 3.7- and 2.0-fold (CYP2B2) and 9.8- and 5.8– fold (CYP2E1), respectively, and a 3.8-fold increase of CYP2B1 in MPR90. No major alterations were detected in CYP protein expression. The most relevant CYP catalytic activities’ alterations were observed in EROD, BROD and PNPH. Nevertheless, they did not follow the same pattern observed for mRNA expression, except for an induction of EROD in MPR90 (3.5-fold) and of PNPH in MPR60 (2.2-fold). Together, these results suggest that MPR during lactation was capable of altering the expression and activity of the hepatic CYP enzymes evaluated in the offspring along development. PMID:27828666

  7. Maternal protein restriction during lactation modulated the expression and activity of rat offspring hepatic CYP1A1, CYP1A2, CYP2B1, CYP2B2, and CYP2E1 during development.

    PubMed

    Da Costa, N Meireles; Visoni, S B C; Dos Santos, I L; Barja-Fidalgo, T C; Ribeiro-Pinto, L F

    2016-01-01

    Early nutrition plays a long-term role in the predisposition to chronic diseases and influences the metabolism of several drugs. This may happen through cytochromes P450 (CYPs) regulation, which are the main enzymes responsible for the metabolism of xenobiotics. Here, we analyzed the effects of maternal protein restriction (MPR) on the expression and activity of hepatic offspring's CYPs during 90 days after birth, using Wistar rats as a mammal model. Hepatic CYP1A1, CYP1A2, CYP2B1, CYP2B2 and CYP2E1 mRNA and protein expression, and associated catalytic activities (ECOD, EROD, MROD, BROD, PROD and PNPH) were evaluated in 15-, 30-, 60-, and 90-day-old offspring from dams fed with either a 0% protein (MPR groups) or a standard diet (C groups) during the 10 first days of lactation. Results showed that most CYP genes were induced in 60- and 90-day-old MPR offspring. The inductions detected in MPR60 and MPR90 were of 5.0- and 2.0-fold (CYP1A2), 3.7- and 2.0-fold (CYP2B2) and 9.8- and 5.8- fold (CYP2E1), respectively, and a 3.8-fold increase of CYP2B1 in MPR90. No major alterations were detected in CYP protein expression. The most relevant CYP catalytic activities' alterations were observed in EROD, BROD and PNPH. Nevertheless, they did not follow the same pattern observed for mRNA expression, except for an induction of EROD in MPR90 (3.5-fold) and of PNPH in MPR60 (2.2-fold). Together, these results suggest that MPR during lactation was capable of altering the expression and activity of the hepatic CYP enzymes evaluated in the offspring along development.

  8. Design synthesis and evaluation of the inhibitory selectivity of novel trans-resveratrol analogues on human recombinant CYP1A1 CYP1A2 and CYP1B1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A series of trans-stilbene derivatives containing 4’-thiomethyl substituent were synthesized and evaluated for inhibitory activities on human recombinant cytochrome P450(s): CYP1A1, CYP1A2, and CYP1B1. CYP1A2-related metabolism of stilbene derivatives was estimated by using NADPH oxidation assay. A...

  9. Active Site Mutations as a Suitable Tool Contributing to Explain a Mechanism of Aristolochic Acid I Nitroreduction by Cytochromes P450 1A1, 1A2 and 1B1

    PubMed Central

    Milichovský, Jan; Bárta, František; Schmeiser, Heinz H.; Arlt, Volker M.; Frei, Eva; Stiborová, Marie; Martínek, Václav

    2016-01-01

    Aristolochic acid I (AAI) is a plant drug found in Aristolochia species that causes aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI is activated via nitroreduction producing genotoxic N-hydroxyaristolactam, which forms DNA adducts. The major enzymes responsible for the reductive bioactivation of AAI are NAD(P)H:quinone oxidoreductase and cytochromes P450 (CYP) 1A1 and 1A2. Using site-directed mutagenesis we investigated the possible mechanisms of CYP1A1/1A2/1B1-catalyzed AAI nitroreduction. Molecular modelling predicted that the hydroxyl groups of serine122/threonine124 (Ser122/Thr124) amino acids in the CYP1A1/1A2-AAI binary complexes located near to the nitro group of AAI, are mechanistically important as they provide the proton required for the stepwise reduction reaction. In contrast, the closely related CYP1B1 with no hydroxyl group containing residues in its active site is ineffective in catalyzing AAI nitroreduction. In order to construct an experimental model, mutant forms of CYP1A1 and 1A2 were prepared, where Ser122 and Thr124 were replaced by Ala (CYP1A1-S122A) and Val (CYP1A2-T124V), respectively. Similarly, a CYP1B1 mutant was prepared in which Ala133 was replaced by Ser (CYP1B1-A133S). Site-directed mutagenesis was performed using a quickchange approach. Wild and mutated forms of these enzymes were heterologously expressed in Escherichia coli and isolated enzymes characterized using UV-vis spectroscopy to verify correct protein folding. Their catalytic activity was confirmed with CYP1A1, 1A2 and 1B1 marker substrates. Using 32P-postlabelling we determined the efficiency of wild-type and mutant forms of CYP1A1, 1A2, and 1B1 reconstituted with NADPH:CYP oxidoreductase to bioactivate AAI to reactive intermediates forming covalent DNA adducts. The S122A and T124V mutations in CYP1A1 and 1A2, respectively, abolished the efficiency of CYP1A1 and 1A2 enzymes to generate AAI-DNA adducts. In contrast

  10. Genomic characterization and dynamic methylation of promoter facilitates transcriptional regulation of H2A variants, H2A.1 and H2A.2 in various pathophysiological states of hepatocyte.

    PubMed

    Tyagi, Monica; Reddy, Divya; Gupta, Sanjay

    2017-02-03

    Differential expression of homomorphous variants of H2A family of histone H2A.1 and H2A.2 have been associated with hepatocellular carcinoma and maintenance of undifferentiated state of hepatocyte. However, not much is known about the transcriptional regulation of these H2A variants. The current study revealed the presence of 43bp 5'-regulatory region upstream of translation start site and a 26bp 3' stem loop conserved region for both the H2A.1 and H2A.2 variants. However, alignment of both H2A.1 and H2A.2 5'-untranslated region (UTR) sequences revealed no significant degree of homology between them despite the coding exon being very similar amongst the variants. Further, transient transfection coupled with dual luciferase assay of cloned 5' upstream sequences of H2A.1 and H2A.2 of length 1.2 (-1056 to +144) and 1.379kb (-1160 to +219) from experimentally identified 5'UTR in rat liver cell line (CL38) confirmed their promoter activity. Moreover, in silico analysis revealed a presence of multiple CpG sites interspersed in the cloned promoter of H2A.1 and a CpG island near TSS for H2A.2, suggesting that histone variants transcription might be regulated epigenetically. Indeed, treatment with DNMT and HDAC inhibitors increased the expression of H2A.2 with no significant change in H2A.1 levels. Further, methyl DNA immunoprecipitation coupled with quantitative analysis of DNA methylation using real-time PCR revealed hypo-methylation and hyper-methylation of H2A.1 and H2A.2 respectively in embryonic and HCC compared to control adult liver tissue. Collectively, the data suggests that differential DNA methylation on histone promoters is a dynamic player regulating their expression status in different pathophysiological stages of liver.

  11. Operation JANGLE. Particle Studies. Projects 2.5a-1, 2.5a-2, 2.5a-3, 2. 8,

    DTIC Science & Technology

    1979-10-01

    destroy regularity of the size separation. For a similar reason, the housing packing must be kept well oiled to pre- vent leakage through the bearings. To...chemical composition and physical properties become more and more necessary as research in contamination-decontauination %easuft and inhalation ...magnification of approximately 520X was obtained usii.g a 431 B and L objective and a filer micrometer ocular. - 26 - PROJECT 2.5a-2 Th us. of oil innersion type

  12. HTR-PROTEUS Pebble Bed Experimental Program Cores 1, 1A, 2, and 3: Hexagonal Close Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    John D. Bess; Barbara H. Dolphin; James W. Sterbentz; Luka Snoj; Igor Lengar; Oliver Köberl

    2012-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. Four benchmark experiments were evaluated in this report: Cores 1, 1A, 2, and 3. These core configurations represent the hexagonal close packing (HCP) configurations of the HTR-PROTEUS experiment with a moderator-to-fuel pebble ratio of 1:2. Core 1 represents the only configuration utilizing ZEBRA control rods. Cores 1A, 2, and 3 use withdrawable, hollow, stainless steel control rods. Cores 1 and 1A are similar except for the use of different control rods; Core 1A also has one less layer of pebbles (21 layers instead of 22). Core 2 retains the first 16 layers of pebbles from Cores 1 and 1A and has 16 layers of moderator pebbles stacked above the fueled layers. Core 3 retains the first 17 layers of pebbles but has polyethylene rods inserted between pebbles to simulate water ingress. The additional partial pebble layer (layer 18) for Core 3 was not included as it was used for core operations and not the reported critical configuration. Cores 1, 1A, 2, and 3 were determined to be acceptable benchmark experiments.

  13. HTR-PROTEUS Pebble Bed Experimental Program Cores 1, 1A, 2, and 3: Hexagonal Close Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    John D. Bess; Barbara H. Dolphin; James W. Sterbentz; Luka Snoj; Igor Lengar; Oliver Köberl

    2013-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. Four benchmark experiments were evaluated in this report: Cores 1, 1A, 2, and 3. These core configurations represent the hexagonal close packing (HCP) configurations of the HTR-PROTEUS experiment with a moderator-to-fuel pebble ratio of 1:2. Core 1 represents the only configuration utilizing ZEBRA control rods. Cores 1A, 2, and 3 use withdrawable, hollow, stainless steel control rods. Cores 1 and 1A are similar except for the use of different control rods; Core 1A also has one less layer of pebbles (21 layers instead of 22). Core 2 retains the first 16 layers of pebbles from Cores 1 and 1A and has 16 layers of moderator pebbles stacked above the fueled layers. Core 3 retains the first 17 layers of pebbles but has polyethylene rods inserted between pebbles to simulate water ingress. The additional partial pebble layer (layer 18) for Core 3 was not included as it was used for core operations and not the reported critical configuration. Cores 1, 1A, 2, and 3 were determined to be acceptable benchmark experiments.

  14. The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Myocardial Infarction: A Meta-Analysis

    PubMed Central

    Floyd, Christopher N.; Mustafa, Agnesa; Ferro, Albert

    2014-01-01

    Background The PlA2 polymorphism of glycoprotein IIIa (GPIIIa) has been previously identified as being associated with myocardial infarction (MI), but whether this represents a true association is entirely unclear due to differences in findings from different studies. We performed a meta-analysis to evaluate whether this polymorphism is a risk factor for MI. Methods Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where acute coronary events were recorded in association with genetic analysis, pooled odds ratios (ORs) were calculated using fixed-effects and random-effects models. The primary outcome measure was MI, and a secondary analysis was also performed for acute coronary syndromes (ACS) more generally. Findings 57 studies were eligible for statistical analysis and included 17,911 cases and 24,584 controls. Carriage of the PlA2 allele was significantly associated with MI (n = 40,692; OR 1.077, 95% CI 1.024–1.132; p = 0.004) but with significant publication bias (p = 0.040). The degree of association with MI increased with decreasing age of subjects (≤45 years old: n = 9,547; OR 1.205, 95% CI 1.067–1.360; p = 0.003) and with adjustment of data for conventional cardiovascular risk factors (n = 12,001; OR 1.240, 95% CI 1.117–1.376; p<0.001). There was a low probability of publication bias for these subgroup analyses (all p<0.05). Conclusions The presence of significant publication bias makes it unclear whether the association between carriage of the PlA2 allele and MI is true for the total population studied. However for younger subjects, the relative absence of conventional cardiovascular risk factors results in a significant association between carriage of the PlA2 allele and MI. PMID:24988220

  15. 75 FR 76624 - Airworthiness Directives; Rolls-Royce Deutschland Ltd & Co KG Models BR700-710A1-10; BR700-710A2...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-09

    ... (Service Bulletin (SB) No. SB-BR700-72- 101466 not incorporated). BRR23952 BR700-710C4-11 (SB No. 3,800 SB...,200 BRR23953 BR700-710C4-11 (SB No. 6,200 SB-BR700-72-101466 not incorporated). BRR23953 BR700-710C4-11 (SB No. 3,800 SB-BR700-72-101466 incorporated). BRR23954 BR700-710A1-10........ 6,200...

  16. Pyranoflavones: A Group of Small-molecule Probes for Exploring the Active Site Cavities of Cytochrome P450 Enzymes 1A1, 1A2, and 1B1

    PubMed Central

    Liu, Jiawang; Taylor, Shannon F.; Dupart, Patrick S.; Arnold, Corey L.; Sridhar, Jayalakshmi; Jiang, Quan; Wang, Yuji; Skripnikova, Elena V.; Zhao, Ming; Foroozesh, Maryam

    2013-01-01

    Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes towards P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor, 5-hydroxy-4′-propargyloxyflavone (5H4′FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. Alpha-naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while beta-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively. PMID:23600958

  17. Solution structure determination of monomeric human IgA2 by X-ray and neutron scattering, analytical ultracentrifugation and constrained modelling: a comparison with monomeric human IgA1.

    PubMed

    Furtado, Patricia B; Whitty, Patrick W; Robertson, Alexis; Eaton, Julian T; Almogren, Adel; Kerr, Michael A; Woof, Jenny M; Perkins, Stephen J

    2004-05-14

    Immunoglobulin A (IgA), the most abundant human immunoglobulin, mediates immune protection at mucosal surfaces as well as in plasma. It exists as two subclasses IgA1 and IgA2, and IgA2 is found in at least two allotypic forms, IgA2m(1) or IgA2m(2). Compared to IgA1, IgA2 has a much shorter hinge region, which joins the two Fab and one Fc fragments. In order to assess its solution structure, monomeric recombinant IgA2m(1) was studied by X-ray and neutron scattering. Its Guinier X-ray radius of gyration R(G) is 5.18 nm and its neutron R(G) is 5.03 nm, both of which are significantly smaller than those for monomeric IgA1 at 6.1-6.2 nm. The distance distribution function P(r)for IgA2m(1) showed a broad peak with a subpeak and gave a maximum dimension of 17 nm, in contrast to the P(r) curve for IgA1, which showed two distinct peaks and a maximum dimension of 21 nm. The sedimentation coefficients of IgA1 and IgA2m(1) were 6.2S and 6.4S, respectively. These data show that the solution structure of IgA2m(1) is significantly more compact than IgA1. The complete monomeric IgA2m(1) structure was modelled using molecular dynamics to generate random IgA2 hinge structures, to which homology models for the Fab and Fc fragments were connected to generate 10,000 full models. A total of 104 compact best-fit IgA2m(1) models gave good curve fits. These best-fit models were modified by linking the two Fab light chains with a disulphide bridge that is found in IgA2m(1), and subjecting these to energy refinement to optimise this linkage. The averaged solution structure of the arrangement of the Fab and Fc fragments in IgA2m(1) was found to be predominantly T-shaped and flexible, but also included Y-shaped structures. The IgA2 models show full steric access to the two FcalphaRI-binding sites at the Calpha2-Calpha3 interdomain region in the Fc fragment. Since previous scattering modelling had shown that IgA1 also possessed a flexible T-shaped solution structure, such a T-shape may be

  18. Earth Observing System/Advanced Microwave Sounding Unit-A (EOS/AMSU-A): Reliability prediction report for module A1 (channels 3 through 15) and module A2 (channels 1 and 2)

    NASA Technical Reports Server (NTRS)

    Geimer, W.

    1995-01-01

    This report documents the final reliability prediction performed on the Earth Observing System/Advanced Microwave Sounding Unit-A (EOS/AMSU-A). The A1 Module contains Channels 3 through 15, and is referred to herein as 'EOS/AMSU-A1'. The A2 Module contains Channels 1 and 2, and is referred herein as 'EOS/AMSU-A2'. The 'specified' figures were obtained from Aerojet Reports 8897-1 and 9116-1. The predicted reliability figure for the EOS/AMSU-A1 meets the specified value and provides a Mean Time Between Failures (MTBF) of 74,390 hours. The predicted reliability figure for the EOS/AMSU-A2 meets the specified value and provides a MTBF of 193,110 hours.

  19. Human natural killer cell microRNA: differential expression of MIR181A1B1 and MIR181A2B2 genes encoding identical mature microRNAs.

    PubMed

    Presnell, S R; Al-Attar, A; Cichocki, F; Miller, J S; Lutz, C T

    2015-01-01

    Natural killer (NK) and T lymphocytes share many properties, yet only NK cells respond rapidly to infection and cancer without pre-activation. We found that few microRNAs (miRNAs) differed significantly between human NK and T cells. Among those miRNAs, miR-181a and miR-181b levels rose during NK cell differentiation. Prior studies indicate that miR-181a and miR-181b are critical for human NK cell development and are co-transcribed from genes on chromosome 1 (MIR181A1B1) and on chromosome 9 (MIR181A2B2). We mapped human MIR181A1B1 and MIR181A2B2 transcription start sites to 78.3 kb and 34.0 kb upstream of the mature miRNAs, generating predominantly unspliced transcripts of 80-127 kb and ~60 kb, respectively. Unlike mouse thymocytes, human T cells expressed both MIR181A1B1 and MIR181A2B2. We tested the hypothesis that NK cells differentially transcribe the two genes during development and in response to immune regulatory cytokines. During NK-cell differentiation, MIR181A2B2 expression rose markedly and exceeded that of MIR181A1B1. TGF-β treatment increased NK-cell MIR181A2B2 transcription, whereas IL-2, IL-15 and IL-12/IL-18 treatments upregulated MIR181A1B1. The MIR181A2B2 promoter was strongly transactivated by SMAD3 and SMAD4 transcription factors, suggesting that TGF-β signaling upregulates MIR181A2B2 expression, at least in part, through SMAD-dependent promoter activation.

  20. Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2*

    PubMed Central

    Pallan, Pradeep S.; Nagy, Leslie D.; Lei, Li; Gonzalez, Eric; Kramlinger, Valerie M.; Azumaya, Caleigh M.; Wawrzak, Zdzislaw; Waterman, Michael R.; Guengerich, F. Peter; Egli, Martin

    2015-01-01

    Cytochrome P450 (P450) 17A enzymes play a critical role in the oxidation of the steroids progesterone (Prog) and pregnenolone (Preg) to glucocorticoids and androgens. In mammals, a single enzyme, P450 17A1, catalyzes both 17α-hydroxylation and a subsequent 17α,20-lyase reaction with both Prog and Preg. Teleost fish contain two 17A P450s; zebrafish P450 17A1 catalyzes both 17α-hydroxylation and lyase reactions with Prog and Preg, and P450 17A2 is more efficient in pregnenolone 17α-hydroxylation but does not catalyze the lyase reaction, even in the presence of cytochrome b5. P450 17A2 binds all substrates and products, although more loosely than P450 17A1. Pulse-chase and kinetic spectral experiments and modeling established that the two-step P450 17A1 Prog oxidation is more distributive than the Preg reaction, i.e. 17α-OH product dissociates more prior to the lyase step. The drug orteronel selectively blocked the lyase reaction of P450 17A1 but only in the case of Prog. X-ray crystal structures of zebrafish P450 17A1 and 17A2 were obtained with the ligand abiraterone and with Prog for P450 17A2. Comparison of the two fish P450 17A-abiraterone structures with human P450 17A1 (DeVore, N. M., and Scott, E. E. (2013) Nature 482, 116–119) showed only a few differences near the active site, despite only ∼50% identity among the three proteins. The P450 17A2 structure differed in four residues near the heme periphery. These residues may allow the proposed alternative ferric peroxide mechanism for the lyase reaction, or residues removed from the active site may allow conformations that lead to the lyase activity. PMID:25533464

  1. N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors.

    PubMed

    Drabczyńska, Anna; Müller, Christa E; Karolak-Wojciechowska, Janina; Schumacher, Britta; Schiedel, Anke; Yuzlenko, Olga; Kieć-Kononowicz, Katarzyna

    2007-07-15

    Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose.

  2. The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles.

    PubMed

    Squarcialupi, Lucia; Betti, Marco; Catarzi, Daniela; Varano, Flavia; Falsini, Matteo; Ravani, Annalisa; Pasquini, Silvia; Vincenzi, Fabrizio; Salmaso, Veronica; Sturlese, Mattia; Varani, Katia; Moro, Stefano; Colotta, Vittoria

    2017-12-01

    New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1-24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki = 11 nM) and good selectivity for the hA1 AR. The 5-(N(4)-substituted-piperazin-1-yl) derivatives 15-24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.[Formula: see text].

  3. Sequencing and characterization of mixed function monooxygenase genes CYP1A1 and CYP1A2 of Mink (Mustela vison) to facilitate study of dioxin-like compounds

    SciTech Connect

    Zhang Xiaowei; Moore, Jeremy N.; Newsted, John L.; Hecker, Markus Zwiernik, Matthew J.; Jones, Paul D.; Bursian, Steven J.

    2009-02-01

    As part of an ongoing effort to understand aryl hydrocarbon receptor (AhR) mediated toxicity in mink, cDNAs encoding for CYP1A1 and the CYP1A2 mixed function monooxygenases were cloned and characterized. In addition, the effects of selected dibenzofurans on the expression of these genes and the presence of their respective proteins (P4501A) were investigated, and then correlated with the catalytic activities of these proteins as measured by ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) activities. The predicted protein sequences for CYP1A1 and CYP1A2 comprise 517 and 512 amino acid residues, respectively. The phylogenetic analysis of the mink CYP1As with protein sequences of other mammals revealed high sequence homology with sea otter, seals and the dog, with amino acid identities ranging from 89 to 95% for CYP1A1 and 81 to 93% for CYP1A2. Since exposure to both 2,3,7,8-Tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) resulted in dose-dependent increases of CYP1A1 mRNA, CYP1A2 mRNA and CYP1A protein levels an underlying AhR-mediated mechanism is suggested. The up-regulation of CYP1A mRNA in liver was more consistent to the sum adipose TEQ concentration than to the liver TEQ concentration in minks treated with TCDF or PeCDF. The result suggested that the hepatic-sequestered fraction of PeCDF was biologically inactive to the induction of CYP1A1 and CYP1A2.

  4. STAT5a promotes the transcription of mature mmu-miR-135a in 3T3-L1 cells by binding to both miR-135a-1 and miR-135a-2 promoter elements.

    PubMed

    Wei, Xiajie; Cheng, Xiaoyan; Peng, Yongdong; Zheng, Rong; Chai, Jin; Jiang, Siwen

    2016-08-01

    Despite extensive research on the role of miR-135a in biological processes, very little attention has been paid to the regulation of its transcription. We have previously reported that miR-135a suppresses 3T3-L1 preadipocyte differentiation and adipogenesis by directly targeting the adenomatous polyposis coli (APC) gene and activating the canonical Wnt/β-catenin signaling pathway, but the regulatory elements that regulate the expression of the two isoforms of miR-135a (miR-135a-1 and miR-135a-2) remain poorly understood. Here, by using deletion analysis, we predicted two binding sites (-874/-856 and -2020/-2002) for the transcription factor Signal Transducers and Activators of Transcription 5a (STAT5a) within the core promoters of miR-135a-1 and miR-135a-2 (-1128/-556 and -2264/-1773), and the subsequent site-directed mutagenesis indicated that the two STAT5a binding sites regulated the activity of the miR-135a-1 and miR-135a-2 promoters. The binding of STAT5a to the miR-135a-1/2 core promoters in vitro and in cell culture was identified by electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays. Overexpression and RNAi knockdown of STAT5a showed that the transcription factor regulated the endogenous miR-135a expression. Additionally, The expression time frame of STAT5a and APC indicated a potential negative feedback between them. In sum, the overall results from this study indicate that STAT5a regulates miR-135a transcription by binding to both miR-135a-1 and miR135a-2 promoter elements and the findings provide novel insights into the molecular regulatory mechanisms of miR-135a during adipogenesis.

  5. Effect of polyunsaturated fatty acids ω-3 on the induction of activity and expression of CYP1A1 and CYP1A2 genes in the liver of rats under the influence of indole-3-carbinol.

    PubMed

    Kravchenko, L V; Tutel'yan, V A; Trusov, N V; Guseva, G V; Aksenov, I V

    2014-01-01

    Supplementation of the ration with eicosapentaenoic and docosahexaenoic ω-3 polyunsaturated fatty acids (PUFA) in doses of 0.3 and 1 g/kg body weight for 4 weeks had no effect on ethoxyresorufin O-dealkylase (EROD) activity and expression of the CYP1A1 gene in male Wistar rats, but caused a dose-dependent increase in methoxyresorufin O-dealkylase (MROD) activity of CYP1A2 (by 28 and 73%, respectively) without significant changes in CYP1A2 mRNA expression. ω-3 PUFA had no effect on the indole-3-carbinol-induced (20 mg/kg body weight over the last 7 days of the experiment) EROD activity and expression of CYP1A1 mRNA. The indole-3-carbinol-induced MROD activity was shown to increase by 6.2 times in rats not receiving ω-3 PUFA and only by 3.9 and 2.7 times in animals receiving ω-3 PUFA. The indole-3-carbinol-induced expression of CYP1A2 mRNA slightly increased in animals receiving ω-3 PUFA. Our results suggest that the effect of ω-3 PUFA on the induced and basal activity of CYP1A2 is not related to modulation of CYP1A2 gene expression.

  6. Ethanol and 4-methylpyrazole increase DNA adduct formation of furfuryl alcohol in FVB/N wild-type mice and in mice expressing human sulfotransferases 1A1/1A2.

    PubMed

    Sachse, Benjamin; Meinl, Walter; Glatt, Hansruedi; Monien, Bernhard H

    2016-03-01

    Furfuryl alcohol (FFA) is a carcinogenic food contaminant, which is formed by acid- and heat-catalyzed degradation of fructose and glucose. The activation by sulfotransferases (SULTs) yields a DNA reactive and mutagenic sulfate ester. The most prominent DNA adduct, N(2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N(2)-MF-dG), was detected in FFA-treated mice and also in human tissue samples. The dominant pathway of FFA detoxification is the oxidation via alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The activity of these enzymes may be greatly altered in the presence of inhibitors or competitive substrates. Here, we investigated the impact of ethanol and the ADH inhibitor 4-methylpyrazole (4MP) on the DNA adduct formation by FFA in wild-type and in humanized mice that were transgenic for human SULT1A1/1A2 and deficient in the mouse (m) Sult1a1 and Sult1d1 genes (h1A1/1A2/1a1(-)/1d1(-)). The administration of FFA alone led to hepatic adduct levels of 4.5 N(2)-MF-dG/10(8) nucleosides and 33.6 N(2)-MF-dG/10(8) nucleosides in male and female wild-type mice, respectively, and of 19.6 N(2)-MF-dG/10(8) nucleosides and 95.4 N(2)-MF-dG/10(8) nucleosides in male and female h1A1/1A2/1a1(-)/1d1(-) mice. The coadministration of 1.6g ethanol/kg body weight increased N(2)-MF-dG levels by 2.3-fold in male and by 1.7-fold in female wild-type mice and by 2.5-fold in male and by 1.5-fold in female h1A1/1A2/1a1(-)/1d1(-) mice. The coadministration of 100mg 4MP/kg body weight had a similar effect on the adduct levels. These findings indicate that modulators of the oxidative metabolism, e.g. the drug 4MP or consumption of alcoholic beverages, may increase the genotoxic effects of FFA also in humans.

  7. Identification and analysis of the maize P700 chlorophyll a apoproteins PSI-A1 and PSI-A2 by high pressure liquid chromatography analysis and partial sequence determination.

    PubMed

    Fish, L E; Bogorad, L

    1986-06-25

    We recently described a pair of partially homologous maize chloroplast genes, one of which was shown to code for an apoprotein of the P700 chlorophyll a complex of photosystem I (Fish, L.E., Kück, U., and Bogorad, L. (1985) J. Biol. Chem. 260, 1413-1421). Two chlorophyll-free apoprotein bands from maize chlorophyll-protein complex I (CPI) can be resolved on lithium dodecyl sulfate (LDS)-urea polyacrylamide gels. Proteins in both bands react with antibodies prepared against CPI, but antibodies prepared against two synthetic peptides corresponding to predicted sequences of PSI-A1 react only with the upper band. The presence of products of the two genes, ps1A1 and ps1A2, in CPI was verified by analysis of cyanogen bromide (CNBr) fragments of the lower apoprotein band obtained from LDS-urea polyacrylamide gels by reverse-phase high pressure liquid chromatography. Amino-terminal sequencing of five CNBr fragments indicates that the lower band contains a product of the ps1A2 gene. The possibility of extensive processing was investigated because the apparent molecular masses of the maize CPI proteins are about 58-70 kDa on LDS-polyacrylamide gels rather than the predicted sizes of about 83 kDa. Antibodies against a synthetic peptide corresponding to a predicted sequence in PSI-A1 were used to determine that the amino-terminal end of PSI-A1 is intact beyond about position 52. The amino-terminal CNBr fragment of PSI-A2 was identified by sequencing, indicating that the amino-terminal end of PSI-A2 is not processed. The carboxyl-terminal CNBr fragment of PSI-A2 was also identified by sequencing. These results indicate that the PSI-A1 and PSI-A2 polypeptides are not extensively processed, although some processing at the carboxyl-terminal end has not been ruled out.

  8. TSU-16, (Z)-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, is a potent activator of aryl hydrocarbon receptor and increases CYP1A1 and CYP1A2 expression in human hepatocytes.

    PubMed

    Matsuoka-Kawano, Kazuaki; Yoshinari, Kouichi; Nagayama, Sekio; Yamazoe, Yasushi

    2010-04-15

    (Z)-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (TSU-16), is a potent anti-angiogenic agent that inhibits the tyrosine kinase of vascular endothelial growth factor receptor-2. In clinical trials with daily or twice weekly intravenous administration of TSU-16, its increased clearance was observed. To understand the mechanism underlying this observation, we have investigated the TSU-16-mediated regulation of cytochrome P450 expression. In human hepatocytes, TSU-16 increased mRNA levels of CYP1A1 and CYP1A2, but not CYP2B6 and CYP3A4. The extent of increase and profiles of the time-dependent changes in CYP1A1 and CYP1A2 mRNA levels after TSU-16 treatment were similar to those after treatment with 3-methylcholanthrene (3MC), a well-known activator of the aryl hydrocarbon receptor (AhR). In reporter assays using a plasmid construct that contained the human CYP1A1 5'-flanking region including the region crucial for the AhR-dependent transcription of both human CYP1A1 and CYP1A2, TSU-16 treatment increased reporter activities to an extent similar to that obtained with 3MC. Treatment of HepG2 cells and human hepatocytes with AhR-targeting siRNA suppressed the increase in both mRNA levels and CYP1A activities after treatment with TSU-16 as well as after that with omeprazole or 3MC. TSU-16 also time-dependently reduced cellular AhR protein levels in HepG2 cells to a similar extent with 3MC treatment. Furthermore, we demonstrated that unlabeled TSU-16 and 3MC but not omeprazole completely inhibited the specific binding of [(3)H]-3MC to mouse Hepa1c1c7 cytosol, suggesting TSU-16 as an AhR ligand. In conclusion, our present results suggest that TSU-16 binds to and activates AhR to enhance the expression of both human CYP1A1 and CYP1A2. Because TSU-16 is metabolized mainly by CYP1A2, its increased clearance after repeated dosing may be attributed to the enhanced expression of hepatic CYP1A2.

  9. Tissue- and cell type-specific expression of cytochrome P450 1A1 and cytochrome P450 1A2 mRNA in the mouse localized in situ hybridization.

    PubMed

    Dey, A; Jones, J E; Nebert, D W

    1999-08-01

    We used in situ hybridization to examine organ- and cell type-specific constitutive and 3-methylcholanthrene (3MC)-inducible cytochrome P450 (CYP)1A1 and CYP1A2 mRNA expression in various tissues of the C57BL/6N mouse. In situ hybridization was carried out 10 hr after the mice had received intraperitoneal 3MC, or vehicle alone. We detected levels of 3MC-induced CYP1A1 mRNA in: liver (centrilobular, more so than periportal, regions); lung (Clara Type II cells much more than Type I epithelial cells); brain, especially endothelial cells lining the vascular surface of the choroid plexus; the digestive tract (duodenum > jejunum > ileum > colon > esophagus > stomach--in particular, the villous epithelium, plus cells surrounding glands in the lamina propria); renal corpuscles of the kidney; the ovary (medulla more so than cortex); and the endothelial cells of blood vessels throughout the animal. Constitutive CYP1A1 mRNA was not detectable by in situ hybridization in any of these tissues. In contrast, constitutive CYP1A2 mRNA was measurable in liver, and 3MC-inducible CYP1A2 mRNA was observed only in liver, lung, and duodenum (having cell-type locations similar to those of CYP1A1); the other above-mentioned tissues were negative for CYP1A2 mRNA. These data demonstrate the striking differences in tissue- and cell type-specific expression between the two members of the mouse Cypla subfamily. Because of the ubiquitous nature of 3MC-inducible CYP1A1 throughout the animal rather than just "portals of entry," these results support our hypothesis that CYP1A1, induced by particular endogenous signals in various tissues and cell types, might participate in one or more critical life processes--in addition to its well-established role of metabolism of polycyclic hydrocarbons, certain drugs, and other environmental pollutants.

  10. Loss of Interdependent Binding by the FoxO1 and FoxA1/A2 Forkhead Transcription Factors Culminates in Perturbation of Active Chromatin Marks and Binding of Transcriptional Regulators at Insulin-sensitive Genes.

    PubMed

    Yalley, Akua; Schill, Daniel; Hatta, Mitsutoki; Johnson, Nicole; Cirillo, Lisa Ann

    2016-04-15

    FoxO1 binds to insulin response elements located in the promoters of insulin-like growth factor-binding protein 1 (IGFBP1) and glucose-6-phosphatase (G6Pase), activating their expression. Insulin-mediated phosphorylation of FoxO1 promotes cytoplasmic translocation, inhibiting FoxO1-mediated transactivation. We have previously demonstrated that FoxO1 opens and remodels chromatin assembled from the IGFBP1 promoter via a highly conserved winged helix motif. This finding, which established FoxO1 as a "pioneer" factor, suggested a model whereby FoxO1 chromatin remodeling at regulatory targets facilitates binding and recruitment of additional regulatory factors. However, the impact of FoxO1 phosphorylation on its ability to bind chromatin and the effect of FoxO1 loss on recruitment of neighboring transcription factors at its regulatory targets in liver chromatin is unknown. In this study, we demonstrate that an amino acid substitution that mimics insulin-mediated phosphorylation of a serine in the winged helix DNA binding motif curtails FoxO1 nucleosome binding. We also demonstrate that shRNA-mediated loss of FoxO1 binding to the IGFBP1 and G6Pase promoters in HepG2 cells significantly reduces binding of RNA polymerase II and the pioneer factors FoxA1/A2. Knockdown of FoxA1 similarly reduced binding of RNA polymerase II and FoxO1. Reduction in acetylation of histone H3 Lys-27 accompanies loss of FoxO1 and FoxA1/A2 binding. Interdependent binding of FoxO1 and FoxA1/A2 possibly entails cooperative binding because FoxO1 and FoxA1/A2 facilitate one another's binding to IGFPB1 promoter DNA. These results illustrate how transcription factors can nucleate transcriptional events in chromatin in response to signaling events and suggest a model for regulation of hepatic glucose metabolism through interdependent FoxO/FoxA binding.

  11. Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients

    PubMed Central

    Guzmán, Fanny; Rosas, Fernando; Thomas, M. Carmen; López, Manuel Carlos; González, John Mario; Cuéllar, Adriana; Puerta, Concepción J.

    2016-01-01

    Background TcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide. Methodology/Principal Findings From 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN-γ, TNFα, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07–0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation. Conclusion/Significance These results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy. PMID:26974162

  12. Beyond Donor-Acceptor (D-A) Approach: Structure-Optoelectronic Properties-Organic Photovoltaic Performance Correlation in New D-A1 -D-A2 Low-Bandgap Conjugated Polymers.

    PubMed

    Chochos, Christos L; Drakopoulou, Sofia; Katsouras, Athanasios; Squeo, Benedetta M; Sprau, Christian; Colsmann, Alexander; Gregoriou, Vasilis G; Cando, Alex-Palma; Allard, Sybille; Scherf, Ullrich; Gasparini, Nicola; Kazerouni, Negar; Ameri, Tayebeh; Brabec, Christoph J; Avgeropoulos, Apostolos

    2017-04-01

    Low-bandgap near-infrared polymers are usually synthesized using the common donor-acceptor (D-A) approach. However, recently polymer chemists are introducing more complex chemical concepts for better fine tuning of their optoelectronic properties. Usually these studies are limited to one or two polymer examples in each case study so far, though. In this study, the dependence of optoelectronic and macroscopic (device performance) properties in a series of six new D-A1 -D-A2 low bandgap semiconducting polymers is reported for the first time. Correlation between the chemical structure of single-component polymer films and their optoelectronic properties has been achieved in terms of absorption maxima, optical bandgap, ionization potential, and electron affinity. Preliminary organic photovoltaic results based on blends of the D-A1 -D-A2 polymers as the electron donor mixed with the fullerene derivative [6,6]-phenyl-C71 -butyric acid methyl ester demonstrate power conversion efficiencies close to 4% with short-circuit current densities (J sc ) of around 11 mA cm(-2) , high fill factors up to 0.70, and high open-circuit voltages (V oc s) of 0.70 V. All the devices are fabricated in an inverted architecture with the photoactive layer processed in air with doctor blade technique, showing the compatibility with roll-to-roll large-scale manufacturing processes.

  13. 32 CFR 809a.0 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Purpose. 809a.0 Section 809a.0 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL... civil disturbances and in supporting disaster relief operations. This part applies to installations...

  14. Genome sequencing of Giardia lamblia genotypes A2 and B isolates (DH and GS) and comparative analysis with the genomes of genotypes A1 and E (WB and Pig).

    PubMed

    Adam, Rodney D; Dahlstrom, Eric W; Martens, Craig A; Bruno, Daniel P; Barbian, Kent D; Ricklefs, Stacy M; Hernandez, Matthew M; Narla, Nirmala P; Patel, Rima B; Porcella, Stephen F; Nash, Theodore E

    2013-01-01

    Giardia lamblia (syn G. intestinalis, G. duodenalis) is the most common pathogenic intestinal parasite of humans worldwide and is a frequent cause of endemic and epidemic diarrhea. G. lamblia is divided into eight genotypes (A-H) which infect a wide range of mammals and humans, but human infections are caused by Genotypes A and B. To unambiguously determine the relationship among genotypes, we sequenced GS and DH (Genotypes B and A2) to high depth coverage and compared the assemblies with the nearly completed WB genome and draft sequencing surveys of Genotypes E (P15; pig isolate) and B (GS; human isolate). Our results identified DH as the smallest Giardia genome sequenced to date, while GS is the largest. Our open reading frame analyses and phylogenetic analyses showed that GS was more distant from the other three genomes than any of the other three were from each other. Whole-genome comparisons of DH_A2 and GS_B with the optically mapped WB_A1 demonstrated substantial synteny across all five chromosomes but also included a number of rearrangements, inversions, and chromosomal translocations that were more common toward the chromosome ends. However, the WB_A1/GS_B alignment demonstrated only about 70% sequence identity across the syntenic regions. Our findings add to information presented in previous reports suggesting that GS is a different species of Giardia as supported by the degree of genomic diversity, coding capacity, heterozygosity, phylogenetic distance, and known biological differences from WB_A1 and other G. lamblia genotypes.

  15. Genetic variations in the xenobiotic-metabolizing enzymes CYP1A1, CYP1A2, CYP2C9, CYP2C19 and susceptibility to colorectal cancer among Turkish people.

    PubMed

    Özhan, Gül; Mutur, Mine; Ercan, Gulcin; Alpertunga, Buket

    2014-04-01

    Cytochrome P450 (CYP) enzymes are genetically polymorphic and play key roles in the metabolism of xenobiotics. Colorectal cancer (CRC) is one of the most common malignant tumors in Turkey as well as in the world. In this study, it was aimed both to evaluate the effects of CYP variants on the susceptibility to CRC and to predict the individual response of the Turkish people to xenobiotics metabolized by CYP enzymes. For that, we assessed the association of CYP1A1, CYP1A2, CYP2C9, and CYP2C19 polymorphisms in patients with CRC in the Turkish population through a case-control study. Distributions of the variants were determined in 104 patients with CRC and 183 healthy volunteers. As results, CYP1A1 6235T/C was significantly associated with CRC risk (odds ratio [OR]=2.53; 95% confidence interval [CI]=0.99-6.45; p=0.046). In a haplotype-based analysis, CYP1A1 haplotype C6235-A2455 might be associated with the development of CRC (OR=2.70; 95% CI=0.58-5.90; p=0.046). We believe that the findings are the first results of CYP allele distributions in the Turkish population and provide an understanding of the epidemiological studies that correlate therapeutic approaches and etiology of CRC especially in Turkish patients.

  16. Structure-function relationships of inhibition of human cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives.

    PubMed

    Shimada, Tsutomu; Tanaka, Katsuhiro; Takenaka, Shigeo; Murayama, Norie; Martin, Martha V; Foroozesh, Maryam K; Yamazaki, Hiroshi; Guengerich, F Peter; Komori, Masayuki

    2010-12-20

    Structure-function relationships for the inhibition of human cytochrome P450s (P450s) 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives were studied. Thirty-two of the 33 flavonoids tested produced reverse type I binding spectra with P450 1B1, and the potencies of binding were correlated with the abilities to inhibit 7-ethoxyresorufin O-deethylation activity. The presence of a hydroxyl group in flavones, for example, 3-, 5-, and 7-monohydroxy- and 5,7-dihydroxyflavone, decreased the 50% inhibition concentration (IC50) of P450 1B1 from 0.6 μM to 0.09, 0.21, 0.25, and 0.27 μM, respectively, and 3,5,7-trihydroxyflavone (galangin) was the most potent, with an IC50 of 0.003 μM. The introduction of a 4'-methoxy- or 3',4'-dimethoxy group into 5,7-dihydroxyflavone yielded other active inhibitors of P450 1B1 with IC50 values of 0.014 and 0.019 μM, respectively. The above hydroxyl and/or methoxy groups in flavone molecules also increased the inhibition activity with P450 1A1 but not always toward P450 1A2, where 3-, 5-, or 7-hydroxyflavone and 4'-methoxy-5,7-dihydroxyflavone were less inhibitory than flavone itself. P450 2C9 was more inhibited by 7-hydroxy-, 5,7-dihydroxy-, and 3,5,7-trihydroxyflavones than by flavone but was weakly inhibited by 3- and 5-hydroxyflavone. Flavone and several other flavonoids produced type I binding spectra with P450 3A4, but such binding was not always related to the inhibitiory activities toward P450 3A4. These results indicate that there are different mechanisms of inhibition for P450s 1A1, 1A2, 1B1, 2C9, and 3A4 by various flavonoid derivatives and that the number and position of hydroxyl and/or methoxy groups highly influence the inhibitory actions of flavonoids toward these enzymes. Molecular docking studies suggest that there are different mechanisms involved in the interaction of various flavonoids with the active site of P450s, thus causing differences in inhibition of these P450 catalytic activities by flavonoids.

  17. Structure-Function Relationships of Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 Flavonoid Derivatives

    PubMed Central

    Shimada, Tsutomu; Tanaka, Katsuhiro; Takenaka, Shigeo; Murayama, Norie; Martin, Martha V.; Foroozesh, Maryam K.; Yamazaki, Hiroshi; Guengerich, F. Peter; Komori, Masayuki

    2010-01-01

    Structure-function relationships for inhibition of human cytochrome P450s (P450s) 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives were studied. Thirty-two of the 33 flavonoids tested produced Reverse Type I binding spectra with P450 1B1, and the potencies of binding were correlated with the abilities to inhibit 7-ethoxyresorufin O-deethylation activity. The presence of a hydroxyl group in flavones, e.g. 3-, 5-, and 7-monohydroxy- and 5,7-dihydroxyflavone, decreased the 50% inhibition concentration (IC50) of P450 1B1 from 0.6 µM to 0.09, 0.21, 0.25, and 0.27 µM, respectively, and 3,5,7-trihydroxyflavone (galangin) was the most potent, with an IC50 of 0.003 µM. The introduction of a 4’-methoxy- or 3’,4’-dimethoxy group into 5,7-dihydroxyflavone yielded other active inhibitors of P450 1B1 with IC50 values of 0.014 and 0.019 µM, respectively. The above hydroxyl- and/or methoxy-groups in flavone molecules also increased the inhibition activity with P450 1A1 but not always towards P450 1A2, where 3-, 5-, or 7-hydroxyflavone, and 4’-methoxy-5,7-dihydroxyflavone were less inhibitory than flavone itself. P450 2C9 was more inhibited by 7-hydroxy-,5,7-dihydroxy-, and 3,5,7-trihydroxyflavones than by flavone but was weakly inhibited by 3-and 5-hydroxyflavone. Flavone and several other flavonoids produced Type I binding spectra with P450 3A4, but such binding was not always related to the inhibitiory activities towards P450 3A4. These results indicate that there are different mechanisms of inhibition for P450s 1A1, 1A2, 1B1, 2C9, and 3A4 by various flavonoid derivatives and that the number and position of hydroxyl and/or methoxy groups highly influence the inhibitory actions of flavonoids towards these enzymes. Molecular docking studies suggest that there are different mechanisms involved in the interaction of various flavonoids with the active site of P450s, thus causing differences in inhibition of these P450 catalytic activities by flavonoids. PMID

  18. Elemental abundance analyses with DAO spectrograms. XXVII. The superficially normal stars theta And (A2 IV), epsilon Del (B6 III), epsilon Aqr (A1.5 V), and iota And (B9 V)

    NASA Astrophysics Data System (ADS)

    Kocer, D.; Adelman, S. J.; Caliskan, H.; Gulliver, A. F.; Gokmen Tektunali, H.

    2003-08-01

    The superficially normal stars theta And (A2 V), epsilon Del (B6 III), epsilon Aqr (A1.5 V), and iota And (B9 V), which have rotationally broadened line profiles, are analyzed in a manner consistent with previous studies of this series using 2.4 Åmm-1 spectrograms obtained with CCD detectors and S/N >=200. Their variable radial velocities strongly suggest they are spectroscopic binaries. As no evidence is seen for lines of their companions they are analyzed as single stars. Their derived abundances are generally near solar. But those for theta And suggest that it is possibly a fast rotating Am star. Table 5 is only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/406/975

  19. Induction of CYP1A1, CYP1A2, CYP1B1, increased oxidative stress and inflammation in the lung and liver tissues of rats exposed to incense smoke.

    PubMed

    Hussain, Tajamul; Al-Attas, Omar S; Al-Daghri, Nasser M; Mohammed, Arif A; De Rosas, Edgard; Ibrahim, Shebl; Vinodson, Benjamin; Ansari, Mohammed G; El-Din, Khaled I Alam

    2014-06-01

    Incense smoke is increasingly being recognized as a potential environmental contaminant and is linked to malignant and non-malignant respiratory diseases. The detoxification of environmental contaminants including polycyclic aromatic hydrocarbons (PAHs) involves the induction of cytochrome P-450 family enzymes (CYPs) by PAHs. However, the detoxification of PAHs also results in the generation of reactive and unstable intermediary metabolites which are implicated in the oxidative stress, DNA damage, and inflammation. It is unclear whether CYPs are similarly induced by incense smoke, which incidentally contains substantial amounts of PAHs. Here, we examined the impact of long-term incense smoke exposure on the induction of CYPs in male Wister Albino rats. Incense smoke exposure significantly induced the expression of CYP1A1, CYP1A2, and CYP1B1 mRNAs in both lung and liver tissues. The extent of CYP1A1 and CYP1B1 induction was significantly higher in the liver compared to that in the lung, while that of CYP1A2 was greater in the lung than in liver. Incense smoke exposure also increased malondialdehyde and reduced glutathione levels in lung and liver tissues, and the catalase activity in the liver tissues to significant levels. Furthermore incense smoke exposure led to a marked increase in TNF-α and IL-4 levels. The data demonstrate for the first time the capacity of incense smoke to induce CYP1 family enzymes in the target and non-target tissues. Induction of CYPs increased oxidative stress and inflammation appear to be intimately linked to promote the carcinogenesis and health complications in people chronically exposed to incense smoke.

  20. Comparable Efficacy of a 1-L PEG and Ascorbic Acid Solution Administered with Bisacodyl versus a 2-L PEG and Ascorbic Acid Solution for Colonoscopy Preparation: A Prospective, Randomized and Investigator-Blinded Trial

    PubMed Central

    Im, Jong Pil; Kim, Su Hwan; Koh, Seong-Joon; Kim, Byeong Gwan; Lee, Kook Lae; Kim, Sang Gyun; Kim, Joo Sung; Jung, Hyun Chae

    2016-01-01

    Background Two liters of polyethylene glycol (PEG) solution administered with ascorbic acid (Asc) can provide efficacy similar to that of a 4-L PEG solution for colonoscopy preparation. In addition, oral bisacodyl (Bis) has been shown to reduce the volume of PEG needed for a bowel preparation with comparable efficacy. This study aimed to compare the efficacy, tolerability and safety of a 2-L PEG solution mixed with Asc versus the combination of Bis, Asc and a 1-L PEG solution. Methods This was a prospective, randomized, multi-centre, single-blind, non-inferiority trial. Participants who were scheduled for colonoscopy were included and randomized to receive either 2-L PEG and Asc (2L PEG/Asc group) or 1-L PEG, Asc and 20 mg Bis (1L PEG/Asc + Bis group). The quality of bowel preparation was assessed using the Boston Bowel Preparation Scale. Data regarding tolerance, compliance and adverse events were also gathered. Results A total of 187 participants were analyzed; 96 were allocated to the 2L PEG/Asc group and 91 to the 1L PEG/Asc + Bis group. Bowel preparation was adequate in 87.5% (84/96) of patients in the 2L PEG/Asc group and 94.5% of the 1L PEG/Asc + Bis group (86/91, p = 0.10). There was no significant difference between the two groups with respect to compliance, tolerability or safety. The patients allocated to the 1L PEG/Asc + Bis group expressed more willingness to repeat the procedure than patients in the 2L PEG/Asc group (p = 0.01). Conclusions Bowel preparation with Bis and a 1-L PEG/Asc solution is as effective, well-tolerated, and safe as a 2-L PEG/Asc solution. Trial Registration ClinicalTrials.gov NCT 01745835; Clinical Research Information Service (CRiS) KCT0000708 PMID:27588943

  1. Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter.

    PubMed

    Conolly, R B; Andersen, M E

    1997-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatic tumor promoter in female rats. We used a quantitative, stochastic initiation-promotion model based on R. B. Conolly and J. S. Kimbell (Toxicol. Appl. Pharmacol. 124, 284-295, 1994) to analyze initiation-promotion results from a previously published study (H. C. Pitot et al., Carcinogenesis 8, 1491-1499, 1987) within the context of a negative selection model of tumor promotion. In this model, two types of initiated cells (called A and B cells) are produced by DEN initiation. Visually excellent correspondence between model predictions and data (i.e., foci/cm3 liver and percentage of liver occupied by foci) are obtained when TCDD is described as having dose-responsive effects on division and death (apoptotic) rates of these two cell types. For A cells, both the division and the death rates increase while the difference between division and apoptotic rates decreases. For B cells, the difference between division and apoptotic rates increases, primarily due to a decrease in the apoptotic rate. We also linked these alterations in cell kinetics to a pharmacokinetic model for TCDD incorporating a five subcompartment model of the liver acinus with induction of CYP1A1 and 1A2 genes in the subcompartments. Alterations in A cell kinetics correlate with effects of TCDD in the region most sensitive to induction (subcompartment 5-centrilobular region); B cell dynamics correlate with induction in subcompartments 3-5 (centrilobular and mid-zonal regions). In summary, these modeling exercises show that (1) the two-cell model, without presuming effects of TCDD on the mutation rate of normal hepatocytes, reproduces the data of Pitot et al. (1987) and (2) induction of CYP1A1/1A2 in different regions of the hepatic acinus can be used as a general correlate of these presumed changes in cell growth kinetics.

  2. The environmental pollutant and carcinogen 3-nitrobenzanthrone and its human metabolite 3-aminobenzanthrone are potent inducers of rat hepatic cytochromes P450 1A1 and -1A2 and NAD(P)H:quinone oxidoreductase.

    PubMed

    Stiborová, Marie; Dracínská, Helena; Hájková, Jana; Kaderábková, Pavla; Frei, Eva; Schmeiser, Heinz H; Soucek, Pavel; Phillips, David H; Arlt, Volker M

    2006-08-01

    3-Nitrobenzanthrone (3-NBA), a suspected human carcinogen occurring in diesel exhaust and air pollution, and its human metabolite 3-aminobenzanthrone (3-ABA) were investigated for their ability to induce biotransformation enzymes in rat liver and the influence of such induction on DNA adduct formation by the compounds. Rats were treated (i.p.) with 0.4, 4, or 40 mg/kg body weight 3-NBA or 3-ABA. When hepatic cytosolic fractions from rats treated with 40 mg/kg body weight 3-NBA or 3-ABA were incubated with 3-NBA, DNA adduct formation, measured by 32P-postlabeling analysis, was 10-fold higher in incubations with cytosols from pretreated rats than with controls. The increase in 3-NBA-derived DNA adduct formation corresponded to a dose-dependent increase in protein levels and enzymatic activity of NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is the major enzyme reducing 3-NBA in human and rat livers. Incubations of 3-ABA with hepatic microsomes of rats treated with 3-NBA or 3-ABA (40 mg/kg body weight) led to as much as a 12-fold increase in 3-ABA-derived DNA adduct formation compared with controls. The observed stimulation of DNA adduct formation by both compounds was attributed to their potential to induce protein expression and enzymatic activity of cytochromes P450 1A1 and/or -1A2 (CYP1A1/2), the major enzymes responsible for 3-ABA activation in human and rat livers. Collectively, these results demonstrate for the first time, to our knowledge, that by inducing hepatic NQO1 and CYP1A1/2, both 3-NBA and 3-ABA increase the enzymatic activation of these two compounds to reactive DNA adduct-forming species, thereby enhancing their own genotoxic potential.

  3. 26 CFR 1.263(a)-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... taxpayers. (k) Treatment of related parties and indirect payments. (l) Examples. (m) Amortization. (n... of the Internal Revenue Code. (k) Treatment of indirect payments. (l) Examples. (m) Effective date...) under § 1.263(a)-0T. § 1.263(a)-2Amounts paid to acquire or produce tangible property. (a) through...

  4. Ab initio calculations on the X~ 2B1 and A~ 2A1 states of AsH2, and Franck-Condon simulation, including anharmonicity, of the A~(0,0,0)-X~ single vibronic level emission spectrum of AsH2

    NASA Astrophysics Data System (ADS)

    Lee, Edmond P. F.; Mok, Daniel K. W.; Chau, Foo-tim; Dyke, John M.

    2010-06-01

    Restricted-spin coupled-cluster single-double plus perturbative triple excitation {RCCSD(T)} calculations were carried out on the X˜ B21 and à A21 states of AsH2 employing the fully relativistic small-core effective core potential (ECP10MDF) for As and basis sets of up to the augmented correlation-consistent polarized valence quintuple-zeta (aug-cc-pV5Z) quality. Minimum-energy geometrical parameters and relative electronic energies were evaluated, including contributions from extrapolation to the complete basis set limit and from outer core correlation of the As 3d10 electrons employing additional tight 4d3f2g2h functions designed for As. In addition, simplified, explicitly correlated CCSD(T)-F12 calculations were also performed employing different atomic orbital basis sets of up to aug-cc-pVQZ quality, and associated complementary auxiliary and density-fitting basis sets. The best theoretical estimate of the relative electronic energy of the à A21 state of AsH2 relative to the X˜ B21 state including zero-point energy correction (T0) is 19 954(32) cm-1, which agrees very well with available experimental T0 values of 19 909.4531(18) and 19 909.4910(17) cm-1 obtained from recent laser induced fluorescence and cavity ringdown absorption spectroscopic studies. In addition, potential energy functions (PEFs) of the X˜ B21 and à A21 states of AsH2 were computed at different RCCSD(T) and CCSD(T)-F12 levels. These PEFs were used in variational calculations of anharmonic vibrational wave functions, which were then utilized to calculate Franck-Condon factors (FCFs) between these two states, using a method which includes allowance for anharmonicity and Duschinsky rotation. The Ã(0,0,0)-X˜ single vibronic level (SVL) emission spectrum of AsH2 was simulated using these computed FCFs. Comparison between simulated and available experimental vibrationally resolved spectra of the Ã(0,0,0)-X˜ SVL emission of AsH2, which consist essentially of the bending (2n) series, suggests that there is a significant loss in intensity in the low emission energy region of the experimental spectrum.

  5. The influence of genetic polymorphisms in Ahr, CYP1A1, CYP1A2, CYP1B1, GST M1, GST T1 and UGT1A1 on urine 1-hydroxypyrene glucuronide concentrations in healthy subjects from Rio Grande do Sul, Brazil.

    PubMed

    Abnet, Christian C; Fagundes, Renato B; Strickland, Paul T; Kamangar, Farin; Roth, Mark J; Taylor, Philip R; Dawsey, Sanford M

    2007-01-01

    Polymorphisms in genes encoding polycyclic aromatic hydrocarbon (PAH) metabolizing enzymes may alter metabolism of these carcinogens and contribute to inter-individual difference in urine concentrations. We investigated the influence of genetic polymorphism on PAH metabolism in urine from 199 healthy subjects from Southern Brazil. We measured urine 1-hydroxypyrene glucuronide (1-OHPG) concentrations using immunoaffinity chromatography and synchronous fluorescence spectroscopy and genotyped subjects using standard methods. Genetic variants in CYP1B1 (rs1056827, rs1800440, rs10012) were strongly associated with urine 1-OHPG with P-values < 0.010. Variants in aryl hydrocarbon receptor (Ahr) (rs4986826), CYP1A1 (rs1799814) and CYP1A2 (rs2069514) were also, although less strongly, associated with changes in urine 1-OHPG concentrations. These variants had P-values of 0.074, 0.040 and 0.025, respectively. The median urine 1-OHPG concentrations (pmol/ml) in the homozygous wild-type and homozygous variants for CYP1B1 (rs10012) and the Ahr, CYP1A1 and CYP1A2 variants listed above were 2.16 and 0.10, 2.16 and 0.41, 2.03 and 0.46, 2.19 and 2.79, respectively. We found no effect of deletions in GST M1 or GST T1, or different alleles of UGT1A1*28. Adjusting for age, sex, place of residence, tobacco smoke exposure, maté drinking, cachaça and barbeque preparation had only a minor impact on the associations. A model containing just exposure variables had an r2 of 0.21; a model with single genotypes for Ahr, CYP1A1, CYP1A2 and CYP1B1 had an r2 of 0.10; and a model combining both exposure and genotype information had a total r2 of 0.33. Our results suggest that CYP1B1 genotypes are strongly associated with urine 1-OHPG concentrations in this population.

  6. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies

    PubMed Central

    Butterfield, Russell J.; Foley, A. Reghan; Dastgir, Jahannaz; Asman, Stephanie; Dunn, Diane M.; Zou, Yaqun; Hu, Ying; Flanigan, Kevin M.; Swoboda, Kathryn J.; Winder, Thomas L.; Weiss, Robert B.; Bönnemann, Carsten G.

    2015-01-01

    Glycine substitutions in the conserved Gly-X-Y motif in the triple helical domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the triple helical domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, intermediate, and mild phenotypes even from patients with identical mutations. Intermediate phenotypes were most common, accounting for almost half of patients, emphasizing the importance of intermediate phenotypes to the overall phenotypic spectrum. Glycine substitutions in the triple helical domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10 to 15, accounting for only 5% of the triple helical domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. PMID:24038877

  7. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies.

    PubMed

    Butterfield, Russell J; Foley, A Reghan; Dastgir, Jahannaz; Asman, Stephanie; Dunn, Diane M; Zou, Yaqun; Hu, Ying; Donkervoort, Sandra; Flanigan, Kevin M; Swoboda, Kathryn J; Winder, Thomas L; Weiss, Robert B; Bönnemann, Carsten G

    2013-11-01

    Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix.

  8. Genotoxicity of three food processing contaminants in transgenic mice expressing human sulfotransferases 1A1 and 1A2 as assessed by the in vivo alkaline single cell gel electrophoresis assay

    PubMed Central

    Høie, Anja Hortemo; Svendsen, Camilla; Brunborg, Gunnar; Glatt, Hansruedi; Alexander, Jan; Meinl, Walter

    2015-01-01

    The food processing contaminants 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), 5‐hydroxymethylfurfural (HMF) and 2,5 dimethylfuran (DMF) are potentially both mutagenic and carcinogenic in vitro and/or in vivo, although data on DMF is lacking. The PHIP metabolite N‐hydroxy‐PhIP and HMF are bioactivated by sulfotransferases (SULTs). The substrate specificity and tissue distribution of SULTs differs between species. A single oral dose of PhIP, HMF or DMF was administered to wild‐type (wt) mice and mice expressing human SULT1A1/1A2 (hSULT mice). DNA damage was studied using the in vivo alkaline single cell gel electrophoresis (SCGE) assay. No effects were detected in wt mice. In the hSULT mice, PhIP and HMF exposure increased the levels of DNA damage in the liver and kidney, respectively. DMF was not found to be genotoxic. The observation of increased DNA damage in hSULT mice compared with wt mice supports the role of human SULTs in the bioactivation of N‐hydroxy‐PhIP and HMF in vivo. Environ. Mol. Mutagen. 56:709–714, 2015. © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. PMID:26270892

  9. The aryl hydrocarbon receptor-interacting protein (AIP) is required for dioxin-induced hepatotoxicity but not for the induction of the Cyp1a1 and Cyp1a2 genes.

    PubMed

    Nukaya, Manabu; Lin, Bernice C; Glover, Edward; Moran, Susan M; Kennedy, Gregory D; Bradfield, Christopher A

    2010-11-12

    The aryl hydrocarbon receptor (AHR) plays an essential role in the toxic response to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), in the adaptive up-regulation of xenobiotic metabolizing enzymes, and in hepatic vascular development. In our model of AHR signaling, the receptor is found in a cytosolic complex with a number of molecular chaperones, including Hsp90, p23, and the aryl hydrocarbon receptor-interacting protein (AIP), also known as ARA9 and XAP2. To understand the role of AIP in adaptive and toxic aspects of AHR signaling, we generated a conditional mouse model where the Aip locus can be deleted in hepatocytes. Using this model, we demonstrate two important roles for the AIP protein in AHR biology. (i) The expression of AIP in hepatocytes is essential to maintain high levels of functional cytosolic AHR protein in the mammalian liver. (ii) Expression of the AIP protein is essential for dioxin-induced hepatotoxicity. Interestingly, classical AHR-driven genes show differential dependence on AIP expression. The Cyp1b1 and Ahrr genes require AIP expression for normal up-regulation by dioxin, whereas Cyp1a1 and Cyp1a2 do not. This differential dependence on AIP provides evidence that the mammalian genome contains more than one class of AHR-responsive genes and suggests that a search for AIP-dependent, AHR-responsive genes may guide us to the targets of the dioxin-induced hepatotoxicity.

  10. Genotoxicity of three food processing contaminants in transgenic mice expressing human sulfotransferases 1A1 and 1A2 as assessed by the in vivo alkaline single cell gel electrophoresis assay.

    PubMed

    Høie, Anja Hortemo; Svendsen, Camilla; Brunborg, Gunnar; Glatt, Hansruedi; Alexander, Jan; Meinl, Walter; Husøy, Trine

    2015-10-01

    The food processing contaminants 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 5-hydroxymethylfurfural (HMF) and 2,5 dimethylfuran (DMF) are potentially both mutagenic and carcinogenic in vitro and/or in vivo, although data on DMF is lacking. The PHIP metabolite N-hydroxy-PhIP and HMF are bioactivated by sulfotransferases (SULTs). The substrate specificity and tissue distribution of SULTs differs between species. A single oral dose of PhIP, HMF or DMF was administered to wild-type (wt) mice and mice expressing human SULT1A1/1A2 (hSULT mice). DNA damage was studied using the in vivo alkaline single cell gel electrophoresis (SCGE) assay. No effects were detected in wt mice. In the hSULT mice, PhIP and HMF exposure increased the levels of DNA damage in the liver and kidney, respectively. DMF was not found to be genotoxic. The observation of increased DNA damage in hSULT mice compared with wt mice supports the role of human SULTs in the bioactivation of N-hydroxy-PhIP and HMF in vivo.

  11. Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations.

    PubMed Central

    Körkkö, J; Ala-Kokko, L; De Paepe, A; Nuytinck, L; Earley, J; Prockop, D J

    1998-01-01

    Although >90% of patients with osteogenesis imperfecta (OI) have been estimated to have mutations in the COL1A1 and COL1A2 genes for type I procollagen, mutations have been difficult to detect in all patients with the mildest forms of the disease (i.e., type I). In this study, we first searched for mutations in type I procollagen by analyses of protein and mRNA in fibroblasts from 10 patients with mild OI; no evidence of a mutation was found in 2 of the patients by the protein analyses, and no evidence of a mutation was found in 5 of the patients by the RNA analyses. We then searched for mutations in the original 10 patients and in 5 additional patients with mild OI, by analysis of genomic DNA. To assay the genomic DNA, we established a consensus sequence for the first 12 kb of the COL1A1 gene and for 30 kb of new sequences of the 38-kb COL1A2 gene. The sequences were then used to develop primers for PCR for the 103 exons and exon boundaries of the two genes. The PCR products were first scanned for heteroduplexes by conformation-sensitive gel electrophoresis, and then products containing heteroduplexes were sequenced. The results detected disease-causing mutations in 13 of the 15 patients and detected two additional probable disease-causing mutations in the remaining 2 patients. Analysis of the data developed in this study and elsewhere revealed common sequences for mutations causing null alleles. PMID:9443882

  12. Sinomenine potentiates degranulation of RBL-2H3 basophils via up-regulation of phospholipase A2 phosphorylation by Annexin A1 cleavage and ERK phosphorylation without influencing on calcium mobilization.

    PubMed

    Huang, Lufen; Li, Ting; Zhou, Hua; Qiu, Ping; Wu, Jianlin; Liu, Liang

    2015-10-01

    Sinomenine (SIN), an alkaloid derived from the Chinese medicinal plant Sinomenium acutum, is the major component of Zhengqing Fongtong Ning (ZQFTN), a pharmaceutical drug produced by Hunan Zhengqing Pharmaceutical Co. Ltd. in China for the treatment of rheumatoid arthritis and other autoimmune diseases. Some clinic reports indicate that ZQFTN may induce an anaphylactic reaction via potentiating the degranulation of immune cells. In the current study, we aimed to examine whether SIN is capable of inducing the degranulation of basophilic leukemia 2H3 (RBL-2H3) cells to elucidate how the anaphylactic reaction occurs. The results revealed that SIN could up-regulate β-hexosaminidase levels in RBL-2H3 cells without significant cytotoxicity, suggesting that SIN could induce the degranulation of RBL-2H3 cells. Furthermore, SIN increased the release of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) in RBL-2H3 cells via promoting the expression of phosphorylated-extracellular signal-regulated kinase (P-ERK), the cleavage of Annexin A1 (ANXA1), and phosphorylated-cytosolic phospholipase A2 (P-cPLA2), as well as cyclooxygenase-2 (COX-2). The ERK inhibitor, PD98059, significantly attenuated the up-regulatory effect of SIN on cPLA2 phosphorylation. Interestingly, SIN did not significantly increase Ca(2+) influx in the cells. These findings not only explored the anaphylactic reaction and underlying mechanism of ZQFTN in RBL-2H3 cells, but may promote the development of relevant strategies for overcoming the adverse effects of the drug.

  13. Renal tumours in a Tsc1+/- mouse model show epigenetic suppression of organic cation transporters Slc22a1, Slc22a2 and Slc22a3, and do not respond to metformin.

    PubMed

    Yang, Jian; Kalogerou, Maria; Gallacher, John; Sampson, Julian R; Shen, Ming Hong

    2013-04-01

    Metformin, a substrate of several poly-specific organic cation transporters, is a widely used biguanide for the treatment of type II diabetes. Recent studies suggest that metformin attenuates mTORC1 signalling by the activation of 5' adenosine monophosphate-activated protein kinase (AMPK) in the presence or absence of a functional hamartin/tuberin (TSC1/TSC2) complex. Metformin has also been reported to inhibit mTORC1 independent of AMPK through p53-dependent regulated in development and DNA damage responses 1 (REDD1) or by inhibiting Rag GTPases. These observations suggest that metformin could have therapeutic potential for tuberous sclerosis, an inherited disorder characterised by the aberrant activation of mTORC1 and the development of tumours in many organs, including the kidneys. In this study, we investigated the effect of metformin on renal lesions in a Tsc1(+/-) mouse model of tuberous sclerosis. Continuous treatment of metformin for 9 months at doses of up to 600 mg/kg/day had no significant effect on renal lesions in nine treated mice compared to 10 controls. Metformin treatment appeared to attenuate mTORC1 signalling in Tsc1(+/-) kidney tissues but not in renal tumours. Surprisingly, the expression of the organic cation transporters Slc22a1, Slc22a2 and Slc22a3 essential for the cellular uptake of metformin was highly suppressed in renal tumours. Treatment of cultured cells derived from a Tsc1-associated renal tumour with 5-aza-2-deoxycytidine or trichostatin A greatly increased the expression of these genes. These data suggest that the epigenetic suppression of the organic cation transporters in Tsc-associated mouse renal tumours may contribute to the lack of response to metformin treatment.

  14. Structure of a C-terminal AHNAK peptide in a 1:2:2 complex with S100A10 and an acetylated N-terminal peptide of annexin A2

    PubMed Central

    Ozorowski, Gabriel; Milton, Saskia; Luecke, Hartmut

    2013-01-01

    AHNAK, a large 629 kDa protein, has been implicated in membrane repair, and the annexin A2–S100A10 hetero­tetramer [(p11)2(AnxA2)2)] has high affinity for several regions of its 1002-amino-acid C-terminal domain. (p11)2(AnxA2)2 is often localized near the plasma membrane, and this C2-symmetric platform is proposed to be involved in the bridging of membrane vesicles and trafficking of proteins to the plasma membrane. All three proteins co-localize at the intracellular face of the plasma membrane in a Ca2+-dependent manner. The binding of AHNAK to (p11)2(AnxA2)2 has been studied previously, and a minimal binding motif has been mapped to a 20-amino-acid peptide corresponding to residues 5654–5673 of the AHNAK C-­terminal domain. Here, the 2.5 Å resolution crystal structure of this 20-amino-acid peptide of AHNAK bound to the AnxA2–S100A10 heterotetramer (1:2:2 symmetry) is presented, which confirms the asymmetric arrangement first described by Rezvanpour and coworkers and explains why the binding motif has high affinity for (p11)2(AnxA2)2. Binding of AHNAK to the surface of (p11)2(AnxA2)2 is governed by several hydrophobic inter­actions between side chains of AHNAK and pockets on S100A10. The pockets are large enough to accommodate a variety of hydrophobic side chains, allowing the consensus sequence to be more general. Additionally, the various hydrogen bonds formed between the AHNAK peptide and (p11)2(AnxA2)2 most often involve backbone atoms of AHNAK; as a result, the side chains, particularly those that point away from S100A10/AnxA2 towards the solvent, are largely interchangeable. While the structure-based consensus sequence allows interactions with various stretches of the AHNAK C-terminal domain, comparison with other S100 structures reveals that the sequence has been optimized for binding to S100A10. This model adds new insight to the understanding of the specific interactions that occur in this membrane-repair scaffold. PMID:23275167

  15. De novo synthesis of a 2-acetamido-4-amino-2,4,6-trideoxy-D-galactose (AAT) building block for the preparation of a Bacteroides fragilis A1 polysaccharide fragment.

    PubMed

    Pragani, Rajan; Stallforth, Pierre; Seeberger, Peter H

    2010-04-02

    Zwitterionic polysaccharides (ZPSs) are potent T-cell activators that naturally occur on the cell surface of bacteria and show potential as immunostimulatory agents. An unusual, yet important component of many ZPSs is 2-acetamido-4-amino-2,4,6-trideoxy-D-galactose (AAT). AAT building block 2 was prepared via a de novo synthesis from N-Cbz-L-threonine 5. Furthermore, building block 2 was used to synthesize disaccharide 15 that constitutes a fragment of zwitterionic polysaccharide A1 (PS A1) found in Bacteroides fragilis.

  16. 78 FR 56921 - South Bay Salt Pond Restoration Project, Phase 2 (Ponds R3, R4, R5, S5, A1, A2W, A8, A8S, A19...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-16

    ... Fish and Wildlife Service South Bay Salt Pond Restoration Project, Phase 2 (Ponds R3, R4, R5, S5, A1... 2 of the South Bay Salt Pond Restoration Project and consists of restoring and enhancing over 2,000.... The overall south bay salt pond restoration area includes 15,100 acres which the USFWS and the...

  17. Mercury modulates the cytochrome P450 1a1, 1a2 and 1b1 in C57BL/6J mice: in vivo and in vitro studies

    SciTech Connect

    Amara, Issa E.A.; Anwar-Mohamed, Anwar; Abdelhamid, Ghada; El-Kadi, Ayman O.S.

    2013-02-01

    In the current study C57BL/6J mice were injected intraperitoneally with Hg{sup 2+} in the absence and presence of TCDD. After 6 and 24 h the liver was harvested and the expression of Cyps was determined. In vitro, isolated hepatocytes were incubated with TCDD in the presence and absence of Hg{sup 2+}. At the in vivo level, Hg{sup 2+} significantly decreased the TCDD-mediated induction of Cyps at 6 h while potentiating their levels at 24 h. In vitro, Hg{sup 2+} significantly inhibited the TCDD-mediated induction of Cyp1a1 in a concentration- and time-dependent manner. Interestingly, Hg{sup 2+} increased the serum hemoglobin (Hb) levels in mice treated for 24 h. Upon treatment of isolated hepatocytes with Hb alone, there was an increase in the AhR-dependent luciferase activity with a subsequent increase in Cyp1a1 protein and catalytic activity levels. Importantly, when hepatocytes were treated for 2 h with Hg{sup 2+} in the presence of TCDD, then the medium was replaced with new medium containing Hb, there was potentiation of the TCDD-mediated effect. In addition, Hg{sup 2+} increased heme oxygenase-1 (HO-1) mRNA, which coincided with a decrease in the Cyp1a1 activity level. When the competitive HO-1 inhibitor, tin mesoporphyrin was applied to the hepatocytes there was a partial restoration of Hg{sup 2+}-mediated inhibition of Cyp1a1 activity. In conclusion, we demonstrate for the first time that there is a differential modulation of the TCDD-mediated induction of Cyp1a1 by Hg{sup 2+} in C57BL/6J mice livers and isolated hepatocytes. Moreover, this study implicates Hb as an in vivo specific modulator of Cyp1 family. -- Highlights: ► In vivo, Hg{sup 2+} decreased the Cyps at 6 h while potentiating their levels at 24 h. ► In vitro, Hg{sup 2+} significantly inhibited the TCDD-mediated induction of Cyps. ► Hg{sup 2+} increased the serum Hb levels in animals treated for 24 h. ► Hb potentiated the TCDD-mediated effect on Cyps. ► Tin mesoporphyrin partially

  18. Synthesis, Structure, and Magnetic Properties of A2Cu5(TeO3)(SO4)3(OH)4 (A = Na, K): The First Compounds with a 1D Kagomé Strip Lattice.

    PubMed

    Tang, Yingying; Guo, Wenbin; Xiang, Hongping; Zhang, Suyun; Yang, Ming; Cui, Meiyan; Wang, Nannan; He, Zhangzhen

    2016-01-19

    Two new tellurite-sulfates A2Cu5(TeO3)(SO4)3(OH)4 (A = Na, K) have been synthesized by a conventional hydrothermal method. Both compounds feature 1D kagomé strip structure built by distorted CuO6 octahedra, which can be regarded as the dimensional reduction of kagomé lattice. Magnetic measurements confirmed that the titled compounds possess antiferromagnetic ordering at low temperature, while a field-induced magnetic transition can be observed at critical field. To the best of our knowledge, this is the first time to obtain distorted kagomé strip compounds.

  19. 17-allyamino-17-demethoxygeldanamycin treatment results in a magnetic resonance spectroscopy-detectable elevation in choline-containing metabolites associated with increased expression of choline transporter SLC44A1 and phospholipase A2

    PubMed Central

    2010-01-01

    Introduction 17-allyamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is currently in clinical trials in breast cancer. However, 17-AAG treatment often results in inhibition of tumor growth rather than shrinkage, making detection of response a challenge. Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) are noninvasive imaging methods than can be used to monitor metabolic biomarkers of drug-target modulation. This study set out to examine the MRS-detectable metabolic consequences of Hsp90 inhibition in a breast cancer model. Methods MCF-7 breast cancer cells were investigated, and MRS studies were performed both on live cells and on cell extracts. 31P and 1H MRS were used to determine total cellular metabolite concentrations and 13C MRS was used to probe the metabolism of [1,2-13C]-choline. To explain the MRS metabolic findings, microarray and RT-PCR were used to analyze gene expression, and in vitro activity assays were performed to determine changes in enzymatic activity following 17-AAG treatment. Results Treatment of MCF-7 cells with 17-AAG for 48 hours caused a significant increase in intracellular levels of choline (to 266 ± 18% of control, P = 0.05) and phosphocholine (PC; to 181 ± 10% of control, P = 0.001) associated with an increase in expression of choline transporter SLC44A1 and an elevation in the de novo synthesis of PC. We also detected an increase in intracellular levels of glycerophosphocholine (GPC; to 176 ± 38% of control, P = 0.03) associated with an increase in PLA2 expression and activity. Conclusions This study determined that in the MCF-7 breast cancer model inhibition of Hsp90 by 17-AAG results in a significant MRS-detectable increase in choline, PC and GPC, which is likely due to an increase in choline transport into the cell and phospholipase activation. 1H MRSI can be used in the clinical setting to detect levels of total choline-containing metabolite (t-Cho, composed of intracellular

  20. 26 CFR 1.6038A-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) Material profit and loss statements. (4) Existing records test. (5) Significant industry segment test. (i... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Table of contents. 1.6038A-0 Section 1.6038A-0...) INCOME TAXES (CONTINUED) Information Returns § 1.6038A-0 Table of contents. This section lists...

  1. 26 CFR 1.6038A-0 - Table of contents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Material profit and loss statements. (4) Existing records test. (5) Significant industry segment test. (i... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Table of contents. 1.6038A-0 Section 1.6038A-0...) INCOME TAXES (CONTINUED) Information Returns § 1.6038A-0 Table of contents. This section lists...

  2. Proteomic analysis of trichloroethylene-induced alterations in expression, distribution, and interactions of SET/TAF-Iα and two SET/TAF-Iα-binding proteins, eEF1A1 and eEF1A2, in hepatic L-02 cells

    SciTech Connect

    Hong, Wen-Xu; Yang, Liang; Chen, Moutong; Yang, Xifei; Ren, Xiaohu; Fang, Shisong; Ye, Jinbo; Huang, Haiyan; Peng, Chaoqiong; Zhou, Li; Huang, Xinfeng; Yang, Fan; Wu, Desheng; Zhuang, Zhixiong; Liu, Jianjun

    2012-09-01

    Emerging evidence indicates that trichloroethylene (TCE) exposure causes severe hepatotoxicity. However, the mechanisms of TCE hepatotoxicity remain unclear. Recently, we reported that TCE exposure up-regulated the expression of the oncoprotein SET/TAF-Iα and SET knockdown attenuated TCE-induced cytotoxicity in hepatic L-02 cells. To decipher the function of SET/TAF-Iα and its contributions to TCE-induced hepatotoxicity, we employed a proteomic analysis of SET/TAF-Iα with tandem affinity purification to identify SET/TAF-Iα-binding proteins. We identified 42 novel Gene Ontology co-annotated SET/TAF-Iα-binding proteins. The identifications of two of these proteins (eEF1A1, elongation factor 1-alpha 1; eEF1A2, elongation factor 1-alpha 2) were confirmed by Western blot analysis and co-immunoprecipitation (Co-IP). Furthermore, we analyzed the effects of TCE on the expression, distribution and interactions of eEF1A1, eEF1A2 and SET in L-02 cells. Western blot analysis reveals a significant up-regulation of eEF1A1, eEF1A2 and two isoforms of SET, and immunocytochemical analysis reveals that eEF1A1 and SET is redistributed by TCE. SET is redistributed from the nucleus to the cytoplasm, while eFE1A1 is translocated from the cytoplasm to the nucleus. Moreover, we find by Co-IP that TCE exposure significantly increases the interaction of SET with eEF1A2. Our data not only provide insights into the physiological functions of SET/TAF-Iα and complement the SET interaction networks, but also demonstrate that TCE exposure induces alterations in the expression, distribution and interactions of SET and its binding partners. These alterations may constitute the mechanisms of TCE cytotoxicity. -- Highlights: ► Identify 62 SET/TAF-Iα-associated proteins in human L-02 cells ► Trichloroethylene (TCE) alters the interaction of SET with eEF1A1 and eEF1A2. ► TCE induces the translocation and up-regulation of SET. ► TCE induces the translocation and up-regulation of eEF1A.

  3. OTR interferometry diagnostic for the A0 photoinjector

    SciTech Connect

    Kazakevich, G.; Edwards, Helen Thom; Fliller, R.; Lebedev, V.; Nagaitsev, S.; Thurman-Keup, R.; /Fermilab

    2007-06-01

    OTR interferometry (OTRI) is an attractive diagnostic for investigation of relativistic electron beam parameters. The diagnostic is currently under development at the A0 Photoinjector. This diagnostic is also applicable for NML accelerator test facility that will be built at Fermilab. The experimental setup of the OTR Interferometer for the FNAL A0 Photoinjector is described in the report. Results of simulations and measurements are presented and discussed.

  4. A1C test

    MedlinePlus

    HbA1C test; Glycated hemoglobin test; Glycohemoglobin test; Hemoglobin A1C; Diabetes - A1C; Diabetic - A1C ... gov/pubmed/26696680 . Chernecky CC, Berger BJ. Glycosylated hemoglobin (GHb, glycohemoglobin, glycated hemoglobin, HbA1a, HbA1b, HbA1c - blood. ...

  5. 26 CFR 1.468A-0T - Nuclear decommissioning costs; table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 6 2010-04-01 2010-04-01 false Nuclear decommissioning costs; table of contents... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Taxable Year for Which Deductions Taken § 1.468A-0T Nuclear...) Definitions. (c) Special rules applicable to certain experimental nuclear facilities. § 1.468A-2TTreatment...

  6. Optical transition radiation interferometry for the A0 photoinjector

    SciTech Connect

    Kazakevich, G.; Edwards, H.; Fliller, R.; Nagaitsev, S.; Ruan, J.; Thurman-Keup, R.; /Fermilab

    2008-06-01

    Optical Transition Radiation Interferometry (OTRI) is a promising diagnostic technique and has been successfully developed and used for investigation of relativistic beams. For mid-energy accelerators the technique is traditionally based on thin polymer films (the first one is being transparent for visible light), which causes beam multiple scattering of about 1 mrad. A disadvantage of those films is unacceptable vacuum properties for photoinjectors and accelerators using superconducting cavities. We have studied the application of thin mica sheets for the OTRI diagnostics at the A0 Photoinjector in comparison with 2.5 {micro}m thick Mylar films. This diagnostic is also applicable for the ILCTA-NML accelerator test facility that is planned at Fermilab. This report discusses the experimental setups of the OTR interferometer for the A0 Photoinjector and presents comparisons of simulations and measurements obtained using Mylar and mica-based interferometers.

  7. Theory of multiresonant metamaterials for A0 Lamb waves

    NASA Astrophysics Data System (ADS)

    Williams, Earl G.; Roux, Philippe; Rupin, Matthieu; Kuperman, W. A.

    2015-03-01

    We develop an analytical wave approach to describe the physics properties of multiresonant metamaterials for Lamb waves propagating in plates. The metamaterial that we characterize consists of a 10 by 10 uniform, periodic array of long rods attached to the surface of the plate that forms the substrate in which antisymmetric A0 Lamb waves are excited. We show that the A0 Lamb wave propagation through the metamaterial can be accurately modeled using a simplified theory that replaces the two-dimensional array with a one-dimensional beam with a linear array of 10 rods. The wave propagation problem is solved rigorously for this one-dimensional system using the scattering matrix for a single rod. The exact eigenvalues of the system are approximated in a long wavelength expansion to determine a simple expression for the effective wave number and dispersion of the metamaterial. The modeled dispersion is compared with an experimental measurement of the dispersion inside the metamaterial with excellent agreement. The multiresonant rods, restricted to longitudinal vibration consistent with A0 Lamb waves excited in the plate, produce two wide stop bands in the frequency domain from 0 to 10 kHz where the stop or passband boundaries align with the minima and maxima of the rod's impedance. We show that a negative effective density is obtained in the stop band. With the simple yet highly accurate relations given in this paper we have a tool to develop more complex metamaterials with rods and plates of different properties.

  8. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... payment of the section 2056A estate tax. (a) Distributions during surviving spouse's life. (b) Tax at death of surviving spouse. (c) Extension of time for paying section 2056A estate tax. (1) Extension of time for paying tax under section 6161(a)(2). (2) Extension of time for paying tax under section...

  9. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... payment of the section 2056A estate tax. (a) Distributions during surviving spouse's life. (b) Tax at death of surviving spouse. (c) Extension of time for paying section 2056A estate tax. (1) Extension of time for paying tax under section 6161(a)(2). (2) Extension of time for paying tax under section...

  10. Intial synchroscan streak camera imaging at the A0 photoinjector

    SciTech Connect

    Lumpkin, A.H.; Ruan, J.; /Fermilab

    2008-04-01

    At the Fermilab A0 photoinjector facility, bunch-length measurements of the laser micropulse and the e-beam micropulse have been done in the past with a single-sweep module of the Hamamatsu C5680 streak camera with an intrinsic shot-to-shot trigger jitter of 10 to 20 ps. We have upgraded the camera system with the synchroscan module tuned to 81.25 MHz to provide synchronous summing capability with less than 1.5-ps FWHM trigger jitter and a phase-locked delay box to provide phase stability of {approx}1 ps over 10s of minutes. This allowed us to measure both the UV laser pulse train at 244 nm and the e-beam via optical transition radiation (OTR). Due to the low electron beam energies and OTR signals, we typically summed over 50 micropulses with 1 nC per micropulse. We also did electron beam bunch length vs. micropulse charge measurements to identify a significant e-beam micropulse elongation from 10 to 30 ps (FWHM) for charges from 1 to 4.6 nC. This effect is attributed to space-charge effects in the PC gun as reproduced by ASTRA calculations. Chromatic temporal dispersion effects in the optics were also characterized and will be reported.

  11. Lamb wave (A0 mode) scattering directionality at defects

    NASA Astrophysics Data System (ADS)

    Fromme, Paul

    2017-02-01

    Localized and distributed guided ultrasonic waves array systems offer an efficient way for the structural health monitoring of large structures. The detection sensitivity for fatigue cracks depends on the orientation of the crack relative to the location of the sensor elements. Crack-like defects have a directionality pattern of the scattered field depending on the angle of the incident wave relative to the defect orientation and on the ratio of the defect depth and length to the wavelength. From FE simulations it has been shown that for cracks and notches almost no energy is scattered in certain directions from the defect, i.e., the data processing algorithm must take into account that for some transducer combinations no change in the signal even for a significant defect will be detected. The scattered wave field directionality pattern for an incident low frequency A0 Lamb wave mode was predicted from 3D Finite Element simulations and verified from experimental measurements at machined part-through and through-thickness notches using a laser interferometer. Good agreement was found and the directionality pattern can be predicted accurately. The amplitude of the scattered wave was quantified for a systematic variation of the angle of the incident wave relative to the defect orientation, the defect depth, and the ratio of the characteristic defect size to the wavelength. Based on these results the detection sensitivity for crack-like defects in plate structures using guided wave sensor arrays can be quantified.

  12. Experimental study of A0 Lamb wave tomography

    SciTech Connect

    Seher, Matthias Huthwaite, Peter Lowe, Michael Cawley, Peter

    2015-03-31

    Corrosion damage in inaccessible regions presents a significant challenge to the petrochemical industry, and determining the remaining wall thickness is important to establish the remaining service life. Guided wave tomography is one solution and involves transmitting Lamb waves through the area of interest and using the received signals to reconstruct the remaining wall thickness. This avoids the need to access all points on the surface, making the technique well suited to inspection beneath supports. For this purpose a tomography system for pipe inspections is developed using low frequency A0 Lamb waves that are excited and detected with two arrays of electromagnetic acoustic transducers (EMATs). Two different defect depths are considered with different contrasts relative to the nominal wall thickness and in a first step, the repeatability of the measurements is demonstrated. Due to the limited view array configuration, the maximum depth of the reconstruction underestimates the true depth. In a second experimental study, the influence of a pipe clamp on the thickness reconstruction is considered, representing an inspection problem with restricted access. Preliminary results have shown that the maximum defect depth is further underestimated when compared to the thickness reconstructions without the clamp. However, it is possible to detect the defect underneath the clamp for all conducted experiments.

  13. A1C Test

    MedlinePlus

    ... eAG on their DiabetesPro web site . The NGSP web site also provides a calculator to convert hemoglobin A1c in SI units mmol/mol into percentage. ^ Back to top Is there anything else I should know? The A1c test will not reflect temporary, acute blood glucose increases ...

  14. A1C

    MedlinePlus

    A1C is a blood test for type 2 diabetes and prediabetes. It measures your average blood glucose, or blood sugar, level over the past 3 ... A1C alone or in combination with other diabetes tests to make a diagnosis. They also use the ...

  15. A 0.23 pJ 11.05-bit ENOB 125-MS/s pipelined ADC in a 0.18 μm CMOS process

    NASA Astrophysics Data System (ADS)

    Yong, Wang; Jianyun, Zhang; Rui, Yin; Yuhang, Zhao; Wei, Zhang

    2015-05-01

    This paper describes a 12-bit 125-MS/s pipelined analog-to-digital converter (ADC) that is implemented in a 0.18 μm CMOS process. A gate-bootstrapping switch is used as the bottom-sampling switch in the first stage to enhance the sampling linearity. The measured differential and integral nonlinearities of the prototype are less than 0.79 least significant bit (LSB) and 0.86 LSB, respectively, at the full sampling rate. The ADC exhibits an effective number of bits (ENOB) of more than 11.05 bits at the input frequency of 10.5 MHz. The ADC also achieves a 10.5 bits ENOB with the Nyquist input frequency at the full sample rate. In addition, the ADC consumes 62 mW from a 1.9 V power supply and occupies 1.17 mm2, which includes an on-chip reference buffer. The figure-of-merit of this ADC is 0.23 pJ/step. Project supported by the Foundation of Shanghai Municipal Commission of Economy and Informatization (No. 130311).

  16. OPERATION JANGLE. Blast and Shock Measurements 1. Project 1.1. Ground Acceleration Measurement (WT-388). Project 1.2a-1. Peak Air Blast Pressures along the Ground from Shock Velocity Measurements (WT-323). Project 1.2a-2. Transient Ground Mechanical Effects from HE and Nuclear Explosions (WT-385)

    DTIC Science & Technology

    1952-06-01

    reinforced concrete wall 5 ft thick. 2.8.1 EE of Accelertions to "e Measured. ; On the basis of these considerations of damage it was * decided that...1200 1800 2500 3500 50~00 700 R’ OISTA14CF FROM ZEIA0 (F T) vig. A.1. 4,000 Lb shot - Prediction of Maximuim Acceleration frcc I Lapon’s Theory and...of I concrete . The cast aluminum housing: called the velocity head, which contained one blast switch and two microphones is illustrated in Fig. 2.9. 0

  17. Initial beam-profiling tests with the NML prototype station at the Fermilab A0 Photoinjector

    SciTech Connect

    Lumpkin, A.; Flora, R.; Johnson, A.S.; Ruan, J.; Santucci, J.; Scarpine, V.; Sun, Y.-E.; Thurman-Keup, R.; Church, M.; Wendt, M.; /Fermilab

    2011-03-01

    The beam-profile diagnostics station prototype for the superconducting rf electron linac being constructed at Fermilab at the New Muon Lab has been tested. The station uses intercepting radiation converter screens for the low-power beam mode: either a 100-{micro}m thick YAG:Ce single crystal scintillator or a 1-{micro}m thin Al optical transition radiation (OTR) foil. The screens are oriented with the surface perpendicular to the beam direction. A downstream mirror with its surface at 45 degrees to the beam direction is used to direct the radiation into the optical transport. The optical system has better than 20 (10) {micro}m rms spatial resolution when covering a vertical field of view of 18 (5) mm. The initial tests were performed at the A0 Photoinjector at a beam energy of {approx}15 MeV and with micropulse charges from 25 to 500 pC for beam sizes of 45 to 250 microns. Example results will be presented.

  18. Search for a low-mass higgs boson in Upsilon(3S)-->gammaA(0), A(0)-->tau(+)tau(-) at BABAR.

    PubMed

    Aubert, B; Karyotakis, Y; Lees, J P; Poireau, V; Prencipe, E; Prudent, X; Tisserand, V; Tico, J Garra; Grauges, E; Martinelli, M; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Battaglia, M; Brown, D N; Kerth, L T; Kolomensky, Yu G; Lynch, G; Osipenkov, I L; Tackmann, K; Tanabe, T; Hawkes, C M; Soni, N; Watson, A T; Koch, H; Schroeder, T; Asgeirsson, D J; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Randle-Conde, A; Blinov, V E; Bukin, A D; Buzykaev, A R; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Atmacan, H; Gary, J W; Liu, F; Long, O; Vitug, G M; Yasin, Z; Sharma, V; Campagnari, C; Hong, T M; Kovalskyi, D; Mazur, M A; Richman, J D; Beck, T W; Eisner, A M; Heusch, C A; Kroseberg, J; Lockman, W S; Martinez, A J; Schalk, T; Schumm, B A; Seiden, A; Wang, L; Winstrom, L O; Cheng, C H; Doll, D A; Echenard, B; Fang, F; Hitlin, D G; Narsky, I; Ongmongkolkul, P; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Bloom, P C; Ford, W T; Gaz, A; Hirschauer, J F; Nagel, M; Nauenberg, U; Smith, J G; Wagner, S R; Ayad, R; Toki, W H; Wilson, R J; Feltresi, E; Hauke, A; Jasper, H; Karbach, T M; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Kobel, M J; Nogowski, R; Schubert, K R; Schwierz, R; Bernard, D; Latour, E; Verderi, M; Clark, P J; Playfer, S; Watson, J E; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Fioravanti, E; Franchini, P; Luppi, E; Munerato, M; Negrini, M; Petrella, A; Piemontese, L; Santoro, V; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Contri, R; Guido, E; Lo Vetere, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Tosi, S; Chaisanguanthum, K S; Morii, M; Adametz, A; Marks, J; Schenk, S; Uwer, U; Bernlochner, F U; Klose, V; Lacker, H M; Lueck, T; Volk, A; Bard, D J; Dauncey, P D; Tibbetts, M; Behera, P K; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Derkach, D; da Costa, J Firmino; Grosdidier, G; Le Diberder, F; Lepeltier, V; Lutz, A M; Malaescu, B; Pruvot, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Touramanis, C; Bevan, A J; Clarke, C K; Di Lodovico, F; Sacco, R; Sigamani, M; Cowan, G; Paramesvaran, S; Wren, A C; Brown, D N; Davis, C L; Denig, A G; Fritsch, M; Gradl, W; Hafner, A; Alwyn, K E; Bailey, D; Barlow, R J; Jackson, G; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Salvati, E; Cowan, R; Dujmic, D; Fisher, P H; Henderson, S W; Sciolla, G; Spitznagel, M; Yamamoto, R K; Zhao, M; Patel, P M; Robertson, S H; Schram, M; Biassoni, P; Lazzaro, A; Lombardo, V; Palombo, F; Stracka, S; Cremaldi, L; Godang, R; Kroeger, R; Sonnek, P; Summers, D J; Zhao, H W; Simard, M; Taras, P; Nicholson, H; De Nardo, G; Lista, L; Monorchio, D; Onorato, G; Sciacca, C; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Wang, W F; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Castelli, G; Gagliardi, N; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Del Amo Sanchez, P; Ben-Haim, E; Bonneaud, G R; Briand, H; Chauveau, J; Hamon, O; Leruste, Ph; Marchiori, G; Ocariz, J; Perez, A; Prendki, J; Sitt, S; Gladney, L; Biasini, M; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Calderini, G; Carpinelli, M; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Lopes Pegna, D; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Anulli, F; Baracchini, E; Cavoto, G; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Gioi, L Li; Mazzoni, M A; Morganti, S; Piredda, G; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Franek, B; Olaiya, E O; Wilson, F F; Emery, S; Esteve, L; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Allen, M T; Aston, D; Bartoldus, R; Benitez, J F; Cenci, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Sevilla, M Franco; Gabareen, A M; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Lindquist, B; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; Neal, H; Nelson, S; O'Grady, C P; Ofte, I; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; West, C A; Wisniewski, W J; Wittgen, M; Wright, D H; Wulsin, H W; Yarritu, A K; Young, C C; Ziegler, V; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Bellis, M; Burchat, P R; Edwards, A J; Miyashita, T S; Ahmed, S; Alam, M S; Ernst, J A; Pan, B; Saeed, M A; Zain, S B; Soffer, A; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Wray, B C; Drummond, B W; Izen, J M; Lou, X C; Bianchi, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Choi, H H F; Hamano, K; King, G J; Kowalewski, R; Lewczuk, M J; Nugent, I M; Roney, J M; Sobie, R J; Gershon, T J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Puccio, E M T; Band, H R; Chen, X; Dasu, S; Flood, K T; Pan, Y; Prepost, R; Vuosalo, C O; Wu, S L

    2009-10-30

    We search for a light Higgs boson A0 in the radiative decay Upsilon(3S)-->gammaA(0), A(0)-->tau+tau-, tau+-->e+nu(e)nu(tau), or tau+-->mu+nu(mu)nu(tau). The data sample contains 122x10(6) Upsilon(3S) events recorded with the BABAR detector. We find no evidence for a narrow structure in the studied tau+tau- invariant mass region of 4.03gammaA(0))xB(A(0)-->tau+tau-)>(1.5-16)x10(-5) across the m(tau+tau-) range. We also set a 90% C.L. upper limit on the tau+tau- decay of the eta(b) at B(eta(b)-->tau+tau-)<8%.

  19. A study of mass loss from the mid-ultraviolet spectrum of Alpha Cygni /A2 Ia/, Beta Orionis /B8 Ia/, and Eta Leonis /A0 Ib/

    NASA Technical Reports Server (NTRS)

    Lamers, H. J. G. L. M.; Stalio, R.; Kondo, Y.

    1978-01-01

    Results are presented for a study of mass loss from A and late-B supergiants based on high-resolution mid-UV spectra obtained with the echelle spectrograph of the Balloon-borne Ultraviolet Stellar Spectrometer. Spectra of Alpha Cyg, Beta Ori, Eta Leo, and Alpha Lyr are compared in selected wavelength regions; particular attention is given to previous observations of each star, the Mg II and Fe II resonance lines, lines due to other ions, and evidence for mass ejection. The results indicate that mass loss from late-B and A supergiants is variable, that a considerable fraction of envelope material is ejected in 'puffs', and that the puffs may be due to photospheric instabilities. A mass-loss rate of about 1 hundred-millionth of a solar mass per year is derived for Alpha Cyg and shown to be two orders of magnitude smaller than the value determined from the observed IR excess. This discrepancy is attributed to excess ionization in the envelope.

  20. A 0.5 Tesla Transverse-Field Alternating Magnetic Field Demagnetizer

    NASA Astrophysics Data System (ADS)

    Schillinger, W. E.; Morris, E. R.; Finn, D. R.; Coe, R. S.

    2015-12-01

    We have built an alternating field demagnetizer that can routinely achieve a maximum field of 0.5 Tesla. It uses an amorphous magnetic core with an air-cooled coil. We have started with a 0.5 T design, which satisfies most of our immediate needs, but we can certainly achieve higher fields. In our design, the magnetic field is transverse to the bore and uniform to 1% over a standard (25 mm) paleomagnetic sample. It is powered by a 1 kW power amplifier and is compatible with our existing sample handler for automated demagnetization and measurement (Morris et al., 2009). It's much higher peak field has enabled us to completely demagnetize many of the samples that previously we could not with commercial equipment. This capability is especially needed for high-coercivity sedimentary and igneous rocks that contain magnetic minerals that alter during thermal demagnetization. It will also enable detailed automated demagnetization of high coercivity phases in extraterrestrial samples, such as native iron, iron-alloy and sulfide minerals that are common in lunar rocks and meteorites. Furthermore, it has opened the door for us to use the rock-magnetic technique of component analysis, using coercivity distributions derived from very detailed AF demagnetization of NRM and remanence produced in the laboratory to characterize the magnetic mineralogy of sedimentary rocks. In addition to the many benefits this instrument has brought to our own research, a much broader potential impact is to replace the transverse coils in automated AF demagnetization systems, which typically are limited to peak fields around 0.1 T.

  1. Gamma-ray bursts: discovering the progenitors and understanding the explosion - visits A0-R0

    NASA Astrophysics Data System (ADS)

    Kulkarni, Shrinivas

    2000-07-01

    Gamma-ray burst astronomy, one of the most active and exciting frontiers in astrophysics, is now entering a critical stage - with dramatic leaps in our understanding of these events, as well as new discoveries imminent. In the upcoming year, improvements in triggering and positioning accuracy provided by the SAX and HETE-2 gamma-ray satellites will allow entirely new classes of events to be studied. Given the recent progress in this field, we are now in a position to design precision, broadband measurements that can provide quantitative information on the as-yet unknown energy sources, the explosion geometry, and the surrounding medium. In particular, the growing evidence of an intimate connection between SNe and GRBs can be definitively tested. Who can activate the proposal: Shri Kulkarni srk@astro.caltech.edu Work: {626} 395-4010 Mobile: {626} 676-4721 Home: {626} 795-7894 Alan Diercks ad@astro.caltech.edu Work: {626} 395-4970 Mobile {626} 676-4724 Home: {626} 577-7390 Titus Galama tjg@astro.caltech.edu Work: {626} 395-8495 Mobile {626} 676-4723 Home: {626} 568-3937-The STIS CCD imaging should occur as quickly as possible after activiation. {visits 1-72.}-The UV sepctroscopy {Visits UW and UV} should begin 2-3 days after activation.-The STIS UV imaging should occur approximately {A0, C0, E0, G0, I0, K0, M0, O0, Q0} 1 week after activation. and goes with The WFPC2 imaging {A1-B0, C1-D0, E1-F0, G1-H0, I1-J0, K1-L0, M1-N0, O1-P0, Q1-R0} should start 15-20 daysafter activation depending on redshfit.

  2. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...×105 Pm-151 2.0 5.4×101 6.0×10−1 1.6×101 2.7×104 7.3×105 Po-210 Polonium (84) 4.0×101 1.1×103 2.0×10−2....7×10−9 1.0×106 2.7×10−5 Po-210 Polonium (84) 1.0×101 2.7×10−10 1.0×104 2.7×10−7 Pr-142 Praseodymium...-210 1.0 2.7×101 6.0×10−1 1.6×101 4.6×103 1.2×105 Bi-210m (a) 6.0×10−1 1.6×101 2.0×10−2 5.4×10−1...

  3. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Neodymium (60) 6.0 1.6×102 6.0×10−1 1.6×101 3.0×103 8.1×104 Nd-149 6.0×10−1 1.6×101 5.0×10−1 1.4×101 4.5×105... Nd-147 Neodymium (60) 1.0×102 2.7×10−9 1.0×106 2.7×10−5 Nd-149 1.0×102 2.7×10−9 1.0×106 2.7×10−5...

  4. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Neodymium (60) 6.0 1.6×102 6.0×10−1 1.6×101 3.0×103 8.1×104 Nd-149 6.0×10−1 1.6×101 5.0×10−1 1.4×101 4.5×105... Neodymium (60) 1.0×102 2.7×10−9 1.0×106 2.7×10−5 Nd-149 1.0×102 2.7×10−9 1.0×106 2.7×10−5 Ni-59 Nickel...

  5. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Neodymium (60) 6.0 1.6×102 6.0×10−1 1.6×101 3.0×103 8.1×104 Nd-149 6.0×10−1 1.6×101 5.0×10−1 1.4×101 4.5×105... Neodymium (60) 1.0×102 2.7×10−9 1.0×106 2.7×10−5 Nd-149 1.0×102 2.7×10−9 1.0×106 2.7×10−5 Ni-59 Nickel...

  6. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Neodymium (60) 6.0 1.6×102 6.0×10−1 1.6×101 3.0×103 8.1×104 Nd-149 6.0×10−1 1.6×101 5.0×10−1 1.4×101 4.5×105... Nd-147 Neodymium (60) 1.0×102 2.7×10−9 1.0×106 2.7×10−5 Nd-149 1.0×102 2.7×10−9 1.0×106 2.7×10−5...

  7. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 7.0×105 Ho-166m 6.0×10−1 1.6×101 5.0×10−1 1.4×101 6.6×10−2 1.8 I-123 Iodine (53) 6.0 1.6×102 3.0 8.1×101 7.1×104 1.9×106 I-124 1.0 2.7×101 1.0 2.7×101 9.3×103 2.5×105 I-125 2.0×101 5.4×102 3.0 8.1×101 6... 4.0×10−1 1.1×101 1.5×104 4.0×105 Sb-124 6.0×10−1 1.6×101 6.0×10−1 1.6×101 6.5×102 1.7×104 Sb-125...

  8. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 7.0×105 Ho-166m 6.0×10−1 1.6×101 5.0×10−1 1.4×101 6.6×10−2 1.8 I-123 Iodine (53) 6.0 1.6×102 3.0 8.1×101 7.1×104 1.9×106 I-124 1.0 2.7×101 1.0 2.7×101 9.3×103 2.5×105 I-125 2.0×101 5.4×102 3.0 8.1×101 6... 4.0×10−1 1.1×101 1.5×104 4.0×105 Sb-124 6.0×10−1 1.6×101 6.0×10−1 1.6×101 6.5×102 1.7×104 Sb-125...

  9. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 7.0×105 Ho-166m 6.0×10−1 1.6×101 5.0×10−1 1.4×101 6.6×10−2 1.8 I-123 Iodine (53) 6.0 1.6×102 3.0 8.1×101 7.1×104 1.9×106 I-124 1.0 2.7×101 1.0 2.7×101 9.3×103 2.5×105 I-125 2.0×101 5.4×102 3.0 8.1×101 6... 4.0×10−1 1.1×101 1.5×104 4.0×105 Sb-124 6.0×10−1 1.6×101 6.0×10−1 1.6×101 6.5×102 1.7×104 Sb-125...

  10. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 7.0×105 Ho-166m 6.0×10−1 1.6×101 5.0×10−1 1.4×101 6.6×10−2 1.8 I-123 Iodine (53) 6.0 1.6×102 3.0 8.1×101 7.1×104 1.9×106 I-124 1.0 2.7×101 1.0 2.7×101 9.3×103 2.5×105 I-125 2.0×101 5.4×102 3.0 8.1×101 6...×101 1.5×104 4.0×105 Sb-124 6.0×10−1 1.6×101 6.0×10−1 1.6×101 6.5×102 1.7×104 Sb-125 2.0 5.4×101 1.0...

  11. Measurement of the proton $A_1$ and $A_2$ spin asymmetries. Probing Color Forces

    SciTech Connect

    Armstrong, Whitney

    2015-05-01

    The Spin Asymmetries of the Nucleon Experiment (SANE) measured the proton spin structure function $g_2$ in a range of Bjorken x, 0.3 < x < 0.8, where extraction of the twist-3 matrix element $d_2^p$ (an integral of $g_2$ weighted by $x^2$) is most sensitive. The data was taken from $Q^2$ equal to 2.5 $GeV^2$ up to 6.5 $GeV^2$. In this polarized electron scattering off a polarized hydrogen target experiment, two double spin asymmetries, A∥ and A⊥ were measured using the BETA (Big Electron Telescope Array) Detector. BETA consisted of a scintillator hodoscope, gas Cerenkov counter, lucite hodoscope and a large lead glass electromagnetic calorimeter. With a unique open geometry, a threshold gas Cerenkov detector allowed BETA to cleanly identify electrons for this inclusive experiment. A measurement of $d_2^p$ is compared to lattice QCD calculations.

  12. 26 CFR 1.408A-0 - Roth IRAs; table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Roth IRAs; table of contents. 1.408A-0 Section 1... (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-0 Roth IRAs; table of contents. This table of contents lists the regulations relating to Roth IRAs under section 408A of...

  13. 26 CFR 1.408A-0 - Roth IRAs; table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Roth IRAs; table of contents. 1.408A-0 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-0 Roth IRAs; table of contents. This table of contents lists the regulations relating to Roth IRAs under section...

  14. 26 CFR 1.408A-0 - Roth IRAs; table of contents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Roth IRAs; table of contents. 1.408A-0 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-0 Roth IRAs; table of contents. This table of contents lists the regulations relating to Roth IRAs under section...

  15. 26 CFR 1.408A-0 - Roth IRAs; table of contents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Roth IRAs; table of contents. 1.408A-0 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-0 Roth IRAs; table of contents. This table of contents lists the regulations relating to Roth IRAs under section...

  16. 26 CFR 1.408A-0 - Roth IRAs; table of contents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Roth IRAs; table of contents. 1.408A-0 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-0 Roth IRAs; table of contents. This table of contents lists the regulations relating to Roth IRAs under section...

  17. 32 CFR 1636.3 - Basis for classification in Class 1-A-0.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Basis for classification in Class 1-A-0. 1636.3 Section 1636.3 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION OF CONSCIENTIOUS OBJECTORS § 1636.3 Basis for classification in Class 1-A-0. (a) A registrant...

  18. 26 CFR 1.641(a)-0 - Scope of subchapter J.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... mitigation of (i) the progressive rates of tax (including mitigation as a result of deferral of tax) or (ii...(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.641(a)-0 Scope of subchapter...

  19. 26 CFR 1.641(a)-0 - Scope of subchapter J.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... mitigation of (i) the progressive rates of tax (including mitigation as a result of deferral of tax) or (ii...(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.641(a)-0 Scope of subchapter...

  20. 26 CFR 1.641(a)-0 - Scope of subchapter J.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... mitigation of (i) the progressive rates of tax (including mitigation as a result of deferral of tax) or (ii...(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.641(a)-0 Scope of subchapter...

  1. 26 CFR 1.641(a)-0 - Scope of subchapter J.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... mitigation of (i) the progressive rates of tax (including mitigation as a result of deferral of tax) or (ii...(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.641(a)-0 Scope of subchapter...

  2. 26 CFR 1.641(a)-0 - Scope of subchapter J.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Scope of subchapter J. 1.641(a)-0 Section 1.641... (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.641(a)-0 Scope of subchapter J. (a) In general. Subchapter J (sections 641 and following), chapter 1 of the Code, deals with the taxation...

  3. 26 CFR 1.860A-0 - Outline of REMIC provisions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Outline of REMIC provisions. 1.860A-0 Section 1... (CONTINUED) INCOME TAXES Real Estate Investment Trusts § 1.860A-0 Outline of REMIC provisions. This section...) Agent. (7) Relief from liability. (i) Transferee furnishes information under penalties of perjury....

  4. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... CLASSIFICATION OF CONSCIENTIOUS OBJECTORS § 1636.5 Exclusion from Class 1-A-0 and Class 1-0. A registrant shall... any form (a selective objection). If a registrant objects to war in any form, but also believes in...

  5. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests...

  6. Identification and analysis of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 in cynomolgus macaques.

    PubMed

    Uno, Yasuhiro; Hosaka, Shinya; Yamazaki, Hiroshi

    2014-12-01

    Cytochromes P450 (P450) are important for not only drug metabolism and toxicity, but also biosynthesis and metabolism of cholesterol and bile acids, and steroid synthesis. In cynomolgus macaques, widely used in biomedical research, we have characterized P450 cDNAs, which were isolated as expressed sequence tags of cynomolgus macaque liver. In this study, cynomolgus CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 cDNAs were characterized by sequence analysis, phylogenetic analysis and tissue expression pattern. By sequence analysis, these five cynomolgus P450s had high sequence identities (94-99%) to the human orthologs in amino acids. By phylogenetic analysis, each cynomolgus P450 was more closely related to the human ortholog as compared with the dog or rat ortholog. By quantitative polymerase chain reaction, among the 10 tissue types, CYP7A1 and CYP17A1 mRNAs were preferentially expressed in liver and adrenal gland, respectively. Cynomolgus CYP27A1 and CYP51A1 mRNAs were most abundantly expressed in liver and testis, respectively. Cynomolgus CYP20A1 mRNA was expressed in all the tissues, including brain and liver. Tissue expression patterns of each cynomolgus P450 were generally similar to that of the human ortholog. These results suggest the molecular similarities of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 between cynomolgus macaques and humans.

  7. Experimental study of coherent synchrotron radiation in the emittance exchange line at the A0-photoinjector

    SciTech Connect

    Thangaraj, Jayakar C.T.; Thurman-Keup, R.; Johnson, A.; Lumpkin, A.H.; Edwards, H.; Ruan, J.; Santucci, J.; Sun, Y.E.-; Church, M.; Piot, P.; /Fermilab /Northern Illinois U.

    2010-08-01

    Next generation accelerators will require a high current, low emittance beam with a low energy spread. Such accelerators will employ advanced beam conditioning systems such as emittance exchanger to manipulate high brightness beams. One of the goals of the Fermilab A0 photoinjector is to investigate the transverse to longitudinal emittance exchange principle. Coherent synchrotron radiation could limit high current operation of the emittance exchanger. In this paper, we report on the preliminary experimental and simulation study of the coherent synchroton radiation (CSR) in the emittance exchange line at A0 photoinjector.

  8. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests solely... theocratic, spiritual war between the forces of good and evil, he may not by reason of that belief alone...

  9. The Scalar Resonances a0/f0(980) at COSY

    SciTech Connect

    Buescher, M.

    2006-02-11

    Fundamental properties of the scalar resonances a0/f0(980), like their masses, widths and couplings to KK-bar, are poorly known. In particular, precise knowledge of the latter quantity would be of great importance since it can be related to the KK-bar content of these resonances.An experimental program is under way at COSY-Juelich aiming at the extraction of the isospin violating a0/f0 mixing amplitude {lambda} which is in leading order proportional to the product of the coupling constants of the a0 and f0 to kaons. a0/f0 production is studied in pp, pn and dd interactions, both for the KK-bar and the {pi}{eta}/{pi}{pi} decays, using the ANKE and WASA spectrometers. The latter will be available for measurements at COSY in 2007.As a first step, isovector KK-bar production has been measured in the reaction pp {yields} dK+K-bar0. The data reveal dominance of the a{sub 0}{sup +} channel, thus demonstrating the feasibility of scalar meson studies at COSY. Analyses of KK-bar- and K-bard-FSI effects yield the corresponding scattering lengths, a(KK-bar)I=1 = -(0.02 {+-} 0.03) - i(0.61 {+-} 0.05) fm and vertical bar Re a(K-bard) vertical bar {<=}1.3 fm, Im a(K-bard){<=}1.3 fm.

  10. Note on the photoproduction of the charged A1

    NASA Astrophysics Data System (ADS)

    Condo, G. T.; Handler, T.

    1987-05-01

    Arguments made nearly 15 years ago by Fox and Hey are updated in the light of recent experimental findings. These indicate that the charge-exchange photoproduction of the A1 should dominate that of the A2. Consistency with the experimental data demands an A1 mass of 1335+/-20 MeV and width of 180+/-55 MeV.

  11. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Credits or refunds. 31.6402(a)-1 Section 31... Revenue Code of 1954) § 31.6402(a)-1 Credits or refunds. (a) In general. For regulations under section 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2,...

  12. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Credits or refunds. 31.6402(a)-1 Section 31... Revenue Code of 1954) § 31.6402(a)-1 Credits or refunds. (a) In general. For regulations under section 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2,...

  13. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Credits or refunds. 31.6402(a)-1 Section 31... Revenue Code of 1954) § 31.6402(a)-1 Credits or refunds. (a) In general. For regulations under section 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2,...

  14. Hermes A-1 Test Rockets

    NASA Technical Reports Server (NTRS)

    1950-01-01

    The first Hermes A-1 test rocket was fired at White Sand Proving Ground (WSPG). Hermes was a modified V-2 German rocket, utilizing the German aerodynamic configuration; however, internally it was a completely new design. Although it did not result in an operational vehicle, the information that was gathered in the process contributed directly to the development of the Redstone rocket.

  15. Numerical design optimization of an EMAT for A0 Lamb wave generation in steel plates

    NASA Astrophysics Data System (ADS)

    Seher, Matthias; Huthwaite, Peter; Lowe, Mike; Nagy, Peter; Cawley, Peter

    2014-02-01

    An electromagnetic acoustic transducer (EMAT) for A0 Lamb wave generation on steel plates is developed to operate at 0.50 MHz-mm. A key objective of the development is to maximize the excitation and reception of the A0 mode, while minimizing those of the S0 mode. The chosen EMAT design consists of an induction coil and a permanent magnet. A finite element (FE) model of the EMAT is developed, coupling the electromagnetic and elastodynamic phenomena. An optimization process using a genetic algorithm is implemented, employing the magnet diameter and liftoff distance from the plate as design parameters and using the FE model to calculate the fitness. The optimal design suggested by the optimization process is physically implemented and the experimental measurements are compared to the FE simulation results. In a further step, the variations of the design parameters are studied numerically and the proposed EMAT design exhibits a robust behavior to small changes of the design parameters.

  16. SEMICONDUCTOR INTEGRATED CIRCUITS: A 0.8 V low power low phase-noise PLL

    NASA Astrophysics Data System (ADS)

    Yan, Han; Xiao, Liang; Haifeng, Zhou; Yinfang, Xie; Waisum, Wong

    2010-08-01

    A low power and low phase noise phase-locked loop (PLL) design for low voltage (0.8 V) applications is presented. The voltage controlled oscillator (VCO) operates from a 0.5 V voltage supply, while the other blocks operate from a 0.8 V supply. A differential NMOS-only topology is adopted for the oscillator, a modified precharge topology is applied in the phase-frequency detector (PFD), and a new feedback structure is utilized in the charge pump (CP) for ultra-low voltage applications. The divider adopts the extended true single phase clock DFF in order to operate in the high frequency region and save circuit area and power. In addition, several novel design techniques, such as removing the tail current source, are demonstrated to cut down the phase noise. Implemented in the SMIC 0.13 μm RF CMOS process and operated at 0.8 V supply voltage, the PLL measures a phase noise of-112.4 dBc/Hz at an offset frequency of 1 MHz from the carrier and a frequency range of 3.166-3.383 GHz. The improved PFD and the novel CP dissipate 0.39 mW power from a 0.8 V supply. The occupied chip area of the PFD and CP is 100 × 100 μm2. The chip occupies 0.63 mm2, and draws less than 6.54 mW from a 0.8 V supply.

  17. Envelope and multi-slit emittance measurements at Fermilab A0 photoinjector and comparison with simulations

    SciTech Connect

    Bhat, C.M.; Carneiro, J.-P.; Fliller, R.P.; Kazakevich, G.; Ruan, J.; Santucci, J.; /Fermilab

    2007-06-01

    Recently we have measured the envelope and the transverse emittance of an 0.85 nC electron beam at the Fermilab A0-Photoinjector facility. The transverse emittance measurement was performed using the multi-slit method. The data have been taken with an unstacked 2.8 ps laser pulse. In this paper we report on these beam measurements and compare the results with the predictions from beam dynamics codes ASTRA and GPT using 3D space charge routines.

  18. Bunch length measurement at the Fermilab A0 photoinjector using a Martin-Puplett interferometer

    SciTech Connect

    Thurman-Keup, Randy; Fliller, Raymond Patrick; Kazakevich, Grigory; /Fermilab

    2008-05-01

    We present preliminary measurements of the electron bunch lengths at the Fermilab A0 Photoinjector using a Martin-Puplett interferometer on loan from DESY. The photoinjector provides a relatively wide range of bunch lengths through laser pulse width adjustment and compression of the beam using a magnetic chicane. We present comparisons of data with simulations that account for diffraction distortions in the signal and discuss future plans for improving the measurement.

  19. Transverse emittance and phase space program developed for use at the Fermilab A0 Photoinjector

    SciTech Connect

    Thurman-Keup, R.; Johnson, A.S.; Lumpkin, A.H.; Ruan, J.; /Fermilab

    2011-03-01

    The Fermilab A0 Photoinjector is a 16 MeV high intensity, high brightness electron linac developed for advanced accelerator R&D. One of the key parameters for the electron beam is the transverse beam emittance. Here we report on a newly developed MATLAB based GUI program used for transverse emittance measurements using the multi-slit technique. This program combines the image acquisition and post-processing tools for determining the transverse phase space parameters with uncertainties. An integral part of accelerator research is a measurement of the beam phase space. Measurements of the transverse phase space can be accomplished by a variety of methods including multiple screens separated by drift spaces, or by sampling phase space via pepper pots or slits. In any case, the measurement of the phase space parameters, in particular the emittance, can be drastically simplified and sped up by automating the measurement in an intuitive fashion utilizing a graphical interface. At the A0 Photoinjector (A0PI), the control system is DOOCS, which originated at DESY. In addition, there is a library for interfacing to MATLAB, a graphically capable numerical analysis package sold by The Mathworks. It is this graphical package which was chosen as the basis for a graphical phase space measurement system due to its combination of analysis and display capabilities.

  20. Upgrade of the A0 photoinjector laser system for NML accelerator test facility at Fermilab

    SciTech Connect

    Ruan, J.; Edwards, H.; Fliller, R.P., III; Santucci, J.K.; /Fermilab

    2007-06-01

    The current Fermilab A0 Photoinjector laser system includes a seed laser, a flashlamp pumped multipass amplifier cavity, a flashlamp pumped 2-pass amplifier system followed by an Infra-Red (IR) to Ultra-Violet (UV) conversion stage. However the current system can only deliver up to 800 pulses due to the low efficiency of Nd:Glass used inside multi-pass cavity. In this paper we will report the effort to develop a new multi pass cavity based on Nd:YLF crystal end-pumped by diode laser. We will also discuss the foreseen design of the laser system for the NML accelerator test facility at Fermilab.

  1. Inhomogeneities in the circumstellar envelope of the A0E herbig star AB aur

    NASA Astrophysics Data System (ADS)

    Beskrovnaya, Nina; Pogodin, Mikhail; Najdenov, Ivan; Romanyuk, Iosiff

    1995-02-01

    Simultaneous high-resolution spectroscopy in Hα andUBVRI polarimetric observations are proposed as an effective method for the search for circumstellar inhomogeneities in A0-type Herbig stars. The new results for AB Aur are presented as a successful example of the use of this method. The analysis of about 100 CCD Hα profiles (R = 30 000) and more than 150 polarimetric measurements obtained in January, 1994 allowed to discover a long-lived stream-like inhomogeneity in the circumstellar gaseous envelope.

  2. 26 CFR 1.263A-0 - Outline of regulations under section 263A.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....263A-15 as follows: § 1.263A-1Uniform Capitalization of Costs. (a) Introduction. (1) In general. (2... persons. (b) Exceptions. (1) Small resellers. (2) Long-term contracts. (3) Costs incurred in certain farming businesses. (4) Costs incurred in raising, harvesting, or growing timber. (5) Qualified...

  3. Radiation shielding for superconducting RF cavity test facility at A0

    SciTech Connect

    Dhanaraj, N.; Ginsburg, C.; Rakhno, I.; Wu, G.; /Fermilab

    2008-11-01

    The results of Monte Carlo radiation shielding study performed with the MARS15 code for the vertical test facility at the A0 north cave enclosure at Fermilab are presented and discussed. The vertical test facility at the A0 north cave is planned to be used for testing 1.3 GHz single-cell superconducting RF cavities with accelerating length of 0.115 m. The operations will be focused on high accelerating gradients--up to 50 MV/m. In such a case the facility can be a strong radiation source [1]. When performing a radiation shielding design for the facility one has to take into account gammas generated due to interactions of accelerated electrons with cavity walls and surroundings (for example, range of 3.7-MeV electrons in niobium is approximately 3.1 mm while the thickness of the niobium walls of such RF cavities is about 2.8 mm). The electrons are usually the result of contamination in the cavity. The radiation shielding study was performed with the MARS15 Monte Carlo code [2]. A realistic model of the source term has been used that describes spatial, energy and angular distributions of the field-emitted electrons inside the RF cavities. The results of the calculations are normalized using the existing experimental data on measured dose rate in the vicinity of such RF cavities.

  4. Noncontact excitation of guided waves (A0 mode) using an electromagnetic acoustic transducer (EMAT)

    NASA Astrophysics Data System (ADS)

    Fromme, Paul

    2016-02-01

    Fatigue damage can develop in aircraft structures at locations of stress concentration, such as fasteners, and has to be detected before reaching a critical size to ensure safe aircraft operation. Guided ultrasonic waves offer an efficient method for the detection and characterization of such defects in large aerospace structures. Electromagnetic acoustic transducers (EMAT) for the noncontact excitation of guided ultrasonic waves were developed. The transducer development for the specific excitation of the A0 Lamb wave mode with an out-of-plane Lorentz force is explained. The achieved radial and angular dependency of the excited guided wave pulses were measured using a noncontact laser interferometer. Based on the induced eddy currents in the plate a theoretical model was developed. The application of the developed transducers for defect detection in aluminum components using fully noncontact guided wave measurements was demonstrated. Excitation of the A0 Lamb wave mode was achieved using the developed EMAT transducer and the guided wave propagation and scattering was measured using a noncontact laser interferometer.

  5. Development of Power Electronics for a 0.2kW-Class Ion Thruster

    NASA Technical Reports Server (NTRS)

    Pinero, Luis R.; Patterson, Michael J.; Bowers, Glen E.

    1997-01-01

    Applications that might benefit from low power ion propulsion systems include Earth-orbit magnetospheric mapping satellite constellations, low Earth-orbit satellites, geosynchronous Earth-orbit satellite north-south stationkeeping, and asteroid orbiters. These spacecraft are likely to have masses on the order of 50 to 500 kg with up to 0.5 kW of electrical power available. A power processing unit for a 0.2 kW-class ion thruster is currently under development for these applications. The first step in this effort is the development and testing of a 0.24 kW beam power supply. The design incorporates a 20 kHz full bridge topology with multiple secondaries connected in series to obtain outputs of up to 1200 V(sub DC). A current-mode control pulse width modulation circuit built using discrete components was selected for this application. An input voltage of 28 +/- 4 V(sub DC) was assumed, since the small spacecraft for which this system is targeted are anticipated to have unregulated low voltage busses. Efficiencies in excess of 91 percent were obtained at maximum output power. The total mass of the breadboard was less than 1.0 kg and the component mass was 0.53 kg. It is anticipated that a complete flight power processor could weigh about 2.0 kg.

  6. 26 CFR 1.408A-2 - Establishing Roth IRAs.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Establishing Roth IRAs. 1.408A-2 Section 1.408A-2...) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-2 Establishing Roth... establishing Roth IRAs: Q-1. Who can establish a Roth IRA? A-1. Except as provided in A-3 of this section,...

  7. Theoretical study on a 0.6 THz third harmonic gyrotron

    SciTech Connect

    Yuan Xuesong; Ma Chunyan; Han Yu; Yan Yang; Lan Ying

    2011-10-15

    A theoretical study on a 0.6 THz third harmonic TE{sub 37} mode gyrotron oscillator is reported in this paper in order to develop a compact, reliable, and high power terahertz radiation source. An output power of 4 kW can be generated in the TE{sub 37} mode (0.6 THz) at a resonant magnetic field of 7.86 T by the gyrotron oscillator operating at 55 kV/2 A with an electron beam radius of 0.32 mm. A magnetron injection gun (MIG) with high compression ratio has been designed. The simulation results of MIG show that the velocity ratio {alpha} is 1.37, and the perpendicular velocity spread and parallel velocity spread are 6.1% and 8.9%, respectively.

  8. pt5m - a 0.5 m robotic telescope on La Palma

    NASA Astrophysics Data System (ADS)

    Hardy, L. K.; Butterley, T.; Dhillon, V. S.; Littlefair, S. P.; Wilson, R. W.

    2015-12-01

    pt5m is a 0.5 m robotic telescope located on the roof of the 4.2 m William Herschel Telescope (WHT) building, at the Roque de los Muchachos Observatory, La Palma. Using a five-position filter wheel and CCD detector, and bespoke control software, pt5m provides a high-quality robotic observing facility. The telescope first began robotic observing in 2012, and is now contributing to transient follow-up and time-resolved astronomical studies. In this paper, we present the scientific motivation behind pt5m, as well as the specifications and unique features of the facility. We also present an example of the science we have performed with pt5m, where we measure the radius of the transiting exoplanet WASP-33b. We find a planetary radius of 1.603 ± 0.014RJ.

  9. Single-shot electro-optic sampling of coherent transition radiation at the A0 Photoinjector

    SciTech Connect

    Maxwell, T.J.; Ruan, J.; Piot, P.; Thurman-Keup, R.; /Fermilab

    2011-08-01

    Future collider applications and present high-gradient laser plasma wakefield accelerators operating with picosecond bunch durations place a higher demand on the time resolution of bunch distribution diagnostics. This demand has led to significant advancements in the field of electro-optic sampling over the past ten years. These methods allow the probing of diagnostic light such as coherent transition radiation or the bunch wakefields with sub-picosecond time resolution. Potential applications in shot-to-shot, non-interceptive diagnostics continue to be pursued for live beam monitoring of collider and pump-probe experiments. Related to our developing work with electro-optic imaging, we present results on single-shot electro-optic sampling of the coherent transition radiation from bunches generated at the A0 photoinjector.

  10. Numerical study on a 0.4 THz second harmonic gyrotron with high power

    SciTech Connect

    Chaojun, Lei; Sheng, Yu; Hongfu, Li; Yinghui, Liu; Xinjian, Niu; Qixiang, Zhao

    2013-07-15

    Terahertz and sub-terahertz science and technology are promising topics today. However, it is difficult to obtain high power source of terahertz wave. In this paper, the mode competition and beam-wave interaction in a gradually tapered cavity are studied to achieve high efficiency of a 0.4THz second harmonic gyrotron in practice. In order to attain high power and stable radiation, the TE{sub 32,5} mode is selected as the operating mode of the desired gyrotron to realize single mode oscillation. The issues of studying on the high-order mode gyrotrons are solved effectively by transforming the generalized telegraphist's equations. The efficiency and output power of the gyrotron under different conditions have been calculated by the code, which is based on the transformed equations. Consequently, the results show that single mode second harmonic radiation with power of over 150 kW at frequency of 0.4 THz could be achieved.

  11. Detecting voids in a 0.6 m coal seam, 7 m deep, using seismic reflection

    USGS Publications Warehouse

    Miller, R.D.; Steeples, D.W.

    1991-01-01

    Surface collapse over abandoned subsurface coal mines is a problem in many parts of the world. High-resolution P-wave reflection seismology was successfully used to evaluate the risk of an active sinkhole to a main north-south railroad line in an undermined area of southeastern Kansas, USA. Water-filled cavities responsible for sinkholes in this area are in a 0.6 m thick coal seam, 7 m deep. Dominant reflection frequencies in excess of 200 Hz enabled reflections from the coal seam to be discerned from the direct wave, refractions, air wave, and ground roll on unprocessed field files. Repetitive void sequences within competent coal on three seismic profiles are consistent with the "room and pillar" mining technique practiced in this area near the turn of the century. The seismic survey showed that the apparent active sinkhole was not the result of reactivated subsidence but probably erosion. ?? 1991.

  12. Group XV phospholipase A2, a lysosomal phospholipase A2

    PubMed Central

    Shayman, James A.; Kelly, Robert; Kollmeyer, Jessica; He, Yongqun; Abe, Akira

    2010-01-01

    A phospholipase A2 was identified from MDCK cell homogenates with broad specificity toward glycerophospholipids including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol. The phospholipase has the unique ability to transacylate short chain ceramides. This phospholipase is calcium-independent, localized to lysosomes, and has an acidic pH optimum. The enzyme was purified from bovine brain and found to be a water-soluble glycoprotein consisting of a single peptide chain with a molecular weight of 45 kDa. The primary structure deduced from the DNA sequences is highly conserved between chordates. The enzyme was named lysosomal phospholipase A2 (LPLA2) and subsequently designated group XV phospholipase A2. LPLA2 has 49 percent of amino acid sequence identity to lecithin cholesterol acyltransferase and is a member of the αβ-hydrolase superfamily. LPLA2 is highly expressed in alveolar macrophages. A marked accumulation of glycerophospholipids and extensive lamellar inclusion bodies, a hallmark of cellular phospholipidosis, is observed in alveolar macrophages in LPLA2−/− mice. This defect can also be reproduced in macrophages that are exposed to cationic amphiphilic drugs such as amiodarone. In addition, older LPLA2−/− mice develop a phenotype similar to human autoimmune disease. These observations indicate that LPLA2 may play a primary role in phospholipid homeostasis, drug toxicity, and host defense. PMID:21074554

  13. Infrastructure Development of Single Cell Testing Capability at A0 Facility

    SciTech Connect

    Dhanaraj, Nandhini; Padilla, R.; Reid, J.; Khabiboulline, T.; Ge, M.; Mukherjee, A.; Rakhnov, I.; Ginsburg, C.; Wu, G.; Harms, E.; Carter, H.; /Fermilab

    2009-09-01

    The objective of this technical note is to document the details of the infrastructure development process that was realized at the A0 photo injector facility to establish RF cold testing capability for 1.3 GHz superconducting niobium single cell cavities. The activity began the last quarter of CY 2006 and ended the first quarter of CY 2009. The whole process involved addressing various aspects such as design of vertical insert and lifting fixture, modification of existing RF test station and design of new couplers, development of a Temperature Mapping (T-Map) system, radiation considerations for the test location (north cave), update of existing High Pressure Rinse (HPR) system, preparation of necessary safety documents and eventually obtaining an Operational Readiness Clearance (ORC). Figure 1 illustrates the various components of the development process. In the past, the north cave test station at A0 has supported the cold testing 3.9 GHz nine cell and single cell cavities, thus some of the components were available for use and some needed modification. The test dewar had the capacity to accommodate 1.3 GHz single cells although a new vertical insert that could handle both cavity types (1.3 and 3.9 GHz) had to be designed. The existing cryogenic system with an average capacity of {approx} 0.5 g/sec was deemed sufficient. The RF system was updated with broadband components and an additional amplifier with higher power capacity to handle higher gradients usually achieved in 1.3 GHz cavities. The initial testing phase was arbitrated to proceed with fixed power coupling. A new temperature mapping system was developed to provide the diagnostic tool for hot spot studies, quench characterization and field emission studies. The defining feature of this system was the use of diode sensors instead of the traditional carbon resistors as sensing elements. The unidirectional current carrying capacity (forward bias) of the diodes provided for the ease of multiplexing of the

  14. SPECTROSCOPIC AND PHOTOMETRIC VARIABILITY IN THE A0 SUPERGIANT HR 1040

    SciTech Connect

    Corliss, David J.; Morrison, Nancy D.; Adelman, Saul J.

    2015-12-15

    A time-series analysis of spectroscopic and photometric observables of the A0 Ia supergiant HR 1040 has been performed, including equivalent widths, radial velocities, and Strömgren photometric indices. The data, obtained from 1993 through 2007, include 152 spectroscopic observations from the Ritter Observatory 1 m telescope and 269 Strömgren photometric observations from the Four College Automated Photoelectric Telescope. Typical of late B- and early A-type supergiants, HR 1040 has a highly variable Hα profile. The star was found to have an intermittent active phase marked by correlation between the Hα absorption equivalent width and blue-edge radial velocity and by photospheric connections observed in correlations to equivalent width, second moment and radial velocity in Si ii λλ6347, 6371. High-velocity absorption (HVA) events were observed only during this active phase. HVA events in the wind were preceded by photospheric activity, including Si ii radial velocity oscillations 19–42 days prior to onset of an HVA event and correlated increases in Si ii W{sub λ} and second moment from 13 to 23 days before the start of the HVA event. While increases in various line equivalent widths in the wind prior to HVA events have been reported in the past in other stars, our finding of precursors in enhanced radial velocity variations in the wind and at the photosphere is a new result.

  15. Experimental study of the A0 and S0 Lamb waves interaction with symmetrical notches.

    PubMed

    Benmeddour, Farouk; Grondel, Sébastien; Assaad, Jamal; Moulin, Emmanuel

    2009-02-01

    The aim of this work is to study the fundamental Lamb modes interaction with defects in isotropic plates. For these experimental investigations, symmetrical notches with various depths milled in aluminum plates are considered. Moreover, the incident Lamb wave of a specific mode is generated by means of two identical thin piezoceramic transducers placed at the opposite sides of the plate. The waves scattered by the notch are recorded with conventional transducers located on the plate surface in front and behind the defect. The selection of the A(0) or the S(0) modes is obtained by exciting the transducers with anti-phased or in-phased signals, respectively. Furthermore, a calibration process is investigated to correct errors caused by the presence of the receiver between the emitters and the defects. The power reflection and transmission coefficients are then obtained and the power balance is verified. Finally, these measurements are compared successfully with those obtained by a numerical method using the finite-element modeling described in a previous work.

  16. A 0-D flame wrinkling equation to describe the turbulent flame surface evolution in SI engines

    NASA Astrophysics Data System (ADS)

    Richard, Stéphane; Veynante, Denis

    2015-03-01

    The current development of reciprocating engines relies increasingly on system simulation for both design activities and conception of algorithms for engine control. These numerical simulation tools require high computational efficiencies, as calculations have to be performed in times close to real-time. Then, they are today mainly based on simple empirical laws to describe the combustion processes in the cylinders. However, with the rapid evolution of emission regulations and fuel formulation, more and more physics is expected in combustion models. A solution consists in reducing 3-D combustion models to build 0-dimensional models that are both CPU-efficient and based on physical quantities. This approach has been used in a previous work to reduce the 3-D ECFM (Extended Coherent Flame Model), leading to the so-called CFM1D. A key feature of the latter is to be based on a 0-D equation for the flame wrinkling derived from the 3-D equation for the flame surface density. The objective of this paper is to present in details the theoretical derivation of the wrinkling equation and the underlying modeling assumptions as well. Academic validations are performed against experimental data for several turbulence intensities and fuels. Finally, the proposed model is applied to engine simulations for a wide range of operating conditions. Comparisons are successfully conducted between in-cylinder measurements and the model predictions, highlighting the interest of reducing 3-D CFD models for calculations performed in the context of system simulation.

  17. Experimental Studies of the Inspection of Areas With Restricted Access Using A0 Lamb Wave Tomography.

    PubMed

    Seher, Matthias; Huthwaite, Peter; Lowe, Michael J S

    2016-09-01

    Corrosion damage in inaccessible regions presents a significant challenge to the petrochemical industry, and determining the remaining wall thickness is important to establish the remaining service life. Guided wave tomography is one solution to this and involves transmitting Lamb waves through the area of interest and, subsequently, using the received signals to reconstruct a thickness map of the remaining wall thickness. This avoids the need to access all points on the surface, making the technique well suited to inspection for areas with restricted access. The influence of these areas onto the ability to detect and size surface conditions, such as corrosion damage, using guided wave tomography is assessed. For that, a guided wave tomography system is employed, which is based on low-frequency A0 Lamb waves that are excited and detected with two arrays of electromagnetic acoustic transducers. Two different defect depths are considered with different contrasts relative to the nominal wall thickness, both of which are smoothly varying and well-defined. The influence of areas with restricted surface access, support locations, pipe clamps, and STOPAQ(R) coatings is experimentally tested, and their influence assessed through comparison to a baseline reconstruction without the respective restriction in place, demonstrating only a small influence on the detected value of the remaining wall thickness.

  18. An a0 resonance in strongly coupled πη, KK¯ scattering from lattice QCD

    DOE PAGES

    Dudek, Jozef J.; Edwards, Robert G.; Wilson, David J.

    2016-05-11

    Here, we present the first calculation of coupled-channel meson-meson scattering in the isospinmore » $=1$, $G$-parity negative sector, with channels $$\\pi \\eta$$, $$K\\overline{K}$$ and $$\\pi \\eta'$$, in a first-principles approach to QCD. From the discrete spectrum of eigenstates in three volumes extracted from lattice QCD correlation functions we determine the energy dependence of the $S$-matrix, and find that the $S$-wave features a prominent cusp-like structure in $$\\pi \\eta \\to \\pi \\eta$$ close to $$K\\overline{K}$$ threshold coupled with a rapid turn on of amplitudes leading to the $$K\\overline{K}$$ final-state. This behavior is traced to an $$a_0(980)$$-like resonance, strongly coupled to both $$\\pi \\eta$$ and $$K\\overline{K}$$, which is identified with a pole in the complex energy plane, appearing on only a single unphysical Riemann sheet. Consideration of $D$-wave scattering suggests a narrow tensor resonance at higher energy.« less

  19. A 0.33-THz second-harmonic frequency-tunable gyrotron

    NASA Astrophysics Data System (ADS)

    Zheng-Di, Li; Chao-Hai, Du; Xiang-Bo, Qi; Li, Luo; Pu-Kun, Liu

    2016-02-01

    Dynamics of the axial mode transition process in a 0.33-THz second-harmonic gyrotron is investigated to reveal the physical mechanism of realizing broadband frequency tuning in an open cavity circuit. A new interaction mechanism about propagating waves, featured by wave competition and wave cooperation, is presented and provides a new insight into the beam-wave interaction. The two different features revealed in the two different operation regions of low-order axial modes (LOAMs) and high-order axial modes (HOAMs) respectively determine the characteristic of the overall performance of the device essentially. The device performance is obtained by the simulation based on the time-domain nonlinear theory and shows that using a 12-kV/150-mA electron beam and TE-3,4 mode, the second harmonic gyrotron can generate terahertz radiations with frequency-tuning ranges of about 0.85 GHz and 0.60 GHz via magnetic field and beam voltage tuning, respectively. Additionally, some non-stationary phenomena in the mode startup process are also analyzed. The investigation in this paper presents guidance for future developing high-performance frequency-tunable gyrotrons toward terahertz applications. Project supported by the National Natural Science Foundation of China (Grant Nos. 61471007, 61531002, 61522101, and 11275206) and the Seeding Grant for Medicine and Information Science of Peking University, China (Grant No. 2014-MI-01).

  20. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... Your 1- to 2-Year-Old Blood Test: Hemoglobin A1c KidsHealth > For Parents > Blood Test: Hemoglobin A1c A A A What's in this article? ... de sangre: hemoglobina A1c What It Is A hemoglobin A1c (HbA1c) test is used to monitor long- ...

  1. A1C Test and Diabetes

    MedlinePlus

    ... Diagnosis The A1C Test & Diabetes The A1C Test & Diabetes What is the A1C test? The A1C test ... A1C test be used to diagnose type 2 diabetes and prediabetes? Yes. In 2009, an international expert ...

  2. Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

    PubMed Central

    Seiser, Eric L.; van Leeuwen, Nienke; Tavendale, Roger; Bennett, Amanda J; Groves, Christopher J.; Coleman, Ruth L.; van der Heijden, Amber A.; Beulens, Joline W.; de Keyser, Catherine E.; Zaharenko, Linda; Rotroff, Daniel M.; Out, Mattijs; Jablonski, Kathleen A.; Chen, Ling; Javorský, Martin; Židzik, Jozef; Levin, Albert M.; Williams, L. Keoki; Dujic, Tanja; Semiz, Sabina; Kubo, Michiaki; Chien, Huan-Chieh; Maeda, Shiro; Witte, John S.; Wu, Longyang; Tkáč, Ivan; Kooy, Adriaan; van Schaik, Ron H.N.; Stehouwer, Coen D.A.; Logie, Lisa; Sutherland, Calum; Klovins, Janis; Pirags, Valdis; Hofman, Albert; Stricker, Bruno H.; Motsinger-Reif, Alison A.; Wagner, Michael J.; Innocenti, Federico; 't Hart, Leen M.; Holman, Rury R.; McCarthy, Mark I.; Hedderson, Monique M.; Palmer, Colin N.A.; Florez, Jose C.; Giacomini, Kathleen M.; Pearson, Ewan R.

    2016-01-01

    Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10-14) greater metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. PMID:27500523

  3. 26 CFR 1.50A-1 - Determination of amount.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Computing Credit for Expenses of Work Incentive Programs § 1.50A-1 Determination of amount. (a) In general. Except as otherwise provided in this section and in § 1.50A-2, the amount of the work incentive program... section); corporations which are members of a controlled group (see paragraph (f) of this...

  4. An Observation of a Transverse to Longitudinal Emittance Exchange at the Fermilab A0 Photoinjector

    SciTech Connect

    Koeth, Timothy W

    2009-05-01

    An experimental program to perform a proof of principle of transverse to longitudinal emittance exchange (ϵxin ↔ ϵzout and ϵxin ↔ ϵzout) has been developed at the Fermilab A0 Photoinjector. A new beamline, including two magnetic dogleg channels and a TM110 deflecting mode radio frequency cavity, were constructed for the emittance exchange experiment. The first priority was a measurement of the Emittance Exchange beamline transport matrix. The method of difference orbits was used to measure the transport matrix. Through varying individual beam input vector elements, such as xin, x'in, yin, y'in, zin, or δin, and measuring the changes in all of the beam output vector's elements, xout, x'out, yout, y'out, zout, δout, the full 6 x 6 transport matrix was measured. The measured emittance exchange transport matrix was in overall good agreement with our calculated transport matrix. A direct observation of an emittance exchange was performed by measuring the electron beam's characteristics before and after the emittance exchange beamline. Operating with a 14.3 MeV, 250pC electron bunch, ϵzin of 21.1 ± 1.5 mm • mrad was observed to be exchanged with ϵxout of 20.8 ± 2.00 mm • mrad. Diagnostic limitations in the ϵzout measurement did not account for an energy-time correlation, thus potentially returning values larger than the actual longitudinal emittance. The ϵxin of 4.67 ± 0.22 mm • mrad was observed to be exchanged with ϵzout of 7.06 ± 0.43 mm • mrad. The apparent ϵzoutgrowth is consistent with calculated values in which the correlation term is neglected.

  5. A 0. 5 to 3. 0 MeV monoenergetic positron beam

    SciTech Connect

    Huomo, H.; AsokaKumar, P.; Henderson, S.D.; Phlips, B.F.; Mayer, R.; McDonough, J.; Hacker, H.; McCorkle, S.; Schnitzenbaumer, P.; Greenberg, J.S.

    1988-01-01

    An adjustable, 0.5--3 MeV monoenergetic positron beam has been constructed at Brookhaven. Currently a /sup 22/Na source with a W(100) foil transmission moderator produces a 1.1 mm FWHN beam with an intensity of 3/times/10/sup 5/ e/sup +//sec at a target located downstream from the accelerator. The divergence of the beam is less than 0.1/degree/ at 2.2 MeV energy. A SOA gun with 2 lens transport system brings the beam to a focus at the entrance of an electrostatic 3 MeV Dynamitron accelerator. The post acceleration beam transport system comprises 3 focusing solenolds, 4 sets of steering magnets and a 90/degree/ double focusing bending magnet. The beam energy spread at the target is <1 keV FWHN deduced from the beam size. Below we describe the positron extraction optics and acceleration, the construction of the beamline and the beam diagnostic devices. The salient beam parameters are listed at the end of this paper. 2 refs., 3 figs., 1 tab.

  6. Second test of base hydrolysate decomposition in a 0.04 gallon per minute scale reactor

    SciTech Connect

    Cena, R.J.; Thorsness, C.B.; Coburn, T.T.; Watkins, B.E.

    1994-10-11

    LLNL has built and operated a pilot plant for processing oil shale using recirculating hot solids. This pilot plant, was adapted in 1993 to demonstrate the feasibility of decomposing base hydrolysate, a mixture of sodium nitrite, sodium formate and other constituents. This material is the waste stream from the base hydrolysis process for destruction of energetic materials. In the Livermore process, the waste feed is thermally treated in a moving packed bed of ceramic spheres, where constituents in the waste decompose, in the presence of carbon dioxide, to form solid sodium carbonate and a suite of gases including: methane, carbon monoxide, oxygen, nitrogen oxides, ammonia and possibly molecular nitrogen. The ceramic spheres are circulated and heated, providing the energy required for thermal decomposition. The spheres provide a large surface area for evaporation and decomposition to occur, avoiding sticking and agglomeration of the waste. We performed a 2.5 hour test of the solids recirculation system, with continuous injection of approximately 0.04 gal/min of waste. Gasses from the packed bed reactor were directed through the lift pipe and water was not condensed. Potassium carbonate (0.356 M) was added to the hydrolysate prior to its introduction to the retort. Continuous on-line gas analysis was invaluable in tracking the progress of the experiment and quantifying the decomposition products. Analyses showed the primary solid product, collected in the lift exit cyclone, was indeed sodium carbonate, as expected. For the reactor condition studied in this test, N{sub 2}O was found to be the primary nitrogen bearing gas species. In the test, approximately equal quantities of ammonia and nitrogen bearing oxide gases were produced. Under proper conditions, this ammonia and NO{sub x} can be recombined downstream to form N{sub 2} and O{sub 2} as the primary effluent gases.

  7. Cyclosporine a 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis

    PubMed Central

    2012-01-01

    Background To evaluate the treatment with topical 0.05% cyclosporine A (CsA) in patients with subepithelial corneal infiltrates (SEI). Methods We reviewed 16 patients (22 eyes) before and after the treatment with 0.05% CsA eye drops. All patients had been treated previously with topical corticosteroids without any improvement and also they had to stop the medication secondary to intraocular pressure elevation. The objective data recorded included best-corrected visual acuity (BCVA), evaluation of corneal subepithelial infiltrate scores (CSIS), intraocular pressure (IOP) prior to treatment and the last follow-up visit. Results Six males (37.5%) and 10 females (62.5%), mean age of 35.2 ± 16.6 years, were included. The patients’ average topical CsA use duration was 5.1 ± 3.5 months (1 – 13 months). The average follow up time of the patients was 9.2 ± 4.7 months (4 – 22 months). One patient, although he didn’t have a 0 scale of SCIS, did not show up for follow up examinations after six months. The mean BCVA (logarithm of the minimum angle of resolution) before and after the treatment were 0.15 ± 0.15 and 0.07 ± 0.07 respectively, CSIS 1.68 ± 0.89 and 0.23 ± 0.53 respectively, IOP 18.50 ± 3.82 and 16.86 ± 2.76 mmHg respectively. There were statistically significant improvements in BCVA (p = 0.002), reduction of CSIS (p = 0.002) and reduction of IOP (p < 0.001) prior to treatment and the last follow-up visit. 18 eyes (81.9%) showed clinical improvement and 4 (18.1%) had decreased SEI which did not fully disappear during the treatment period. The eyes which reached CSIS score 0 (18 eyes) were treated with CsA for 1 – 13 months; while the eyes which had clinical improvement but had not CSIS score 0 (4 eyes) were decided to discontinue of CsA treatment in last follow-up visit. There were recurrences in 2 eyes 3 months after the treatment. Patients reported reduction in the severity of symptoms after the

  8. 26 CFR 1.408A-2 - Establishing Roth IRAs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Establishing Roth IRAs. 1.408A-2 Section 1.408A... (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-2 Establishing Roth IRAs... establishing Roth IRAs: Q-1. Who can establish a Roth IRA? A-1. Except as provided in A-3 of this section,...

  9. Adenosine A2A Receptors and A2A Receptor Heteromers as Key Players in Striatal Function

    PubMed Central

    Ferré, Sergi; Quiroz, César; Orru, Marco; Guitart, Xavier; Navarro, Gemma; Cortés, Antonio; Casadó, Vicent; Canela, Enric I.; Lluis, Carme; Franco, Rafael

    2011-01-01

    A very significant density of adenosine A2A receptors (A2ARs) is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs). In this localization A2ARs establish reciprocal antagonistic interactions with dopamine D2 receptors (D2Rs). In one type of interaction, A2AR and D2R are forming heteromers and, by means of an allosteric interaction, A2AR counteracts D2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striatopallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2AR and D2R that do not form heteromers and takes place at the level of adenylyl cyclase (AC). Due to a strong tonic effect of endogenous dopamine on striatal D2R, this interaction keeps A2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D2R, A2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striatopallidal neuron and with a consequent motor depression. This interaction is probably the main mechanism responsible for the locomotor depression induced by D2R antagonists. Finally, striatal A2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A2ARs heteromerize with A1 receptors (A1Rs) and their activation facilitates glutamate release. These three different types of A2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders. PMID:21731559

  10. High salt diet exacerbates vascular contraction in the absence of adenosine A2A receptor

    PubMed Central

    Pradhan, Isha; Zeldin, Darryl C.; Ledent, Catherine; Mustafa, S. Jamal; Falck, John R.; Nayeem, Mohammed A

    2014-01-01

    High salt (4%NaCl, HS) diet modulates adenosine-induced vascular response through adenosine A2A-receptor (A2AAR). Evidence suggests A2AAR stimulates cyp450-epoxygenases, leading to epoxyeicosatrienoic acids (EETs) generation. The aim of this study was to understand the vascular reactivity to HS and underlying signaling mechanism in the presence or absence of A2AAR. Therefore, we hypothesized that HS enhances adenosine-induced relaxation through EETs in A2AAR+/+, but exaggerates contraction in A2AAR−/−. Organ-bath and Western-blot experiments were conducted in HS and normal salt (NS, 0.18% NaCl)-fed A2AAR+/+ and A2AAR−/− mice aortae. HS produced concentration-dependent relaxation to non-selective adenosine analog, NECA in A2AAR+/+, whereas contraction was observed in A2AAR−/− mice and this was attenuated by A1AR antagonist (DPCPX). CGS-21680 (selective A2AAR-agonist) enhanced relaxation in HS-A2AAR+/+ vs. NS-A2AAR+/+, that was blocked by EETs antagonist (14,15-EEZE). Compared to NS, HS significantly upregulated expression of vasodilators A2AAR and cyp2c29, while vasoconstrictors A1AR and cyp4a in A2AAR+/+ were downregulated. In A2AAR−/− mice, however, HS significantly downregulated the expression of cyp2c29, while A1AR and cyp4a were upregulated compared to A2AAR+/+ mice. Hence, our data suggest that in A2AAR+/+, HS enhances A2AAR-induced relaxation through increased cyp-expoxygenases-derived EETs and decreased A1AR levels, whereas in A2AAR−/−, HS exaggerates contraction through decreased cyp-epoxygenases and increased A1AR levels. PMID:24390173

  11. Aldehyde dehydrogenase 1A1 in stem cells and cancer

    PubMed Central

    Tomita, Hiroyuki; Tanaka, Kaori; Tanaka, Takuji; Hara, Akira

    2016-01-01

    The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies. PMID:26783961

  12. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  13. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  14. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 5 2012-10-01 2012-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for...

  15. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  16. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  17. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  18. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.1 Party. The term Party means any person, employee, group of employees, labor...

  19. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.1 Party. The term Party means any person, employee, group of employees, labor organization, or bank...

  20. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.1 Party. The term Party means any person, employee, group of employees, labor organization, or bank...

  1. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.1 Party. The term Party means any person, employee, group of employees, labor...

  2. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.1 Party. The term Party means any person, employee, group of employees, labor...

  3. 26 CFR 1.408A-2 - Establishing Roth IRAs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Establishing Roth IRAs. 1.408A-2 Section 1.408A... Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to establishing Roth IRAs: Q-1. Who can establish a Roth IRA? A-1. Except as provided in A-3 of this section,...

  4. 26 CFR 1.408A-2 - Establishing Roth IRAs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Establishing Roth IRAs. 1.408A-2 Section 1.408A... Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to establishing Roth IRAs: Q-1. Who can establish a Roth IRA? A-1. Except as provided in A-3 of this section,...

  5. 26 CFR 1.408A-2 - Establishing Roth IRAs.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Establishing Roth IRAs. 1.408A-2 Section 1.408A... Roth IRAs. This section sets forth the following questions and answers that provide rules applicable to establishing Roth IRAs: Q-1. Who can establish a Roth IRA? A-1. Except as provided in A-3 of this section,...

  6. 32 CFR 1630.11 - Class 1-A-0: Conscientious objector available for noncombatant military service only.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... chapter any registrant shall be palced in Class 1-A-0 who has been found, by reason of religious, ethical, or moral belief, to be conscientiously opposed to participation in combatant military tranining...

  7. Draft Genome Sequences of Candida glabrata Isolates 1A, 1B, 2A, 2B, 3A, and 3B

    PubMed Central

    Håvelsrud, Othilde Elise

    2017-01-01

    ABSTRACT Here, we report the draft genome sequences of six Candida glabrata isolates. The isolates were taken from blood samples from patients after recurrent C. glabrata infection. Two isolates were taken from each of three patients a minimum 3 months apart. PMID:28280017

  8. Development and Evaluation of a Simple Job Performance Aid for M151A1, A2 Truck Operators

    DTIC Science & Technology

    1979-11-01

    AMSTE-PL-TS 1 HO, USARPAC. DCSPER. APO SF 96558, ATTN: GPPE SE I USA Armament Cmd. Redstone Arsenal, ATTN: ATSK-TEM I Slimsion Lib. Academy of Health ...Forces Cmd, Ft McPherson, ATTN: Library 1 Medacin Chef, C.E.R.P.A.-Arsonal, Toulon/Naval France 2 USA Aviation Tast Od, Ft Rucker. ATTN: STEBG-PO I

  9. Atomic Scale coexistence of Periodic and quasiperiodic order in a2-fold A1-Ni-Co decagonal quasicrystal surface

    SciTech Connect

    Park, Jeong Young; Ogletree, D. Frank; Salmeron, Miquel; Ribeiro,R.A.; Canfield, P.C.; Jenks, C.J.; Thiel, P.A.

    2005-11-14

    Decagonal quasicrystals are made of pairs of atomic planes with pentagonal symmetry periodically stacked along a 10-fold axis. We have investigated the atomic structure of the 2-fold surface of a decagonal Al-Ni-Co quasicrystal using scanning tunneling microscopy (STM). The surface consists of terraces separated by steps of heights 1.9, 4.7, 7.8, and 12.6{angstrom} containing rows of atoms parallel to the 10-fold direction with an internal periodicity of 4{angstrom}. The rows are arranged aperiodically, with separations that follow a Fibonacci sequence and inflation symmetry. The results indicate that the surfaces are preferentially Al-terminated and in general agreement with bulk models.

  10. Gold-induced nanowires on the Ge(100) surface yield a 2D and not a 1D electronic structure

    NASA Astrophysics Data System (ADS)

    de Jong, N.; Heimbuch, R.; Eliëns, S.; Smit, S.; Frantzeskakis, E.; Caux, J.-S.; Zandvliet, H. J. W.; Golden, M. S.

    2016-06-01

    Atomic nanowires on semiconductor surfaces induced by the adsorption of metallic atoms have attracted a lot of attention as possible hosts of the elusive, one-dimensional Tomonaga-Luttinger liquid. The Au/Ge(100) system in particular is the subject of controversy as to whether the Au-induced nanowires do indeed host exotic, 1D (one-dimensional) metallic states. In light of this debate, we report here a thorough study of the electronic properties of high quality nanowires formed at the Au/Ge(100) surface. The high-resolution ARPES data show the low-lying Au-induced electronic states to possess a dispersion relation that depends on two orthogonal directions in k space. Comparison of the E (kx,ky) surface measured using high-resolution ARPES to tight-binding calculations yields hopping parameters in the two different directions that differ by approximately factor of two. Additionally, by pinpointing the Au-induced surface states in the first, second, and third surface Brillouin zones and analyzing their periodicity in k||, the nanowire propagation direction seen clearly in STM can be imported into the ARPES data. We find that the larger of the two hopping parameters corresponds, in fact, to the direction perpendicular to the nanowires (tperp). This proves that the Au-induced electron pockets possess a two-dimensional, closed Fermi surface, and this firmly places the Au/Ge(100) nanowire system outside potential hosts of a Tomonaga-Luttinger liquid. We combine these ARPES data with scanning tunneling spectroscopic measurements of the spatially resolved electronic structure and find that the spatially straight—wirelike—conduction channels observed up to energies of order one electron volt below the Fermi level do not originate from the Au-induced states seen in the ARPES data. The former are rather more likely to be associated with bulk Ge states that are localized to the subsurface region. Despite our proof of the 2D (two-dimentional) nature of the Au-induced nanowire and subsurface Ge-related states, an anomalous suppression of the density of states at the Fermi level is observed in both the STS and ARPES data, and this phenomenon is discussed in the light of the effects of disorder.

  11. B → a0(1450)phi decays: dominated by the ω-phi mixing in the standard model

    NASA Astrophysics Data System (ADS)

    Zhang, Zhi-Qing; Ou, Hai-Feng; Lü, Lin-Xia

    2011-09-01

    In the two-quark model supposition for the meson a0(1450), which can be viewed as either the first excited state (scenario I) or the lowest lying state (scenario II), the branching ratios and the direct CP-violating asymmetries for decays B- → a-0(1450)phi and \\bar{B}^0\\rightarrow a^{0}_0(1450)\\phi are studied by employing the perturbative QCD factorization approach. We find the following results. (a) If we do not consider the ω-phi mixing, the decays B^-\\rightarrow a^-_0(1450)\\phi (s\\bar{s}) and \\bar{B}^0\\rightarrow a^0_0(1450)\\phi (s\\bar{s}) are highly suppressed by the Okubo-Zweig-Iizuka rule; their branching ratios are at the order of 10-9 in scenario I and even smaller in scenario II. (b) If the ω-phi mixing effect is included, the branching ratios can be dramatically enhanced, especially for the decay \\bar{B}^0\\rightarrow a^{0}_0(1450)\\phi in scenario II, whose branching ratio arrives at the order of 10-8. In scenario I, the branching ratios are about a factor of 4-5 above the ones in the absence of ω-phi mixing. (c) For a more transparent comparison between the predictions and the data, we also calculate the ratio R=\\frac{\\tau (B^0)}{\\tau (B^-)}\\frac{{\\cal B}(B^-\\rightarrow a^{-}_0(1450)\\phi )}{{\\cal B}(\\bar{B}^0\\rightarrow a^{0}_0(1450)\\phi )}. Because it is less sensitive to the nonperturbative inputs, the large deviation of this ratio from the standard-model prediction could reveal a signal of new physics. (d) When the ω-phi mixing effect is included, the interference between the tree and the penguin contributions induces the direct CP violation, which is sensitive to the ω-phi mixing angle θ.

  12. Dynamical Mass Constraints on Low-Mass Pre-Main-Sequence Stellar Evolutionary Tracks: An Eclipsing Binary in Orion with a 1.0 M(solar) Primary and a 0.7 M(solar) Secondary

    DTIC Science & Technology

    2004-04-01

    function of stellar mass and age can provide important con- straints on PMS tracks. We will return to the issue of Li abundances in Luhman et al. (2003...consider here, these are perhaps the most generally favored in the re- cent literature (White et al. 1999; Simon et al. 2000; Luhman et al. 2003...equivalent to the BCAH98 tracks. STASSUN ET AL.376 Vol. 151 The tracks with in ¼ 1:9, favored by the recent analysis of Luhman et al. (2003), are

  13. Dynamical Mass Constraints on Low-Mass Pre-Main-Sequence Stellar Evolutionary Tracks: An Eclipsing Binary in Orion With a 1.0 M Primary and a 0.7 M Secondary

    DTIC Science & Technology

    2003-12-30

    in Luhman et al. (2003). Finally, we can also use the primary and secondary Li lines to infer the relative rotation rates of the two stars. We have... Luhman et al. 2003). The tracks use the nongray NextGen atmospheres of Hauschildt, Allard, & Baron (1999) and treat convection using MLT. These... Luhman et al. (2003), are possibly consistent with the position of the 1.01 M primary of V1174 Ori, but only by pushing the primary near the lower

  14. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...(a)) provides that “ he Secretary may authorize persons engaged in research on mental health... regulations in this part establish procedures under which any person engaged in research on mental health... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 2a.1 Section 2a.1 Public...

  15. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Definitions. 8a.1 Section 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... indebtedness incurred by an eligible veteran to buy, build, remodel, or enlarge a housing unit, the payment...

  16. Annexin A2 Regulates TRPA1-Dependent Nociception

    PubMed Central

    Avenali, Luca; Narayanan, Pratibha; Rouwette, Tom; Cervellini, Ilaria; Sereda, Michael

    2014-01-01

    The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates. PMID:25355205

  17. Annexin A2 regulates TRPA1-dependent nociception.

    PubMed

    Avenali, Luca; Narayanan, Pratibha; Rouwette, Tom; Cervellini, Ilaria; Sereda, Michael; Gomez-Varela, David; Schmidt, Manuela

    2014-10-29

    The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates.

  18. 32 CFR 1630.11 - Class 1-A-0: Conscientious objector available for noncombatant military service only.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Class 1-A-0: Conscientious objector available for noncombatant military service only. 1630.11 Section 1630.11 National Defense Other Regulations...: Conscientious objector available for noncombatant military service only. In accord with part 1636 of...

  19. A Procedure for Generating the Convex Hull of a 0-1 Programming Polytope with Positive Coefficients.

    DTIC Science & Technology

    1980-12-01

    if ax < a0 belongs to e (U). II Observe that the testing of condition (17) merely involves the solution of a linear program. This proposition is now...Programming 8 (1975) 146-164. [2] E. Balas, Facets of One-Dimensional and Multi-Dimensional Knapsack Polytopes, Istituto Nazionale di Alta Matematica

  20. Application of RADSAFE to Model Single Event Upset Response of a 0.25 micron CMOS SRAM

    NASA Technical Reports Server (NTRS)

    Warren, Kevin M.; Weller, Robert A.; Sierawski, Brian; Reed, Robert A.; Mendenhall, Marcus H.; Schrimpf, Ronald D.; Massengill, Lloyd; Porter, Mark; Wilkerson, Jeff; LaBel, Kenneth A.; Adams, James

    2006-01-01

    The RADSAFE simulation framework is described and applied to model Single Event Upsets (SEU) in a 0.25 micron CMOS 4Mbit Static Random Access Memory (SRAM). For this circuit, the RADSAFE approach produces trends similar to those expected from classical models, but more closely represents the physical mechanisms responsible for SEU in the SRAM circuit.

  1. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  2. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  3. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  4. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  5. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  6. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  7. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  8. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  9. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  10. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  11. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 51a.2 Section 51a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases...

  12. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Applicability. 12a.2 Section 12a.2 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  13. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Applicability. 12a.2 Section 12a.2 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  14. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Applicability. 12a.2 Section 12a.2 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  15. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false Applicability. 12a.2 Section 12a.2 Public Welfare Department of Health and Human Services GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  16. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Applicability. 12a.2 Section 12a.2 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  17. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  18. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  19. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 7 2014-07-01 2014-07-01 false Membership. 1912a.2 Section 1912a.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is...

  20. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 7 2012-07-01 2012-07-01 false Membership. 1912a.2 Section 1912a.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is...

  1. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Membership. 1912a.2 Section 1912a.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is...

  2. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 7 2013-07-01 2013-07-01 false Membership. 1912a.2 Section 1912a.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is...

  3. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 false Membership. 1912a.2 Section 1912a.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is...

  4. 32 CFR 352a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Applicability. 352a.2 Section 352a.2 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.2 Applicability. This part applies to...

  5. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  6. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  7. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  8. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  9. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  10. 22 CFR 9a.2 - General policy.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false General policy. 9a.2 Section 9a.2 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.2 General policy. (a) The United States has entered into the... the IEA. Confidentiality is essential to assure the free and open discussion necessary to...

  11. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... few minutes. previous continue What to Expect Either method (finger or heel sticking or vein withdrawal) of ... that since labs and offices may use different methods to measure HbA1c, the range of normal values ...

  12. A1C and eAG

    MedlinePlus

    ... Complications DKA (Ketoacidosis) & Ketones Kidney Disease (Nephropathy) Gastroparesis Mental Health Step On Up Treatment & Care Blood Glucose Testing Medication Doctors, Nurses & More Oral Health & Hygiene Women A1C Insulin Pregnancy ...

  13. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  14. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  15. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  16. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  17. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  18. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  19. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  20. Methamphetamine regulation of sulfotransferase 1A1 and 2A1 expression in rat brain sections.

    PubMed

    Zhou, Tianyan; Huang, Chaoqun; Chen, Yue; Xu, Jiaojiao; Shanbhag, Preeti Devaraya; Chen, Guangping

    2013-01-01

    Sulfotransferase catalyzed sulfation regulates the biological activities of various neurotransmitters/hormones and detoxifies xenobiotics. Rat sulfotransferase rSULT1A1 catalyzes the sulfation of neurotransmitters and xenobiotic phenolic compounds. rSULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotic alcoholic compounds. In this work, Western blot and real-time RT-PCR were used to investigate the effect of methamphetamine on rSULT1A1 and rSULT2A1 protein and mRNA expression in rat cerebellum, frontal cortex, hippocampus, and striatum. After 1-day treatment, significant induction of rSULT1A1 was observed only in the cerebellum; rSULT2A1 was induced significantly in the cerebellum, frontal cortex, and hippocampus. After 7 days of exposure, rSULT1A1 was induced in the cerebellum, frontal cortex, and hippocampus, while rSULT2A1 was induced significantly in all four regions. Western blot results agreed with the real-time RT-PCR results, suggesting that the induction occurred at the gene transcriptional level. Results indicate that rSULT1A1 and rSULT2A1 are expressed in rat frontal cortex, cerebellum, striatum, and hippocampus. rSULT1A1 and rSULT2A1are inducible by methamphetamine in rat brain sections in a time dependable manner. rSULT2A1 is more inducible than rSULT1A1 by methamphetamine in rat brain sections. Induction activity of methamphetamine is in the order of cerebellum>frontal cortex, hippocampus>striatum. These results suggest that the physiological functions of rSULT1A1 and rSULT2A1 in different brain regions can be affected by methamphetamine.

  1. 26 CFR 1.263(a)-1 - Capital expenditures; In general.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... property (as defined in § 1.263A-1T (a)(5)(iii)), including films, sound recordings, video tapes, books, or... tangible personal property (as defined in § 1.263A-2(a)(2)), including films, sound recordings, video tapes... increase the value of any property or estate, or (2) Any amount expended in restoring property or in...

  2. Fatigue Resistant Ti3A1 Composites

    DTIC Science & Technology

    1993-01-01

    WITH AND WITHOUT Ag/Ta INTERFACIAL LAYERS ................ 16 4.1 Experiments ...37 APPENDIX B ANALYSIS OF FIBER DEBONDING AND SLIDING EXPERIMENTS IN BRITTLE MATRIX COMPOSITES...4 2 Force and displacement measurements from fiber pulling experiments on super-a2JSiC composite with Ag/Ta

  3. Impact of glutathione-HbA1c on HbA1c measurement in diabetes diagnosis via array isoelectric focusing, liquid chromatography, mass spectrometry and ELISA.

    PubMed

    Li, Si; Guo, Chen-Gang; Chen, Lu; Yin, Xiao-Yang; Wu, Yi-Xin; Fan, Liu-Yin; Fan, Hui-Zhi; Cao, Cheng-Xi

    2013-10-15

    Hemoglobin A1c (HbA1c) has been proven to be a key biomarker for diabetes screening, and glutathiolation of HbA1c (viz., GSS-HbA1c) has been identified. However, the impact of GSS-HbA1c on the measurement of HbA1c for diabetes screening has not been quantitatively assessed yet. To address the issue, the micropreparative capillary isoelectric focusing (cIEF) developed in our previous work was used for the high resolution separation and purification of hemoglobin (Hb) species. The main fractions of HbA0, HbA3 and HbA1c extracted from the developed cIEF were identified by validated Mono S method. The proposed GSS-HbA1c fractions in the cIEF were pooled and identified by electrospray ionization mass spectrometry (ESI-MS). The HbA1c enzyme-linked immunosorbent assay (ELISA) kit was employed for further quantitative analysis of GSS-HbA1c. A total of 34 blood samples with HbA1c levels from 4.2% to 13.4% were assessed via the above comprehensive strategy of IEF-HPLC-MS-ELISA. It was demonstrated that the HbA1c levels detected by cation exchange LC were considerably influenced by the glutathiolation of Hb and the range of detected GSS-HbA1c values was between 0.23% and 0.74%. The results and developed cIEF methods have considerable significances for investigation of diabetes and clinical diagnosis.

  4. 22 CFR 3a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... UNIFORMED SERVICES § 3a.1 Definitions. For purposes of this part— (a) Applicant means any person who requests approval under this part to accept any civil employment (and compensation therefor) from a foreign... part to continue such employment. (b) Uniformed services means the Armed Forces, the...

  5. NERVA Reactor Based on NRX A1

    NASA Technical Reports Server (NTRS)

    1963-01-01

    This artist's concept from 1963 shows a proposed NERVA (Nuclear Engine for Rocket Vehicle Application) incorporating the NRX-A1, the first NERVA-type cold flow reactor. The NERVA engine, based on Kiwi nuclear reactor technology, was intended to power a RIFT (Reactor-In-Flight-Test) nuclear stage, for which Marshall Space Flight Center had development responsibility.

  6. 45 CFR 12a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... HOMELESS § 12a.1 Definitions. Applicant means any representative of the homeless which has submitted an... assist the homeless. Checklist or property checklist means the form developed by HUD for use by... or a private non-profit organization which provides assistance to the homeless, and which...

  7. 45 CFR 12a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... HOMELESS § 12a.1 Definitions. Applicant means any representative of the homeless which has submitted an... assist the homeless. Checklist or property checklist means the form developed by HUD for use by... or a private non-profit organization which provides assistance to the homeless, and which...

  8. 45 CFR 12a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... HOMELESS § 12a.1 Definitions. Applicant means any representative of the homeless which has submitted an... assist the homeless. Checklist or property checklist means the form developed by HUD for use by... or a private non-profit organization which provides assistance to the homeless, and which...

  9. 45 CFR 12a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... HOMELESS § 12a.1 Definitions. Applicant means any representative of the homeless which has submitted an... assist the homeless. Checklist or property checklist means the form developed by HUD for use by... or a private non-profit organization which provides assistance to the homeless, and which...

  10. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... intending immigrants. The “household income” may not, however, include the income of an intending immigrant, unless the intending immigrant is either the sponsor's spouse or has the same principal residence as...

  11. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... intending immigrants. The “household income” may not, however, include the income of an intending immigrant, unless the intending immigrant is either the sponsor's spouse or has the same principal residence as...

  12. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... Support Contract Between Sponsor and Household Member, on behalf of the sponsor and intending immigrants. The “household income” may not, however, include the income of an intending immigrant, unless...

  13. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... Support Contract Between Sponsor and Household Member, on behalf of the sponsor and intending immigrants. The “household income” may not, however, include the income of an intending immigrant, unless...

  14. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... intending immigrants. The “household income” may not, however, include the income of an intending immigrant, unless the intending immigrant is either the sponsor's spouse or has the same principal residence as...

  15. Performance and loads data from a hover test of a 0.658-scale V-22 rotor and wing

    NASA Technical Reports Server (NTRS)

    Felker, Fort F.; Signor, David B.; Young, Larry A.; Betzina, Mark D.

    1987-01-01

    A hover test of a 0.658-scale model of a V-22 rotor and wing was conducted at the Outdoor Aerodynamic Research Facility at Ames Research Center. The primary objectives of the test were to obtain accurate measurements of the hover performance of the rotor system, and to measure the aerodynamic interactions between the rotor and wing. Data were acquired for rotor tip Mach numbers ranging from 0.1 to 0.73. This report presents data on rotor performance, rotor-wake downwash velocities, rotor system loads, wing forces and moments, and wing surface pressures.

  16. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS... have the same meaning as provided in the Act. As used in this subpart: Act means the Public...

  17. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS... have the same meaning as provided in the Act. As used in this subpart: Act means the Public...

  18. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS... have the same meaning as provided in the Act. As used in this subpart: Act means the Public...

  19. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS... have the same meaning as provided in the Act. As used in this subpart: Act means the Public...

  20. Studies of membrane topology of mitochondrial cholesterol hydroxylases CYPs 27A1 and 11A1

    PubMed Central

    Mast, Natalia; Liao, Wei-Li; Turko, Illarion V.

    2010-01-01

    Mitochondrial cytochrome P450 enzymes (CYP or P450, EC 1.14.13.15) play an important role in metabolism of cholesterol. CYP27A1 hydroxylates cholesterol at position 27 and, thus, initiates cholesterol removal from many extrahepatic tissues. CYP11A1 is a steroidogenic P450 that converts cholesterol to pregnenolone, the first step in the biosynthesis of all steroid hormones. We utilized a new approach to study membrane topology of CYPs 27A1 and 11A1. This approach involves heterologous expression of membrane-bound P450 in E. coli, isolation of the P450-containing E. coli membranes, treatment of the membranes with protease, removal of the digested soluble portion and extraction of the membrane-associated peptides, which are then identified by mass spectrometry. By using this approach, we found four membrane-interacting peptides in CYP27A1, and two peptides in CYP11A1. Peptides in CYP27A1 represent a contiguous portion of the polypeptide chain (residues 210-251) corresponding to the putative F-G loop and adjacent portions of the F and G helices. Peptides in CYP11A1 are from the putative F-G loop (residues 218-225) and the C-terminal portion of the G helix (residues 238-250). This data is consistent with those obtained previously by us and others and provide new information about membrane topology of CYPs 27A1 and 11A1. PMID:18791760

  1. Stimulation of ectodermal organ development by Ectodysplasin-A1.

    PubMed

    Mustonen, Tuija; Pispa, Johanna; Mikkola, Marja L; Pummila, Marja; Kangas, Aapo T; Pakkasjärvi, Leila; Jaatinen, Risto; Thesleff, Irma

    2003-07-01

    Organs developing as ectodermal appendages share similar early morphogenesis and molecular mechanisms. Ectodysplasin, a signaling molecule belonging to the tumor necrosis factor family, and its receptor Edar are required for normal development of several ectodermal organs in humans and mice. We have overexpressed two splice forms of ectodysplasin, Eda-A1 and Eda-A2, binding to Edar and another TNF receptor, Xedar, respectively, under the keratin 14 (K14) promoter in the ectoderm of transgenic mice. Eda-A2 overexpression did not cause a detectable phenotype. On the contrary, overexpression of Eda-A1 resulted in alterations in a variety of ectodermal organs, most notably in extra organs. Hair development was initiated continuously from E14 until birth, and in addition, the transgenic mice had supernumerary teeth and mammary glands, phenotypes not reported previously in transgenic mice. Also, hair composition and structure was abnormal, and the cycling of hairs was altered so that the growth phase (anagen) was prolonged. Both hairs and nails grew longer than normal. Molar teeth were of abnormal shape, and enamel formation was severely disturbed in incisors. Furthermore, sweat gland function was stimulated and sebaceous glands were enlarged. We conclude that ectodysplasin-Edar signaling has several roles in ectodermal organ development controlling their initiation, as well as morphogenesis and differentiation.

  2. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa.

    PubMed

    Kimbi, Gerald C; Kramvis, Anna; Kew, Michael C

    2004-05-01

    Phylogenetic analysis of hepatitis B virus (HBV) has led to its classification into eight genotypes, A to H. The dominant genotype in South Africa is genotype A, which consists of two subgenotypes, A1 and A2. Subgenotype A1 (previously subgroup A') predominates over subgenotype A2 (previously subgroup A minus A'). The complete genome of HBV isolated from 18 asymptomatic carriers of the virus and five acute hepatitis B patients was amplified; the resulting amplicons were cloned and sequenced. All acute hepatitis isolates belonged to subgenotype A1 and had no distinguishing mutations relative to the isolates from asymptomatic carriers, which had a distribution of ten subgenotype A1, two subgenotype A2 and six genotype D. The presence of the previously described amino acid residues that distinguish subgenotype A1 (subgroup A') from the remainder of genotype A in the S and polymerase genes was confirmed. Moreover, the large number of subgenotype A1 isolates sequenced allowed identification in the other open reading frames of additional nucleotide and amino acid changes that are characteristic of subgenotype A1. In particular, nucleotide mutations at positions 1809-1812 that alter the Kozak sequence of the precore/core open reading frame, and A(1888) in the precore region, were found exclusively in subgenotype A1 isolates. Unique sequence alterations of the transcriptional regulatory elements were also found in subgenotype A1 isolates. The mean nucleotide divergence of subgenotype A1 was greater than that of subgenotype A2, suggesting that this subgenotype has been endemic for a longer time in the South African black population than had subgenotype A2.

  3. Acoustic scattering from a finite plate: generation of guided Lamb waves S(0), A(0) and A.

    PubMed

    Cité, N; Chati, F; Décultot, D; Léon, F; Maze, G

    2012-06-01

    In the domain of renewable energies, marine current turbines constitute one of the possibilities of producing electrical energy. Naked-eye inspection, or with the aid of video monitoring systems of these machines to ensure their perfect working order, can be difficult in a turbid environment. Acoustic methods are conceivable. The study focuses on the blades of these machines, by considering rectangular plates. The propagation of Lamb waves in a plate is studied by analyzing experimental time signals obtained from acoustic scattering. These signals are analyzed employing the ray theory. In vacuum, the flexural wave is the A(0) Lamb wave, whilst in water this wave splits in a bifurcation: the A wave with a phase velocity always smaller than the sound speed in water, and the A(0) wave with a phase velocity always higher than the sound speed in water. In the central bandpass of the transducers used in the experiments, mainly the A and S(0) waves exist. However, signals observed in the third harmonic bandpass of the transducers are also analyzed. In order to complement these results, resonance frequencies of the plate studied are calculated taking into account the boundary conditions and compared with the resonance frequencies of the experimental spectra.

  4. A 0.15-scale study of configuration effects on the aerodynamic interaction between main rotor and fuselage

    NASA Technical Reports Server (NTRS)

    Trept, Ted

    1984-01-01

    Hover and forward flight tests were conducted to investigate the mutual aerodynamic interaction between the main motor and fuselage of a conventional helicopter configuration. A 0.15-scale Model 222 two-bladed teetering rotor was combined with a 0.15-scale model of the NASA Ames 40x80-foot wind tunnel 1500 horsepower test stand fairing. Configuration effects were studied by modifying the fairing to simulate a typical helicopter forebody. Separation distance between rotor and body were also investigated. Rotor and fuselage force and moment as well as pressure data are presented in graphical and tabular format. Data was taken over a range of thrust coefficients from 0.002 to 0.007. In forward flight speed ratio was varied from 0.1 to 0.3 with shaft angle varying from +4 to -12 deg. The data show that the rotors effect on the fuselage may be considerably more important to total aircraft performance than the effect of the fuselage on the rotor.

  5. Folate and Thiamine Transporters mediated by Facilitative Carriers (SLC19A1-3 and SLC46A1) and Folate Receptors

    PubMed Central

    Zhao, Rongbao; Goldman, I. David

    2013-01-01

    The reduced folate carrier (RFC,SLC19A1), thiamine transporter-1 (ThTr1,SLC19A2) and thiamine transporter-2 (ThTr2,SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT,SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease). PMID:23506878

  6. Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways

    PubMed Central

    Soranzo, Nicole; Sanna, Serena; Wheeler, Eleanor; Gieger, Christian; Radke, Dörte; Dupuis, Josée; Bouatia-Naji, Nabila; Langenberg, Claudia; Prokopenko, Inga; Stolerman, Elliot; Sandhu, Manjinder S.; Heeney, Matthew M.; Devaney, Joseph M.; Reilly, Muredach P.; Ricketts, Sally L.

    2010-01-01

    OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron

  7. Simulation of the weld heat affected zone of a 0.5Cr-Mo-V steel

    SciTech Connect

    Radhakrishnan, B.; Zacharia, T.

    1995-12-01

    By using a Monte Carlo grain growth algorithm and a methodology for obtaining a one-to-one correlation between Monte Carlo and real parameters of grain size and time, the grain structure in the weld heat affected zone of a 0.5 Mo-Cr-V steel has been simulated. The simulations clearly show that the kinetics of grain growth can be retarded by the presence of steep temperature gradients in the weld heat affected zone. Additional pinning, due to the formation of grain boundary liquid near the solidus temperature, has also been simulated. It is shown that in order to accurately predict the observed grain size in the weld heat affected zone of the 0.5Cr-Mo-V steel, the retardation in growth kinetics due to temperature gradients as well as liquid pinning should be considered.

  8. Search for low-mass WIMPs in a 0.6 kg day exposure of the DAMIC experiment at SNOLAB

    NASA Astrophysics Data System (ADS)

    Aguilar-Arevalo, A.; Amidei, D.; Bertou, X.; Butner, M.; Cancelo, G.; Castañeda Vázquez, A.; Cervantes Vergara, B. A.; Chavarria, A. E.; Chavez, C. R.; de Mello Neto, J. R. T.; D'Olivo, J. C.; Estrada, J.; Fernandez Moroni, G.; Gaïor, R.; Guardincerri, Y.; Hernández Torres, K. P.; Izraelevitch, F.; Kavner, A.; Kilminster, B.; Lawson, I.; Letessier-Selvon, A.; Liao, J.; Mello, V. B. B.; Molina, J.; Peña, J. R.; Privitera, P.; Ramanathan, K.; Sarkis, Y.; Schwarz, T.; Sengul, C.; Settimo, M.; Sofo Haro, M.; Thomas, R.; Tiffenberg, J.; Tiouchichine, E.; Torres Machado, D.; Trillaud, F.; You, X.; Zhou, J.; Damic Collaboration

    2016-10-01

    We present results of a dark matter search performed with a 0.6 kg d exposure of the DAMIC experiment at the SNOLAB underground laboratory. We measure the energy spectrum of ionization events in the bulk silicon of charge-coupled devices down to a signal of 60 eV electron equivalent. The data are consistent with radiogenic backgrounds, and constraints on the spin-independent WIMP-nucleon elastic-scattering cross section are accordingly placed. A region of parameter space relevant to the potential signal from the CDMS-II Si experiment is excluded using the same target for the first time. This result obtained with a limited exposure demonstrates the potential to explore the low-mass WIMP region (<10 GeV c-2 ) with the upcoming DAMIC100, a 100 g detector currently being installed in SNOLAB.

  9. Ugrades of beam diagnostics in support of emittance-exchange experiments at the Fermilab A0 photoinjector

    SciTech Connect

    Lumpkin, A.H.; Johnson, A.S.; Ruan, J.; Santucci, J.; Sun, Y.-E.; Thurman-Keup, R.; Edwards, H.; /Fermilab

    2011-01-01

    The possibility of using electron beam phase space manipulations to support a free-electron laser accelerator design optimization has motivated our research. An ongoing program demonstrating the exchange of transverse horizontal and longitudinal emittances at the Fermilab A0 photoinjector has benefited recently from the upgrade of several of the key diagnostics stations. Accurate measurements of these properties upstream and downstream of the exchanger beamline are needed. Improvements in the screen resolution term and reduced impact of the optical system's depth-of-focus by using YAG:Ce single crystals normal to the beam direction will be described. The requirement to measure small energy spreads (<10 keV) in the spectrometer and the exchange process which resulted in bunch lengths less than 500 fs led to other diagnostics performance adjustments and upgrades as well. A longitudinal to transverse exchange example is also reported.

  10. Landing impact studies of a 0.3-scale model air cushion landing system for a Navy fighter airplane

    NASA Technical Reports Server (NTRS)

    Leland, T. J. W.; Thompson, W. C.

    1975-01-01

    An experimental study was conducted in order to determine the landing-impact behavior of a 0.3-scale, dynamically (but not physically) similar model of a high-density Navy fighter equipped with an air cushion landing system. The model was tested over a range of landing contact attitudes at high forward speeds and sink rates on a specialized test fixture at the Langley aircraft landing loads and traction facility. The investigation indicated that vertical acceleration at landing impact was highly dependent on the pitch angle at ground contact, the higher acceleration of approximately 5g occurring near zero body-pitch attitude. A limited number of low-speed taxi tests were made in order to determine model stability characteristics. The model was found to have good pitch-damping characteristics but stability in roll was marginal.

  11. The effectiveness of a 0.05 blood alcohol concentration (BAC) limit for driving in the United States.

    PubMed

    Fell, James C; Voas, Robert B

    2014-06-01

    The National Transportation Safety Board recently recommended that states establish a per se blood alcohol concentration (BAC) limit of 0.05 or lower for all drivers who are not already required to adhere to lower BAC limits in a national effort to reduce alcohol-impaired driving. There is strong evidence for adopting this recommendation. A comprehensive review of the literature on BAC limits was conducted. The research indicates that virtually all drivers are impaired regarding at least some driving performance measures at a 0.05 BAC. The risk of being involved in a crash increases significantly at 0.05 BAC and above. The relative risk of being killed in a single-vehicle crash with BACs of 0.05-0.079 is 7-21 times higher than for drivers at 0.00 BAC. Lowering the BAC limit from 0.08 to 0.05 has been a proven effective countermeasure in numerous countries around the world. Most Americans do not believe a person should drive after having two or three drinks in 2 hours. It takes at least four drinks for the average 170-pound male to exceed 0.05 BAC in 2 hours (three drinks for the 137-pound female). Most industrialized nations have established a 0.05 BAC limit or lower for driving. Progress in reducing the proportion of drivers in fatal crashes with illegal BACs has stalled over the past 15 years. Lowering the BAC limit for driving from the current 0.08 to 0.05 has substantial potential to reduce the number of people who drink and drive in the United States and get involved in fatal crashes.

  12. Reliability assessment of a 1 MV LTD.

    SciTech Connect

    Portillo, Salvador; Chavez, Raymond; Molina, Isidro; Kim, Alexandre A.; Johnson, David L.; Maenchen, John Eric; Leckbee, Joshua J.; Ziska, Derek Raymond

    2005-07-01

    A 1 MV linear transformer driver (LTD) is being tested with a large area e-beam diode load at Sandia National Laboratories (SNL). The experiments will be utilized to determine the repeatability of the output pulse and the reliability of the components. The 1 MV accelerator is being used to determine the feasibility of designing a 6 MV LTD for radiography experiments. The peak voltage, risetime, and pulse width as well as the cavity timing jitter are analyzed to determine the repeatability of the output pulse.

  13. A1.5 Fusion Performance

    SciTech Connect

    Amendt, P

    2011-03-31

    Analysis and radiation hydrodynamics simulations for expected high-gain fusion target performance on a demonstration 1-GWe Laser Inertial Fusion Energy (LIFE) power plant in the mid-2030s timeframe are presented. The required laser energy driver is 2.2 MJ at a 0.351-{micro}m wavelength, and a fusion target gain greater than 60 at a repetition rate of 16 Hz is the design goal for economic and commercial attractiveness. A scaling-law analysis is developed to benchmark the design parameter space for hohlraum-driven central hot-spot ignition. A suite of integrated hohlraum simulations is presented to test the modeling assumptions and provide a basis for a near-term experimental resolution of the key physics uncertainties on the National Ignition Facility (NIF). The NIF is poised to demonstrate ignition by 2012 based on the central hot spot (CHS) mode of ignition and propagating thermonuclear burn [1]. This immediate prospect underscores the imperative and timeliness of advancing inertial fusion as a carbon-free, virtually limitless source of energy by the mid-21st century to substantially offset fossil fuel technologies. To this end, an intensive effort is underway to leverage success at the NIF and to provide the foundations for a prototype 'LIFE.1' engineering test facility by {approx}2025, followed by a commercially viable 'LIFE.2' demonstration power plant operating at 1 GWe by {approx}2035. The current design goal for LIFE.2 is to accommodate {approx}2.2 MJ of laser energy (entering the high-Z radiation enclosure or 'hohlraum') at a 0.351-{micro}m wavelength operating at a repetition rate of 16 Hz and to provide a fusion target yield of 132 MJ. To achieve this design goal first requires a '0-d' analytic gain model that allows convenient exploration of parameter space and target optimization. This step is then followed by 2- and 3-dimensional radiation-hydrodynamics simulations that incorporate laser beam transport, x-ray radiation transport, atomic physics, and

  14. METSAT: Advanced Microwave Sounding Unit-A2 (AMSU-A2) structural mathematical model

    NASA Technical Reports Server (NTRS)

    Ely, Wayne

    1995-01-01

    This plan describes the Structural Mathematical Model of the METSAT AMSU-A2 instrument. The model is used to verify the structural adequacy of the AMSU-A2 instrument for the specified loading environments.

  15. Decommissioning Project of Bohunice A1 NPP

    SciTech Connect

    Stubna, M.; Pekar, A.; Moravek, J.; Spirko, M.

    2002-02-26

    The first (pilot) nuclear power plant A1 in the Slovak Republic, situated on Jaslovske Bohunice site (60 km from Bratislava) with the capacity of 143 MWel, was commissioned in 1972 and was running with interruptions till 1977. A KS 150 reactor (HWGCR) with natural uranium as fuel, D2O as moderator and gaseous CO2 as coolant was installed in the A1 plant. Outlet steam from primary reactor coolant system with the temperature of 410 C was led to 6 modules of steam generators and from there to turbine generators. Refueling was carried out on-line at plant full power. The first serious incident associated with refueling occurred in 1976 when a locking mechanism at a fuel assembly failed. The core was not damaged during that incident and following a reconstruction of the damaged technology channel, the plant continued in operation. However, serious problems were occurring with the integrity of steam generators (CO2 gas on primary side, water and steam on secondary side) when the plant had to be shut down frequently due to failures and subsequent repairs. The second serious accident occurred in 1977 when a fuel assembly was overheated with a subsequent release of D2O into gas cooling circuit due to a human failure in the course of replacement of a fuel assembly. Subsequent rapid increase in humidity of the primary system resulted in damages of fuel elements in the core and the primary system was contaminated by fission products. In-reactor structures had been damaged, too. Activity had penetrated also into certain parts of the secondary system via leaking steam generators. Radiation situation in the course of both events on the plant site and around it had been below the level of limits specified. Based on a technical and economical justification of the demanding character of equipment repairs for the restoration of plant operation, and also due to a decision made not to continue with further construction of gas cooled reactors in Czechoslovakia, a decision was made in

  16. Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas.

    PubMed

    Bouguéon, Guillaume; Lagarce, Frédéric; Martin, Ludovic; Pailhoriès, Hélène; Bastiat, Guillaume; Vrignaud, Sandy

    2016-07-25

    Medicines for the treatment of rare diseases frequently do not attract the interest of the pharmaceutical industry, and hospital pharmacists are thus often requested by physicians to prepare personalized medicines. Tuberous Sclerosis Complex (TSC) is a rare disease that causes disfiguring lesions named facial angiofibromas. Various topical formulations of rapamycin (=sirolimus) have been proved effective in treating these changes in small case series. The present study provides for the first time characterization of a 0.1% rapamycin cream formulation presenting good rapamycin solubilisation. The first step of the formulation is solubilisation of rapamycin in Transcutol(®), and the second step is the incorporation of the mixture in an oil-in-water cream. A HPLC stability-indicating method was developed. Rapamycin concentration in the cream was tested by HPLC and confirmed that it remained above 95% of the initial concentration for at least 85days, without characteristic degradation peaks. The preparation met European Pharmacopoeia microbial specifications throughout storage in aluminum tubes, including when patient use was simulated. Odour, appearance and colour of the preparation were assessed and no change was evidenced during storage. The rheological properties of the cream also remained stable throughout storage. To conclude, we report preparation of a novel cream formulation presenting satisfactory rapamycin solubilisation for the treatment of TSC cutaneous manifestations, with stability data. The cream is currently being used by our patients. Efficacy and tolerance will be reported later.

  17. A 0.1-1.5 GHz, low jitter, area efficient PLL in 55-nm CMOS process

    NASA Astrophysics Data System (ADS)

    Bo, Zhong; Zhangming, Zhu

    2016-05-01

    A 0.1-1.5 GHz, 3.07 pS root mean squares (RMS) jitter, area efficient phase locked loop (PLL) with multiphase clock outputs is presented in this paper. The size of capacitor in the low pass filter (LPF) is significantly decreased by implementing a dual path charge pump (CP) technique in this PLL. Subject to specified power consumption, a novel optimization method is introduced to optimize the transistor size in the voltage control oscillator (VCO), CP and phase/frequency detector (PFD) in order to minimize clock jitter. This method could improve 3-6 dBc/Hz phase noise. The proposed PLL has been fabricated in 55 nm CMOS process with an integrated 16 pF metal-oxide-metal (MOM) capacitor, occupies 0.05 mm2 silicon area, the measured total power consumption is 2.8 mW @ 1.5 GHz and the phase noise is -102 dBc/Hz @ 1 MHz offset frequency. Project supported by the National Natural Science Foundation of China (Nos. 61234002, 61322405, 61306044, 61376033) and the National High-Tech Program of China (No. 2013AA014103).

  18. Pressure distributions on a 0.02-scale Space Shuttle orbiter nose at Mach 21.5 in helium

    NASA Technical Reports Server (NTRS)

    Ashby, George C., Jr.; Bernot, Peter T.; Woods, William C.

    1994-01-01

    Pressure distributions on a 0.02-scale model of the Space Shuttle orbiter forward fuselage were obtained in the 22-inch aerodynamic leg of the Langley Hypersonic Helium Tunnel Facility at a nominal free-stream Mach number of 21.5 and a ratio of specific heats of 1.67 for inclusion in the database of the Shuttle entry air data system (SEADS). The data were measured at model angles of attack of 0 deg to 50 deg in 5 deg increments for zero sideslip angle and at model sideslip angles of -5 deg to 5 deg for angles of attack equal to 5, 20, 35, and 40 deg. These data displayed trends similar to those observed in other wind tunnels at Mach 6 and 10 in air. Specifically noted is a shift in the location of the stagnation point at angles of attack above 15 deg; this effect did not, however, occur in flight. By comparison, the data obtained at Mach 6 in the Langley Hypersonic CF4 Tunnel, corresponding to a lower ratio of specific heats in the postshock region than those in helium and air, showed some reduction of the stagnation point shift at the higher angles of attack. The differences between flight and wind tunnel pressure distributions are believed due primarily to high-temperature gas chemistry effects in flight, which include lower effective specific heat ratios but which were not completely duplicated in the wind tunnels.

  19. Breast ductoscopy with a 0.55-mm mini-endoscope for direct visualization of intraductal lesions.

    PubMed

    Jacobs, Volker R; Kiechle, Marion; Plattner, Birgit; Fischer, Thorsten; Paepke, Stefan

    2005-01-01

    Standard radiologic examinations of breast duct lesions can give only indirect information. Mini-endoscopy with a breast ductoscope of only 0.55 mm offers direct visualization of the lesion and helps in the decision to perform or avoid exploratory breast tissue resection. We used a LaDuScope (PolyDiagnost, Pfaffenhofen, Germany) with a 0.55- or 0.95-mm outer diameter and a 75-mm working length from October 2003 through July 2004 on 11 women (average age of 48.3 years [range 36-69 years]) with suspicious nipple discharge. The optics have zero-degree direct view, 70-degree field vision, and 3000 or 6000 pixel resolution. Breast ducts and walls could be easily inspected; and irrigation of breast ducts, aspiration, and use of cytology brush were possible under visual control. We had no intraoperative or postoperative complications. The new procedure of mini-ductoscopy is feasible, safe, and helpful as an additional ambulatory diagnostic method for visual inspection of breast ducts. This instrument demonstrates the latest advances of technology and a trend toward less-invasive diagnostics for breast duct lesions.

  20. PLC Software Program for Leak Detector Station A1 SALW-LD-ST-A1

    SciTech Connect

    KOCH, M.R.

    2001-01-25

    This document describes the software program for the programmable logic controller for the leak detector station ''SALW-LD-ST-A1''. The appendices contains a copy of the printout of the software program.

  1. Continuous transformation of a -1/2 wedge disclination line to a +1/2 one

    NASA Astrophysics Data System (ADS)

    Fukuda, Jun-Ichi

    2010-04-01

    It is known that, in the order-parameter space S2/Z2 (a typical example being a uniaxial nematic liquid crystal in three dimensions), a -1/2 wedge disclination line and a +1/2 one are topologically equivalent and can thus be transformed continuously into each other. Here we report the realization of this transformation in a simulation of a cholesteric blue phase under an electric field.

  2. The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation

    SciTech Connect

    Mayo, Jaime L.; Holden, Devin N.; Barrow, Jeffery R.; Bridgewater, Laura C.

    2009-08-01

    The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with an Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.

  3. A role of the SAM domain in EphA2 receptor activation

    PubMed Central

    Shi, Xiaojun; Hapiak, Vera; Zheng, Ji; Muller-Greven, Jeannine; Bowman, Deanna; Lingerak, Ryan; Buck, Matthias; Wang, Bing-Cheng; Smith, Adam W.

    2017-01-01

    Among the 20 subfamilies of protein receptor tyrosine kinases (RTKs), Eph receptors are unique in possessing a sterile alpha motif (SAM domain) at their C-terminal ends. However, the functions of SAM domains in Eph receptors remain elusive. Here we report on a combined cell biology and quantitative fluorescence study to investigate the role of the SAM domain in EphA2 function. We observed elevated tyrosine autophosphorylation levels upon deletion of the EphA2 SAM domain (EphA2ΔS) in DU145 and PC3 prostate cancer cells and a skin tumor cell line derived from EphA1/A2 knockout mice. These results suggest that SAM domain deletion induced constitutive activation of EphA2 kinase activity. In order to explain these effects, we applied fluorescence correlation spectroscopy to investigate the lateral molecular organization of EphA2. Our results indicate that SAM domain deletion (EphA2ΔS-GFP) increases oligomerization compared to the full length receptor (EphA2FL-GFP). Stimulation with ephrinA1, a ligand for EphA2, induced further oligomerization and activation of EphA2FL-GFP. The SAM domain deletion mutant, EphA2ΔS-GFP, also underwent further oligomerization upon ephrinA1 stimulation, but the oligomers were larger than those observed for EphA2FL-GFP. Based on these results, we conclude that the EphA2 SAM domain inhibits kinase activity by reducing receptor oligomerization. PMID:28338017

  4. The A2 Experiment Program at MAMI

    NASA Astrophysics Data System (ADS)

    Briscoe, William; A2 Collaboration

    2014-09-01

    The Mainz Microtron MAMI is an accelerator for electron beams run by the Institut für Kernphysik of the Johannes Gutenberg-Universität Mainz used for hadron physics experiments. Of it's three active experimental halls, the A2 facility, which features the presence of the SLAC Crystal Ball detector, has produced a plethora of experimental results, which has contributed to the understanding of the structure of the nucleon. An overview and update of the current A2 program will be presented. The Mainz Microtron MAMI is an accelerator for electron beams run by the Institut für Kernphysik of the Johannes Gutenberg-Universität Mainz used for hadron physics experiments. Of it's three active experimental halls, the A2 facility, which features the presence of the SLAC Crystal Ball detector, has produced a plethora of experimental results, which has contributed to the understanding of the structure of the nucleon. An overview and update of the current A2 program will be presented. Funded in part by SFB 1044. US collaborators funded by USDOE and USNSF.

  5. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom the...

  6. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom the...

  7. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom the...

  8. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom the...

  9. 29 CFR 4041A.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... plan year, available resources as described in section 4245(b)(3) of ERISA. Benefits subject to... Relating to Labor (Continued) PENSION BENEFIT GUARANTY CORPORATION PLAN TERMINATIONS TERMINATION OF MULTIEMPLOYER PLANS General Provisions § 4041A.2 Definitions. The following terms are defined in § 4001.1...

  10. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means... factor. Institution of higher learning means any college or university accredited by a regionalized body... has higher learning among its purposes and functions and which has a formal affiliation with...

  11. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means inherited disorders caused by the transmission of certain aberrant genes from one generation to another. Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  12. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means inherited disorders caused by the transmission of certain aberrant genes from one generation to another. Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  13. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means inherited disorders caused by the transmission of certain aberrant genes from one generation to another. Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  14. A 1-D dusty plasma photonic crystal

    SciTech Connect

    Mitu, M. L.; Ticoş, C. M.; Toader, D.; Banu, N.; Scurtu, A.

    2013-09-21

    It is demonstrated numerically that a 1-D plasma crystal made of micron size cylindrical dust particles can, in principle, work as a photonic crystal for terahertz waves. The dust rods are parallel to each other and arranged in a linear string forming a periodic structure of dielectric-plasma regions. The dispersion equation is found by solving the waves equation with the boundary conditions at the dust-plasma interface and taking into account the dielectric permittivity of the dust material and plasma. The wavelength of the electromagnetic waves is in the range of a few hundred microns, close to the interparticle separation distance. The band gaps of the 1-D plasma crystal are numerically found for different types of dust materials, separation distances between the dust rods and rod diameters. The distance between levitated dust rods forming a string in rf plasma is shown experimentally to vary over a relatively wide range, from 650 μm to about 1350 μm, depending on the rf power fed into the discharge.

  15. A2A adenosine receptors are up-regulated in lymphocytes from amyotrophic lateral sclerosis patients.

    PubMed

    Vincenzi, Fabrizio; Corciulo, Carmen; Targa, Martina; Casetta, Ilaria; Gentile, Mauro; Granieri, Enrico; Borea, Pier Andrea; Popoli, Patrizia; Varani, Katia

    2013-09-01

    Adenosine, a purine nucleoside interacting with A1, A2A, A2B and A3 adenosine receptors (ARs), is a potent endogenous modulator of inflammatory and neuronal processes involved in the pathophysiology of several neurodegenerative diseases. In the present study, ARs were investigated in lymphocytes from patients with amyotrophic lateral sclerosis (ALS) and compared with age-matched healthy subjects. In ALS patients A2AARs were analysed by using RT-PCR, Western blotting and saturation binding experiments. The effect of A2AAR stimulation on cyclic AMP levels was evaluated in lymphocytes from ALS patients and healthy subjects. An up-regulation of A2AARs was observed in ALS patients with respect to healthy subjects while A1, A2B and A3AR affinity and density did not change. In ALS patients, the A2AAR density values correlated with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Furthermore, the stimulation of A2AARs mediated a significant increase in cyclic AMP levels in lymphocytes from ALS patients, with a higher potency than in lymphocytes from healthy subjects. In conclusion, the positive correlation between A2AAR density and ALSFRS-R scores could indicate a possible protective effect of this receptor subtype, representing an interesting starting point for the study of alternative therapeutic approaches for ALS based on A2AAR modulation.

  16. Efficacy of a 0.0584% hydrocortisone aceponate spray in presumed feline allergic dermatitis: an open label pilot study.

    PubMed

    Schmidt, Vanessa; Buckley, Laura M; McEwan, Neil A; Rème, Christophe A; Nuttall, Tim J

    2012-02-01

    This study evaluated the efficacy of a 0.0584% hydrocortisone aceponate (HCA) spray (Cortavance(®); Virbac SA) in 10 cats with presumed allergic dermatitis. The cats initially received two sprays/100 cm(2) of skin once daily. Clinical lesions (a Feline Dermatitis Extent and Severity Index; FeDESI), pruritus (10 cm visual analog scale with grade descriptors) and owner assessments of efficacy, tolerance and ease of use (from 1=very poor to 5=excellent) were assessed every 14 days. The frequency of treatment was reduced after day 28 in cats with a >50% reduction in FeDESI and pruritus scores. One cat was lost to follow up at day 28 and two at day 42. Intention-to-treat data were analysed. The FeDESI [mean (SD): day 0, 42.2 (15.7) and day 56, 9.9 (11.7); P<0.0001] and pruritus scores [day 0, 61.2 mm (20.1) and day 56, 14.6 mm (16.1); P<0.0001] significantly decreased throughout the trial. The owner scores for tolerance [median (range): day 14, 4 (1-5) and day 56, 4 (3-5); P=0.003] and ease of administration [day 14, 3 (2-5) and day 56, 4 (2-5); P=0.02] significantly increased during the trial, but there was no significant change in efficacy scores [day 14, 4 (3-5) and day 56, 4 (2-5); P=0.5]. There were no adverse effects attributable to the HCA spray, no significant changes in weight [mean (SD): day 0, 5.0 kg (1.4) and day 56, 5.0 kg (1.6); P=0.51] and no significant changes in haematology, biochemistry or urinalysis (n=4). Six cats required every-other-day treatment and four required daily treatment. In conclusion, HCA spray appeared to be effective and safe in these cats, although it is not licensed for use in this species.

  17. Architecture for a 1-GHz Digital RADAR

    NASA Technical Reports Server (NTRS)

    Mallik, Udayan

    2011-01-01

    An architecture for a Direct RF-digitization Type Digital Mode RADAR was developed at GSFC in 2008. Two variations of a basic architecture were developed for use on RADAR imaging missions using aircraft and spacecraft. Both systems can operate with a pulse repetition rate up to 10 MHz with 8 received RF samples per pulse repetition interval, or at up to 19 kHz with 4K received RF samples per pulse repetition interval. The first design describes a computer architecture for a Continuous Mode RADAR transceiver with a real-time signal processing and display architecture. The architecture can operate at a high pulse repetition rate without interruption for an infinite amount of time. The second design describes a smaller and less costly burst mode RADAR that can transceive high pulse repetition rate RF signals without interruption for up to 37 seconds. The burst-mode RADAR was designed to operate on an off-line signal processing paradigm. The temporal distribution of RF samples acquired and reported to the RADAR processor remains uniform and free of distortion in both proposed architectures. The majority of the RADAR's electronics is implemented in digital CMOS (complementary metal oxide semiconductor), and analog circuits are restricted to signal amplification operations and analog to digital conversion. An implementation of the proposed systems will create a 1-GHz, Direct RF-digitization Type, L-Band Digital RADAR--the highest band achievable for Nyquist Rate, Direct RF-digitization Systems that do not implement an electronic IF downsample stage (after the receiver signal amplification stage), using commercially available off-the-shelf integrated circuits.

  18. Experimental validation of a 0-D numerical model for phase change thermal management systems in lithium-ion batteries

    NASA Astrophysics Data System (ADS)

    Schweitzer, Ben; Wilke, Stephen; Khateeb, Siddique; Al-Hallaj, Said

    2015-08-01

    A lumped (0-D) numerical model has been developed for simulating the thermal response of a lithium-ion battery pack with a phase-change composite (PCC™) thermal management system. A small 10s4p battery pack utilizing PCC material was constructed and subjected to discharge at various C-rates in order to validate the lumped model. The 18650 size Li-ion cells used in the pack were electrically characterized to determine their heat generation, and various PCC materials were thermally characterized to determine their apparent specific heat as a function of temperature. Additionally, a 2-D FEA thermal model was constructed to help understand the magnitude of spatial temperature variation in the pack, and to understand the limitations of the lumped model. Overall, good agreement is seen between experimentally measured pack temperatures and the 0-D model, and the 2-D FEA model predicts minimal spatial temperature variation for PCC-based packs at C-rates of 1C and below.

  19. Conceptual design of a 0.1 W magnetic refrigerator for operation between 10 K and 2 K

    NASA Technical Reports Server (NTRS)

    Helvensteijn, Ben P. M.; Kashani, Ali

    1990-01-01

    The design of a magnetic refrigerator for space applications is discussed. The refrigerator is to operate in the temperature range of 10 K-2 K, at a 2 K cooling power of 0.10 W. As in other magnetic refrigerators operating in this temperature range GGG has been selected as the refrigerant. Crucial to the design of the magnetic refrigerator are the heat switches at both the hot and cold ends of the GGG pill. The 2 K heat switch utilizes a narrow He II filled gap. The 10 K heat switch is based on a narrow helium gas gap. For each switch, the helium in the gap is cycled by means of activated carbon pumps. The design concentrates on reducing the switching times of the pumps and the switches as a whole. A single stage system (one magnet; one refrigerant pill) is being developed. Continuous cooling requires the fully stationary system to have at least two stages running parallel/out of phase with each other. In order to conserve energy, it is intended to recycle the magnetic energy between the magnets. To this purpose, converter networks designed for superconducting magnetic energy storage are being studied.

  20. Search for Invisible Decays of a Light Scalar in Radiative Transitions Y(3S)->gamma A0

    SciTech Connect

    Aubert, B

    2008-11-05

    We search for a light scalar particle produced in single-photon decays of the {Upsilon}(3S) resonance through the process {Upsilon}(3S) {yields} {gamma} + A{sup 0}, A{sup 0} {yields} invisible. Such an object appears in Next-to-Minimal Supersymmetric extensions of the Standard Model, where a light CP-odd Higgs boson naturally couples strongly to b-quarks. If, in addition, there exists a light, stable neutralino, decays of A{sup 0} could be preferentially to an invisible final state. We search for events with a single high-energy photon and a large missing mass, consistent with a 2-body decay of {Upsilon}(3S). We find no evidence for such processes in a sample of 122 x 10{sup 6} {Upsilon}(3S) decays collected by the BABAR collaboration at the PEP-II B-factory, and set 90% C.L. upper limits on the branching fraction {Beta}({Upsilon}(3S) {yields} {gamma}A{sup 0}) x {Beta}(A{sup 0} {yields} invisible) at (0.7-31) x 10{sup -6} in the mass range m{sub A{sup 0}} {le} 7.8 GeV. The results are preliminary.

  1. A 0.18 μm CMOS transmit physical coding sublayer IC for 100G Ethernet

    NASA Astrophysics Data System (ADS)

    Weihua, Ruan; Qingsheng, Hu

    2016-03-01

    This paper presents a transmit physical coding sublayer (PCS) circuit for 100G Ethernet. Based on the 4 × 25 Gb/s architecture according to the IEEE P802.3ba and IEEE P802.3bmTM/D1.1 standards, this PCS circuit is designed using a semi-custom design method and consists of 4 modules including 64B/66B encoder, scrambler, multiple lanes distribution and 66 : 8 gearbox. By using the pipeline structure and several optimization techniques, the working speed of the circuit is increased significantly. The parallel scrambling combined with logic optimization also improve the performance. In addition, a kind of phase-independent structure is employed in the design of the gearbox to ensure it can work stably and reliably at high frequency. This PCS circuit has been fabricated based on 0.18 μm CMOS technology and the total area is 1.7 × 1.7 mm2. Measured results show that the circuit can work properly at 100 Gb/s and the power consumption is about 284 mW with a 1.8 V supply. Project supported by the National Natural Science Foundation of China (No. 6504000129) and the National Basic Research Program of China (No. 6504000052).

  2. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

    The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials. In addition to HDL infusion therapy an alternative way to exploit beneficial cardiovascular effects of HDL/ApoA-1 is to use gene transfer. Preclinical studies have shown evidence of benefit using this approach; however clinical validation is yet lacking. This review summarizes our current knowledge of the aforementioned strategies. PMID:26388776

  3. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy

    PubMed Central

    Alavi, Marcel V.; Mao, Mao; Pawlikowski, Bradley T.; Kvezereli, Manana; Duncan, Jacque L.; Libby, Richard T.; John, Simon W. M.; Gould, Douglas B.

    2016-01-01

    Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1+/Δex41mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes. PMID:26813606

  4. A RF receiver frontend for SC-UWB in a 0.18-μm CMOS process

    NASA Astrophysics Data System (ADS)

    Rui, Guo; Haiying, Zhang

    2012-12-01

    A radio frequency (RF) receiver frontend for single-carrier ultra-wideband (SC-UWB) is presented. The front end employs direct-conversion architecture, and consists of a differential low noise amplifier (LNA), a quadrature mixer, and two intermediate frequency (IF) amplifiers. The proposed LNA employs source inductively degenerated topology. First, the expression of input impedance matching bandwidth in terms of gate-source capacitance, resonant frequency and target S11 is given. Then, a noise figure optimization strategy under gain and power constraints is proposed, with consideration of the integrated gate inductor, the bond-wire inductance, and its variation. The LNA utilizes two stages with different resonant frequencies to acquire flat gain over the 7.1-8.1 GHz frequency band, and has two gain modes to obtain a higher receiver dynamic range. The mixer uses a double balanced Gilbert structure. The front end is fabricated in a TSMC 0.18-μm RF CMOS process and occupies an area of 1.43 mm2. In high and low gain modes, the measured maximum conversion gain are 42 dB and 22 dB, input 1 dB compression points are -40 dBm and -20 dBm, and S11 is better than -18 dB and -14.5 dB. The 3 dB IF bandwidth is more than 500 MHz. The double sideband noise figure is 4.7 dB in high gain mode. The total power consumption is 65 mW from a 1.8 V supply.

  5. A2A Adenosine Receptor (A2AAR) as a Therapeutic Target in Diabetic Retinopathy

    PubMed Central

    Ibrahim, Ahmed S.; El-shishtawy, Mamdouh M.; Zhang, Wenbo; Caldwell, Ruth B.; Liou, Gregory I.

    2011-01-01

    In diabetic retinopathy (DR), abnormalities in vascular and neuronal function are closely related to the local production of inflammatory mediators whose potential source is microglia. A2A adenosine receptor (A2AAR) has been shown to possess anti-inflammatory properties that have not been studied in DR. Here, we evaluate the role of A2AAR and its underlying signaling in retinal complications associated with diabetes. Initial studies in wild-type mice revealed that the treatment with the A2AAR agonist resulted in marked decreases in hyperglycemia-induced retinal cell death and tumor necrosis factor (TNF)-α release. To further assess the role of A2AAR in DR, we studied the effects of A2AAR ablation on diabetes-induced retinal abnormalities. Diabetic A2AAR−/− mice had significantly more terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells, TNF-α release, and intercellular adhesion molecule-1 expression compared with diabetic wild-type mice. To explore a potential mechanism by which A2AAR signaling regulates inflammation in DR, we performed additional studies using microglial cells treated with Amadori-glycated albumin, a risk factor in diabetic disorders. The results showed that activation of A2AAR attenuated Amadori-glycated albumin-induced TNF-α release in a cAMP/exchange protein directly activated by cAMP-dependent mechanism and significantly repressed the inflammatory cascade, C-Raf/extracellular signal-regulated kinase (ERK), in activated microglia. Collectively, this work provides pharmacological and genetic evidence for A2AAR signaling as a control point of cell death in DR and suggests that the retinal protective effect of A2AAR is mediated by abrogating the inflammatory response that occurs in microglia via interaction with C-Raf/ERK pathway. PMID:21514428

  6. Importance of UDP-glucuronosyltransferases 2A2 and 2A3 in tobacco carcinogen metabolism.

    PubMed

    Bushey, Ryan T; Dluzen, Douglas F; Lazarus, Philip

    2013-01-01

    UDP-glucuronosyltransferase A1 (UGT2A1) is expressed in the lung and exhibits activity against polycyclic aromatic hydrocarbons (PAHs), suggesting UGT2A1 involvement in the local metabolism of PAH tobacco carcinogens. The goal of the present study was to investigate the importance of two additional UGT2A enzymes, UGT2A2 and UGT2A3, in tobacco carcinogen metabolism. Real-time polymerase chain reaction suggested that wild-type UGT2A2 had the highest expression in the breast, followed by trachea > larynx > kidney. A novel splice variant of UGT2A2 lacking exon 3 (termed UGT2A2Δexon3) was investigated, with UGT2A2Δexon3 expression determined to be 25-50% that of wild-type UGT2A2 in all tissues examined. UGT2A3 was determined to be well expressed in the liver and colon, followed by pancreas > kidney > lung > tonsil > trachea > larynx. Cell homogenates prepared from human embryonic kidney (HEK)293 cells overexpressing wild-type UGT2A2 (termed UGT2A2_i1) exhibited glucuronidation activity, as observed by reverse-phase ultra-pressure liquid chromatography, against 1-hydroxy-(OH)-pyrene, 1-naphthol, and hydroxylated benzo(a)pyrene metabolites, whereas homogenates prepared from HEK293 cells overexpressing UGT2A3 only showed activity against simple PAHs like 1-OH-pyrene and 1-naphthol. Activity assays showed the UGT2A2Δexon3 protein (termed UGT2A2_i2) exhibited no detectable glucuronidation activity against all substrates examined; however, coexpression studies suggested that UGT2A2_i2 negatively modulates UGT2A2_i1 activity. Both UGT2A2 and UGT2A3 exhibited no detectable activity against complex PAH proximate carcinogens, tobacco-specific nitrosamines, or heterocyclic amines. These data suggest that, although UGT2A1 is the only UGT2A enzyme active against PAH proximate carcinogens (including PAH diols), both UGTs 2A1 and 2A2 play an important role in the local detoxification of procarcinogenic monohydroxylated PAH metabolites.

  7. Analysis and design of a 1.8-2.7 GHz tunable 8-band TDD LTE receiver front-end

    NASA Astrophysics Data System (ADS)

    Xiao, Wang; Yuji, Wang; Weiwei, Wang; Xuegui, Chang; Na, Yan; Xi, Tan; Hao, Min

    2011-05-01

    This paper describes the analysis and design of a 0.13 μm CMOS tunable receiver front-end that supports 8 TDD LTE bands, covering the 1.8-2.7 GHz frequency band and supporting the 5/10/15/20 MHz bandwidth and QPSK/16QAM/64QAM modulation schemes. The novel zero-IF receiver core consists of a tunable narrowband variable gain low-noise amplifier (LNA), a current commutating passive down-conversion mixer with a 2nd order low pass trans-impedance amplifier, an LO divider, a rough gain step variable gain pre-amplifier, a tunable 4th order Chebyshev channel select active-RC low pass filter with cutoff frequency calibration circuit and a fine gain step variable gain amplifier. The LNA can be tuned by reconfiguring the output parallel LC tank to the responding frequency band, eliminating the fixed center frequency multiple LNA array for a multi-mode receiver. The large various gain range and bandwidth of the analog baseband can also be tuned by digital configuration to satisfy the specification requirement of various bandwidth and modulation schemes. The test chip is implemented in an SMIC 0.13 μm 1P8M CMOS process. The full receiver achieves 4.6 dB NF, -14.5 dBm out of band IIP3, 30-94 dB gain range and consumes 54 mA with a 1.2 V power supply.

  8. Adenosine receptors and diabetes: Focus on the A(2B) adenosine receptor subtype.

    PubMed

    Merighi, Stefania; Borea, Pier Andrea; Gessi, Stefania

    2015-09-01

    Over the last two decades, diabetes mellitus has become one of the most challenging health problems worldwide. Diabetes mellitus, classified as type I and II, is a pathology concerning blood glucose level in the body. The nucleoside adenosine has long been known to affect insulin secretion, glucose homeostasis and lipid metabolism, through activation of four G protein coupled adenosine receptors (ARs), named A1, A2A, A2B and A3. Currently, the novel promising subtype to develop new drugs for diabetes treatment is the A2BAR subtype. The use of selective agonists and antagonists for A2BAR subtype in various diabetic animal models allowed us to identify several effects of A2BAR signaling in cell metabolism. In particular, the focus of this review is to summarize the studies on purinergic signaling associated with diabetes through A2BARs modulation.

  9. GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

    PubMed Central

    Li, Yan-Jun; Kalyanaraman, Chakrapani; Qiu, Li-Li; Chen, Chen; Xiao, Qi; Liu, Wen-Xue; Zhang, Wei; Yang, Jian-Jun; Chen, Guiquan; Jacobson, Matthew P.; Shi, Yun Stone

    2016-01-01

    AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in full-length GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1–2–1–2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides. PMID:27601647

  10. Percutaneous release of the A1 pulley using a modified Kirschner wire: a cadaveric study.

    PubMed

    Saengnipanthkul, Sukit; Sae-Jung, Surachai; Sumananont, Chat

    2014-08-01

    PURPOSE. To evaluate the outcome of percutaneous release of the A1 pulley in 40 cadaveric fingers using a modified Kirschner wire. METHODS. A 2.5-mm-diameter Kirschner wire measuring >12 cm in length was used. One end of the wire was sharpened into a 'J' shape using a grinder. The J-shaped tip featured a blunt, elongated lower tip, a sharp J-shaped curve, and a blunt upper tip. Completeness of A1 pulley release and injuries to the A2 pulley, flexor tendon, and neurovascular structures were evaluated in 40 cadaveric fingers. RESULTS. Complete release of the A1 pulley was achieved in 8 index, 7 middle, 8 ring, and 8 little fingers, whereas incomplete release of the distal part was noted in 2 index, 2 middle, 2 ring, and one little fingers; release was missed in one middle and one little fingers. Injury to the A2 pulley was noted in 2 index fingers; the injury was minimal and limited to the proximal 2 mm of the A2 pulley. There was no flexor tendon or digital nerve injury in any finger. CONCLUSION. Percutaneous release of the A1 pulley using a modified Kirschner wire achieved complete release in 78% of cadaveric fingers, which is comparable to that using a specially manufactured push knife.

  11. 77 FR 46352 - Approval and Promulgation of Implementation Plans; Kentucky; 110(a)(1) and (2) Infrastructure...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-03

    ... INFORMATION: Table of Contents I. Background II. What elements are required under sections 110(a)(1) and (2... August 26, 2008, and July 17, 2012, satisfy certain required infrastructure elements for the 1997... Statutes (KRS) into the SIP to address element 110(a)(2)(E)(ii), that relates to state board...

  12. The A1 adenosine receptor as a new player in microglia physiology.

    PubMed

    Luongo, L; Guida, F; Imperatore, R; Napolitano, F; Gatta, L; Cristino, L; Giordano, C; Siniscalco, D; Di Marzo, V; Bellini, G; Petrelli, R; Cappellacci, L; Usiello, A; de Novellis, V; Rossi, F; Maione, S

    2014-01-01

    The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2 X4,7 and P2 Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca(2+) influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone.

  13. Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats.

    PubMed

    Mandhane, S N; Chopde, C T; Ghosh, A K

    1997-06-11

    The effect of adenosine A1 and A2 receptor agonists and antagonists was investigated on haloperidol-induced catalepsy in rats. Pretreatment (i.p.) with the non-selective adenosine receptor antagonist, theophylline, or the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), significantly reversed haloperidol-induced catalepsy, whereas the selective adenosine A1 receptor antagonists, 8-phenyltheophylline and 8-cyclopentyl-1,3-dipropylxanthine produced no effect. Similar administration of the adenosine A2 receptor agonists, 5'-(N-cyclopropyl)-carboxamidoadenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and the mixed agonists with predominantly A1 site of action, N6-(2-phenylisopropyl) adenosine or 2-chloroadenosine, potentiated haloperidol-induced catalepsy. Higher doses of the adenosine agonists produced catalepsy when given alone. However, N6-cyclopentyladenosine, a highly selective adenosine A1 receptor agonist, was ineffective in these respects. The per se cataleptic effect of adenosine agonists was blocked by DMPX and the centrally acting anticholinergic agent, scopolamine. Scopolamine also attenuated the potentiation of haloperidol-induced catalepsy by adenosine agonists. Further, i.c.v. administration of NECA and DMPX produced a similar effect as that produced after their systemic administration. These findings demonstrate the differential influence of adenosine A1 and A2 receptors on haloperidol-induced catalepsy and support the hypothesis that the functional interaction between adenosine and dopamine mechanisms might occur through adenosine A2 receptors at the level of cholinergic neurons. The results suggest that adenosine A2, but not A1, receptor antagonists may be of potential use in the treatment of Parkinson's disease.

  14. X-15A-2 with dummy ramjet

    NASA Technical Reports Server (NTRS)

    1967-01-01

    This photo shows the X-15A-2 (56-6671) on a research flight with a dummy ramjet engine attached to the bottom of its wedge-shaped vertical tail. One of the experiments planned for the X-15A-2 involved tests of a functional ramjet at speeds above Mach 5. This photo was taken with a dummy ramjet. On this research flight, the X-15A-2 did not carry the two drop tanks used on its Mach 6.7 flight. It also had not yet been covered with an ablative coating. The X-15A-2 made several flights with the dummy ramjet, leading to the record Mach 6.7 flight on October 3, 1967. Delays in producing the operational ramjet, aerodynamic heating damage to the aircraft during the record flight (despite the ablative coating), and the end of the X-15 program in 1968 resulted in no flights with the actual ramjet. The X-15 was a rocket-powered aircraft. The original three aircraft were about 50 ft long with a wingspan of 22 ft. The modified #2 aircraft (X-15A-2 was longer.) They were a missile-shaped vehicles with unusual wedge-shaped vertical tails, thin stubby wings, and unique side fairings that extended along the side of the fuselage. The X-15 weighed about 14,000 lb empty and approximately 34,000 lb at launch. The XLR-99 rocket engine, manufactured by Thiokol Chemical Corp., was pilot controlled and was rated at 57,000 lb of thrust, although there are indications that it actually achieved up to 60,000 lb. North American Aviation built three X-15 aircraft for the program. The X-15 research aircraft was developed to provide in-flight information and data on aerodynamics, structures, flight controls, and the physiological aspects of high-speed, high-altitude flight. A follow-on program used the aircraft as testbeds to carry various scientific experiments beyond the Earth's atmosphere on a repeated basis. For flight in the dense air of the usable atmosphere, the X-15 used conventional aerodynamic controls such as rudder surfaces on the vertical stabilizers to control yaw and movable

  15. Regulation of endothelial migration and proliferation by ephrin-A1.

    PubMed

    Wiedemann, Elisa; Jellinghaus, Stefanie; Ende, Georg; Augstein, Antje; Sczech, Ronny; Wielockx, Ben; Weinert, Sönke; Strasser, Ruth H; Poitz, David M

    2017-01-01

    Endothelial migration and proliferation are fundamental processes in angiogenesis and wound healing of injured or inflamed vessels. The present study aimed to investigate the regulation of the Eph/ephrin-system during endothelial proliferation and the impact of the ligand ephrin-A1 on proliferation and migration of human umbilical venous (HUVEC) and arterial endothelial cells (HUAEC). Endothelial cells that underwent contact inhibition showed a massive induction of ephrin-A1. In contrast, an injury to a confluent endothelial layer, associated with induction of migration and proliferation, showed reduced ephrin-A1 levels. In addition, reducing ephrin-A1 expression by siRNA led to increased proliferation, whereas the overexpression of ephrin-A1 led to decreased proliferative activity. Due to the fact that wound healing is a combination of proliferation and migration, migration was investigated in detail. First, classical wound-healing assays showed increased wound closure in both ephrin-A1 silenced and overexpressing cells. Live-cell imaging enlightened the underlying differences. Silencing of ephrin-A1 led to a faster but more disorientated migration. In contrast, ephrin-A1 overexpression did not influence velocity of the cells, but the migration was more directed in comparison to the controls. Additional analysis of EphA2-silenced cells showed similar results in terms of proliferation and migration compared to ephrin-A1 silenced cells. Detailed analysis of EphA2 phosphorylation on ligand-dependent phospho-site (Y588) and autonomous activation site (S897) revealed a distinct phosphorylation pattern. Furthermore, the endothelial cells ceased to migrate when they came in contact with an ephrin-A1 coated surface. Using a baculoviral-mediated expression system, ephrin-A1 silencing and overexpression was shown to modulate the formation of focal adhesions. This implicates that ephrin-A1 is involved in changes of the actin cytoskeleton which explains the alterations in

  16. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  17. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1.

    PubMed

    Lin, Samantha; Gordon, Kristin; Kaplan, Nihal; Getsios, Spiro

    2010-11-15

    EphA2 is a receptor tyrosine kinase that is engaged and activated by membrane-linked ephrin-A ligands residing on adjacent cell surfaces. Ligand targeting of EphA2 has been implicated in epithelial growth regulation by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2)-mitogen activated protein kinase (MAPK) pathway. Although contact-dependent EphA2 activation was required for dampening Erk1/2-MAPK signaling after a calcium switch in primary human epidermal keratinocytes, the loss of this receptor did not prevent exit from the cell cycle. Incubating keratinocytes with a soluble ephrin-A1-Fc peptide mimetic to target EphA2 further increased receptor activation leading to its down-regulation. Moreover, soluble ligand targeting of EphA2 restricted the lateral expansion of epidermal cell colonies without limiting proliferation in these primary cultures. Rather, ephrin-A1-Fc peptide treatment promoted epidermal cell colony compaction and stratification in a manner that was associated with increased keratinocyte differentiation. The ligand-dependent increase in keratinocyte adhesion and differentiation relied largely upon the up-regulation of desmoglein 1, a desmosomal cadherin that maintains the integrity and differentiated state of suprabasal keratinocytes in the epidermis. These data suggest that keratinocytes expressing EphA2 in the basal layer may respond to ephrin-A1-based cues from their neighbors to facilitate entry into a terminal differentiation pathway.

  18. Secreted phospholipase A2 and mast cells.

    PubMed

    Murakami, Makoto; Taketomi, Yoshitaka

    2015-01-01

    Phospholipase A2s (PLA2s) are a group of enzymes that hydrolyze the sn-2 position of phospholipids to release (typically unsaturated) fatty acids and lysophospholipids, which serve as precursors for a variety of bioactive lipid mediators. Among the PLA2 superfamily, secreted PLA2 (sPLA2) enzymes comprise the largest subfamily that includes 11 isoforms with a conserved His-Asp catalytic dyad. Individual sPLA2 enzymes exhibit unique tissue and cellular localizations and specific enzymatic properties, suggesting their distinct biological roles. Recent studies using transgenic and knockout mice for individual sPLA2 isofoms have revealed their involvement in various pathophysiological events. Here, we overview the current state of knowledge about sPLA2s, specifically their roles in mast cells (MCs) in the context of allergology. In particular, we highlight group III sPLA2 (PLA2G3) as an "anaphylactic sPLA2" that promotes MC maturation and thereby anaphylaxis through a previously unrecognized lipid-orchestrated circuit.

  19. KW-3902, a selective high affinity antagonist for adenosine A1 receptors.

    PubMed Central

    Nonaka, H.; Ichimura, M.; Takeda, M.; Kanda, T.; Shimada, J.; Suzuki, F.; Kase, H.

    1996-01-01

    1. We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), KW-3902 had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine (CGS21680), indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. 3. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 470 fmol mg-1 of protein) to a single class of recognition sites. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [3H]-KW-3902 and that of [3H]-CHA. 4. KW-3902 showed potent A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively. PMID:8732272

  20. Cyclin A1 is expressed in mouse ovary.

    PubMed

    Wei, Hongquan; Li, Yuanhong; Zhao, Chen; Jiang, Xuejun; Chen, Hongduo; Lang, Ming-Fei; Sun, Jing

    2014-01-01

    Cyclin A1 belongs to the type-A cyclins and participates in cell cycle regulation. Since its discovery, cyclin A1 has been shown mostly in testis. It plays important roles in spermatogenesis. However, there were also reports on ovary expression of cyclin A1. Therefore, we intended to revisit the expression of cyclin A1 in mouse ovary. Our study showed that cyclin A1 was expressed at the mRNA level and the protein level in mouse ovary. Tissue staining revealed that cyclin A1 was expressed in maturating oocytes. With the recent data on the functions of cyclins in somatic and stem cells, we also discussed the possibilities of further studies of cyclin A1 in mouse oocytes and perhaps in the oogonial stem cells. Our findings not only add to the supportive evidence of cyclin A1 expression in oocytes, but also may promote more interest in exploring cyclin A1 functions in ovary.

  1. Central amygdala GluA1 facilitates associative learning of opioid reward.

    PubMed

    Cai, You-Qing; Wang, Wei; Hou, Yuan-Yuan; Zhang, Zhi; Xie, Jun; Pan, Zhizhong Z

    2013-01-23

    GluA1 subunits of AMPA glutamate receptors are implicated in the synaptic plasticity induced by drugs of abuse for behaviors of drug addiction, but GluA1 roles in emotional learning and memories of drug reward in the development of drug addiction remain unclear. In this study of the central nucleus of the amygdala (CeA), which is critical in emotional learning of drug reward, we investigated how adaptive changes in the expression of GluA1 subunits affected the learning process of opioid-induced context-reward association (associative learning) for the acquisition of reward-related behavior. In CeA neurons, we found that CeA GluA1 expression was significantly increased 2 h after conditioning treatment with morphine, but not 24 h after the conditioning when the behavior of conditioned place reference (CPP) was fully established in rats. Adenoviral overexpression of GluA1 subunits in CeA accelerated associative learning, as shown by reduced minimum time of morphine conditioning required for CPP acquisition and by facilitated CPP extinction through extinction training with no morphine involved. Adenoviral shRNA-mediated downregulation of CeA GluA1 produced opposite effects, inhibiting the processes of both CPP acquisition and CPP extinction. Adenoviral knockdown of CeA GluA2 subunits facilitated CPP acquisition, but did not alter CPP extinction. Whole-cell recording revealed enhanced electrophysiological properties of postsynaptic GluA2-lacking AMPA receptors in adenoviral GluA1-infected CeA neurons. These results suggest that increased GluA1 expression of CeA AMPA receptors facilitates the associative learning of context-drug reward, an important process in both development and relapse of drug-seeking behaviors in drug addiction.

  2. Multiple sclerosis lymphocytes upregulate A2A adenosine receptors that are antiinflammatory when stimulated.

    PubMed

    Vincenzi, Fabrizio; Corciulo, Carmen; Targa, Martina; Merighi, Stefania; Gessi, Stefania; Casetta, Ilaria; Gentile, Mauro; Granieri, Enrico; Borea, Pier Andrea; Varani, Katia

    2013-08-01

    Multiple sclerosis (MS) is an autoimmune-mediated inflammatory disease characterized by multifocal areas of demyelination. Experimental evidence indicates that A2A adenosine receptors (ARs) play a pivotal role in the inhibition of inflammatory processes. The aim of this study was to investigate the contribution of A2A ARs in the inhibition of key pro-inflammatory mediators for the pathogenesis of MS. In lymphocytes from MS patients, A1, A2A, A2B, and A3 ARs were analyzed by using RT-PCR, Western blotting, immunofluorescence, and binding assays. Moreover the effect of A2A AR stimulation on proinflammatory cytokine release such as TNF-α, IFN-γ, IL-6, IL-1β, IL-17, and on lymphocyte proliferation was evaluated. The capability of an A2A AR agonist on the modulation of very late antigen (VLA)-4 expression and NF-κB was also explored. A2A AR upregulation was observed in lymphocytes from MS patients in comparison with healthy subjects. The stimulation of these receptors mediated a significant inhibition of TNF-α, IFN-γ, IL-6, IL-1β, IL-17, and cell proliferation as well as VLA-4 expression and NF-κB activation. This new evidence highlights that A2A AR agonists could represent a novel therapeutic tool for MS treatment as suggested by the antiinflammatory role of A2A ARs in lymphocytes from MS patients.

  3. 40 CFR 52.1394 - Section 110(a)(2) infrastructure requirements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 4 2014-07-01 2014-07-01 false Section 110(a)(2) infrastructure requirements. 52.1394 Section 52.1394 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... provisions which meet the requirements of CAA section 110(a)(1) and (2), elements (A), (B), (C) with...

  4. Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

    SciTech Connect

    Salaita, Khalid; Nair, Pradeep M; Petit, Rebecca S; Neve, Richard M; Das, Debopriya; Gray, Joe W; Groves, Jay T

    2009-09-09

    Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

  5. Nucleotide sequence and transcriptional analysis of the type A2 neurotoxin gene cluster in Clostridium botulinum.

    PubMed

    Dineen, Sean S; Bradshaw, Marite; Karasek, Charles E; Johnson, Eric A

    2004-06-01

    The nucleotide sequences of the upstream regions of the botulinum neurotoxin type A1 (BoNT/A1) cluster of Clostridium botulinum strain NCTC 2916 and the BoNT/A2 cluster of strain Kyoto-F were determined. A novel gene, designated orfx3, was identified following the orfx2 gene in both clusters. ORF-X2 and ORF-X3 exhibit similarity to the BoNT cluster associated P-47 protein. The BoNT/A1 and BoNT/A2 clusters share a similar gene arrangement, but exhibit differences in the spacing between certain genes. Sequences with similarity to transposases were identified in these intergenic regions, suggesting that these differences arose from an ancestral insertion event. Transcriptional analysis of the BoNT/A2 cluster revealed that the genes of the cluster are primarily synthesized as three polycistronic transcripts. Two divergent polycistronic transcripts, one encoding the orfx1, orfx2, and orfx3 genes, the second encoding the p47, ntnh, and bont/a2 genes, are transcribed from conserved BoNT cluster promoters. The third polycistronic transcript, expressed at low levels, encodes the positive regulatory botR gene and the orfx genes. This is the first complete analysis of a botulinum toxin A2 cluster.

  6. Arginine Methylation of hnRNP A2 Does Not Directly Govern Its Subcellular Localization

    PubMed Central

    Nouwens, Amanda S.; Wei, Ying; Rothnagel, Joseph A.; Smith, Ross

    2013-01-01

    The hnRNP A/B paralogs A1, A2/B1 and A3 are key components of the nuclear 40S hnRNP core particles. Despite a high degree of sequence similarity, increasing evidence suggests they perform additional, functionally distinct roles in RNA metabolism. Here we identify and study the functional consequences of differential post-translational modification of hnRNPs A1, A2 and A3. We show that while arginine residues in the RGG box domain of hnRNP A1 and A3 are almost exhaustively, asymmetrically dimethylated, hnRNP A2 is dimethylated at only a single residue (Arg-254) and this modification is conserved across cell types. It has been suggested that arginine methylation regulates the nucleocytoplasmic distribution of hnRNP A/B proteins. However, we show that transfected cells expressing an A2R254A point mutant exhibit no difference in subcellular localization. Similarly, immunostaining and mass spectrometry of endogenous hnRNP A2 in transformed cells reveals a naturally-occurring pool of unmethylated protein but an exclusively nuclear pattern of localization. Our results suggest an alternative role for post-translational arginine methylation of hnRNPs and offer further evidence that the hnRNP A/B paralogs are not functionally redundant. PMID:24098712

  7. Muscle developmental defects in heterogeneous nuclear Ribonucleoprotein A1 knockout mice

    PubMed Central

    Liu, Ting-Yuan; Chen, Yu-Chia; Jong, Yuh-Jyh; Tsai, Huai-Jen; Lee, Chien-Chin; Chang, Ya-Sian; Chang, Jan-Gowth

    2017-01-01

    Heterogeneous ribonucleoprotein A1 (hnRNP A1) is crucial for regulating alternative splicing. Its integrated function within an organism has not, however, been identified. We generated hnRNP A1 knockout mice to study the role of hnRNP A1 in vivo. The knockout mice, hnRNP A1−/−, showed embryonic lethality because of muscle developmental defects. The blood pressure and heart rate of the heterozygous mice were higher than those of the wild-type mice, indicating heart function defects. We performed mouse exon arrays to study the muscle development mechanism. The processes regulated by hnRNP A1 included cell adhesion and muscle contraction. The expression levels of muscle development-related genes in hnRNP A1+/− mice were significantly different from those in wild-type mice, as detected using qRT-PCR. We further confirmed the alternative splicing patterns of muscle development-related genes including mef2c, lrrfip1, usp28 and abcc9. Alternative mRNA isoforms of these genes were increased in hnRNP A1+/− mice compared with wild-type mice. Furthermore, we revealed that the functionally similar hnRNP A2/B1 did not compensate for the expression of hnRNP A1 in organisms. In summary, our study demonstrated that hnRNP A1 plays a critical and irreplaceable role in embryonic muscle development by regulating the expression and alternative splicing of muscle-related genes. PMID:28077597

  8. Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation

    PubMed Central

    Barquilla, Antonio; Lamberto, Ilaria; Noberini, Roberta; Heynen-Genel, Susanne; Brill, Laurence M.; Pasquale, Elena B.

    2016-01-01

    The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 “canonical” signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase activity; EphA2 “noncanonical” signaling involves phosphorylation of serine 897 (S897) by AKT and RSK kinases. To identify small molecules counteracting EphA2 canonical signaling, we developed a high-content screening platform measuring inhibition of ephrin-A1–induced PC3 prostate cancer cell retraction. Surprisingly, most hits from a screened collection of pharmacologically active compounds are agents that elevate intracellular cAMP by activating G protein–coupled receptors such as the β2-adrenoceptor. We found that cAMP promotes phosphorylation of S897 by protein kinase A (PKA) as well as increases the phosphorylation of several nearby serine/threonine residues, which constitute a phosphorylation hotspot. Whereas EphA2 canonical and noncanonical signaling have been viewed as mutually exclusive, we show that S897 phosphorylation by PKA can coexist with EphA2 tyrosine phosphorylation and block cell retraction induced by EphA2 kinase activity. Our findings reveal a novel paradigm in EphA2 function involving the interplay of canonical and noncanonical signaling and highlight the ability of the β2-adrenoceptor/cAMP/PKA axis to rewire EphA2 signaling in a subset of cancer cells. PMID:27385333

  9. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Designated Roth Accounts. 1.402A-1 Section 1... (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402A-1 Designated Roth Accounts. Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate account under...

  10. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part 550—Windchill Chart EC01SE91.002 windchill chart in non-metric units... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Windchill Chart A Appendix A-1 to...

  11. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part 550—Windchill Chart EC01SE91.002 windchill chart in non-metric units... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Windchill Chart A Appendix A-1 to...

  12. Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis

    PubMed Central

    Yan, J; De Melo, J; Cutz, J-C; Aziz, T; Tang, D

    2014-01-01

    Background: Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear. Methods: ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression. Results: In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated. Conclusions: We report here the association of ALDH3A1 with PC progression. PMID:24762960

  13. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Registration. 48.4222(a)-1 Section 48.4222(a)-1... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1 Registration. (a) General rule. Except as provided in § 48.4222(b)-1, tax-free sales under section 4221 may...

  14. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Registration. 48.4222(a)-1 Section 48.4222(a)-1... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1 Registration. (a) General rule. Except as provided in § 48.4222(b)-1, tax-free sales under section 4221 may...

  15. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Registration. 48.4222(a)-1 Section 48.4222(a)-1... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1 Registration. (a) General rule. Except as provided in § 48.4222(b)-1, tax-free sales under section 4221 may...

  16. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Registration. 48.4222(a)-1 Section 48.4222(a)-1... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1 Registration. (a) General rule. Except as provided in § 48.4222(b)-1, tax-free sales under section 4221 may...

  17. 7 CFR 15a.1 - Purpose and effective date.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Purpose and effective date. 15a.1 Section 15a.1 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.1 Purpose and effective date. The purpose of...

  18. 7 CFR 15a.1 - Purpose and effective date.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 1 2014-01-01 2014-01-01 false Purpose and effective date. 15a.1 Section 15a.1 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.1 Purpose and effective date. The purpose of...

  19. 7 CFR 15a.1 - Purpose and effective date.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Purpose and effective date. 15a.1 Section 15a.1 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.1 Purpose and effective date. The purpose of...

  20. 7 CFR 15a.1 - Purpose and effective date.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Purpose and effective date. 15a.1 Section 15a.1 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.1 Purpose and effective date. The purpose of...

  1. 7 CFR 15a.1 - Purpose and effective date.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 1 2012-01-01 2012-01-01 false Purpose and effective date. 15a.1 Section 15a.1 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.1 Purpose and effective date. The purpose of...

  2. 26 CFR 1.501(a)-1 - Exemption from taxation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Exemption from taxation. 1.501(a)-1 Section 1.501(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(a)-1 Exemption from taxation. (a)...

  3. 26 CFR 31.3121(a)-1 - Wages.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Wages. 31.3121(a)-1 Section 31.3121(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND... Contributions Act (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(a)-1 Wages....

  4. 26 CFR 1.1311(a)-1 - Introduction.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Introduction. 1.1311(a)-1 Section 1.1311(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Readjustment of Tax Between Years and Special Limitations § 1.1311(a)-1 Introduction....

  5. Loss of organic anion transporting polypeptide 1a1 increases deoxycholic acid absorption in mice by increasing intestinal permeability.

    PubMed

    Zhang, Youcai; Csanaky, Iván L; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2011-12-01

    Deoxycholic acid (DCA) is a known hepatotoxicant, a tissue tumor promoter, and has been implicated in colorectal cancer. Male mice are more susceptible to DCA toxicity than female mice. Organic anion transporting polypeptide 1a1 (Oatp1a1), which is known to transport bile acids (BAs) in vitro, is predominantly expressed in livers of male mice. In addition, the concentrations of DCA and its taurine conjugate (TDCA) are increased in serum of Oatp1a1-null mice. To investigate whether Oatp1a1 contributes to the gender difference in DCA toxicity in mice, wild-type (WT) and Oatp1a1-null mice were fed a 0.3% DCA diet for 7 days. After feeding DCA, Oatp1a1-null mice had 30-fold higher concentrations of DCA in both serum and livers than WT mice. Feeding DCA caused more hepatotoxcity in Oatp1a1-null mice than WT mice. After feeding DCA, Oatp1a1-null mice expressed higher BA efflux-transporters (bile salt-export pump, organic solute transporter (Ost)α/β, and multidrug resistance-associated protein [Mrp]2) and lower BA-synthetic enzymes (cytochrome P450 [Cyp]7a1, 8b1, 27a1, and 7b1) in livers than WT mice. Intravenous administration of DCA and TDCA showed that lack of Oatp1a1 does not decrease the plasma elimination of DCA or TDCA. After feeding DCA, the concentrations of DCA in ileum and colon tissues are higher in Oatp1a1-null than in WT mice. In addition, Oatp1a1-null mice have enhanced intestinal permeability. Taken together, the current data suggest that Oatp1a1 does not mediate the hepatic uptake of DCA or TDCA, but lack of Oatp1a1 increases intestinal permeability and thus enhances the absorption of DCA in mice.

  6. Loss of Organic Anion Transporting Polypeptide 1a1 Increases Deoxycholic Acid Absorption in Mice by Increasing Intestinal Permeability

    PubMed Central

    Zhang, Youcai; Csanaky, Iván L.; Lehman-McKeeman, Lois D.; Klaassen, Curtis D.

    2011-01-01

    Deoxycholic acid (DCA) is a known hepatotoxicant, a tissue tumor promoter, and has been implicated in colorectal cancer. Male mice are more susceptible to DCA toxicity than female mice. Organic anion transporting polypeptide 1a1 (Oatp1a1), which is known to transport bile acids (BAs) in vitro, is predominantly expressed in livers of male mice. In addition, the concentrations of DCA and its taurine conjugate (TDCA) are increased in serum of Oatp1a1-null mice. To investigate whether Oatp1a1 contributes to the gender difference in DCA toxicity in mice, wild-type (WT) and Oatp1a1-null mice were fed a 0.3% DCA diet for 7 days. After feeding DCA, Oatp1a1-null mice had 30-fold higher concentrations of DCA in both serum and livers than WT mice. Feeding DCA caused more hepatotoxcity in Oatp1a1-null mice than WT mice. After feeding DCA, Oatp1a1-null mice expressed higher BA efflux-transporters (bile salt-export pump, organic solute transporter (Ost)α/β, and multidrug resistance-associated protein [Mrp]2) and lower BA-synthetic enzymes (cytochrome P450 [Cyp]7a1, 8b1, 27a1, and 7b1) in livers than WT mice. Intravenous administration of DCA and TDCA showed that lack of Oatp1a1 does not decrease the plasma elimination of DCA or TDCA. After feeding DCA, the concentrations of DCA in ileum and colon tissues are higher in Oatp1a1-null than in WT mice. In addition, Oatp1a1-null mice have enhanced intestinal permeability. Taken together, the current data suggest that Oatp1a1 does not mediate the hepatic uptake of DCA or TDCA, but lack of Oatp1a1 increases intestinal permeability and thus enhances the absorption of DCA in mice. PMID:21914718

  7. Evolutionary Dynamics Analysis of Human Metapneumovirus Subtype A2: Genetic Evidence for Its Dominant Epidemic

    PubMed Central

    Li, Jianguo; Ren, Lili; Guo, Li; Xiang, Zichun; Paranhos-Baccalà, Gláucia; Vernet, Guy; Wang, Jianwei

    2012-01-01

    Human metapneumovirus (hMPV) is a respiratory viral pathogen in children worldwide. hMPV is divided into four subtypes: hMPV_A1, hMPV_A2, hMPV_B1, and hMPV_B2. hMPV_A2 can be further divided into hMPV_A2a and A2b based on phylogenetic analysis. The typical prevalence pattern of hMPV involves a shift of the predominant subtype within one or two years. However, hMPV_A2, in particular hMPV_A2b, has circulated worldwide with a several years long term high epidemic. To study this distinct epidemic behavior of hMPV_A2, we analyzed 294 sequences of partial G genes of the virus from different countries. Molecular evolutionary data indicates that hMPV_A2 evolved toward heterogeneity faster than the other subtypes. Specifically, a Bayesian skyline plot analysis revealed that hMPV_A2 has undergone a generally upward fluctuation since 1997, whereas the other subtypes experienced only one upward fluctuation. Although hMPV_A2 showed a lower value of mean dN/dS than the other subtypes, it had the largest number of positive selection sites. Meanwhile, various styles of mutation were observed in the mutation hotspots of hMPV_A2b. Bayesian phylogeography analysis also revealed two fusions of diffusion routes of hMPV_A2b in India (June 2006) and Beijing, China (June 2008). Sequences of hMPV_A2b retrieved from GenBank boosted simultaneously with the two fusions respectively, indicating that fusion of genetic transmission routes from different regions improved survival of hMPV_A2. Epidemic and evolutionary dynamics of hMPV_A2b were similar to those of hMPV_A2. Overall, our findings provide important molecular insights into hMPV epidemics and viral variation, and explain the occurrence of an atypical epidemic of hMPV_A2, particularly hMPV_A2b. PMID:22479641

  8. Zinc(II)-templated synthesis of a [2]-catenane consisting of a 2,2',6',2' '-terpyridine-incorporating cycle and a 1,10-phenanthroline-containing ring.

    PubMed

    Hamann, Christine; Kern, Jean-Marc; Sauvage, Jean-Pierre

    2003-03-24

    A nonsymmetrical [2]-catenane has been synthesized, with a 5-coordinated metal center (Zn(2+)) as template. One of the two rings contains a terdentate ligand (2,2',6',2' '-terpyridine) and the other one incorporates a bidentate chelate (1,10-phenanthroline). The first ring was prepared separately and, subsequently, Zn(2+) was used as the gathering and threading element to pass the stringlike component through the ring. This open-chain species bears two terminal olefins, which were reacted with Grubbs first-generation catalyst (ring-closing metathesis) to afford the desired catenane. Hydrogenation of the double bond and removal of the zinc(II) template afforded the final free [2]-catenane in 40% yield from the terdentate ligand-containing cycle and the diolefinic compound. Complexation studies on this new pentacoordinating catenane were carried out with Fe(II) or Cu(II). The most interesting observation is that the 5-coordinated complexes obtained are strongly stabilized. Their electrochemical reduction occurs at negative potentials.

  9. Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders.

    PubMed

    Cunha, Rodrigo A; Ferré, Sergi; Vaugeois, Jean-Marie; Chen, Jiang-Fan

    2008-01-01

    The interest on targeting adenosine A(2A) receptors in the realm of psychiatric diseases first arose based on their tight physical and functional interaction with dopamine D(2) receptors. However, the role of central A(2A) receptors is now viewed as much broader than just controlling D(2) receptor function. Thus, there is currently a major interest in the ability of A(2A) receptors to control synaptic plasticity at glutamatergic synapses. This is due to a combined ability of A(2A) receptors to facilitate the release of glutamate and the activation of NMDA receptors. Therefore, A(2A) receptors are now conceived as a normalizing device promoting adequate adaptive responses in neuronal circuits, a role similar to that fulfilled, in essence, by dopamine. This makes A(2A) receptors particularly attractive targets to manage psychiatric disorders since adenosine may act as go-between glutamate and dopamine, two of the key players in mood processing. Furthermore, A(2A) receptors also control glia function and brain metabolic adaptation, two other emerging mechanisms to understand abnormal processing of mood, and A(2A) receptors are important players in controlling the demise of neurodegeneration, considered an amplificatory loop in psychiatric disorders. Current data only provide an indirect confirmation of this putative role of A(2A) receptors, based on the effects of caffeine (an antagonist of both A(1) and A(2A) receptors) in psychiatric disorders. However, the introduction of A(2A) receptors antagonists in clinics as anti-parkinsonian agents is hoped to bolster our knowledge on the role of A(2A) receptors in mood disorders in the near future.

  10. A dispersed fluorescence and ab initio investigation of the X~ 2B1 and A~ 2A1 electronic states of the PH2 molecule

    NASA Astrophysics Data System (ADS)

    Jakubek, Z. J.; Bunker, P. R.; Zachwieja, M.; Nakhate, S. G.; Simard, B.; Yurchenko, S. N.; Thiel, W.; Jensen, Per

    2006-03-01

    In this work, the X˜B12 and ÃA12 electronic states of the phosphino (PH2) free radical have been studied by dispersed fluorescence and ab initio methods. PH2 molecules were produced in a molecular free-jet apparatus by laser vaporizing a silicon rod in the presence of phosphine (PH3) gas diluted in helium. The laser-induced fluorescence, from the excited ÃA12 electronic state down to the ground electronic state, was dispersed and analyzed. Ten (υ1υ2υ3) vibrationally excited levels of the ground electronic state, with υ1⩽2, υ2⩽6, and υ3=0, have been observed. Ab initio potential-energy surfaces for the X˜B12 and ÃA12 electronic states have been calculated at 210 points. These two states correlate with a Πu2 state at linearity and they interact by the Renner-Teller coupling and spin-orbit coupling. Using the ab initio potential-energy surfaces with our RENNER computer program system, the vibronic structure and relative intensities of the ÃA12→X˜B12 emission band system have been calculated in order to corroborate the experimental assignments.

  11. Multiple Language Contact in Tallinn: Transfer B2[greater than]/A1 or B1[greater than]/A2?

    ERIC Educational Resources Information Center

    Verschik, Anna

    2007-01-01

    This paper describes multiple Estonian-Russian language contacts in Estonia. For synchronic microsociolinguistic research it is usual to concentrate on the impact of a sociolinguistically dominant language A on an immigrant/minority language B. In the Soviet setting, the dominant language was usually Russian (despite Russians being a minority).…

  12. Identification, characterization, and genetic mapping of TLR7, TLR8a1 and TLR8a2 genes in rainbow trout (Oncorhynchus mykiss)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Induction of the innate immune pathways is critical for early antiviral defense but there is limited understanding of how teleost fish recognize viral molecules and activate these pathways. In mammals, Toll-like receptors (TLR) 7 and 8 bind single-stranded RNA of viral origin and are activated by s...

  13. 75 FR 910 - Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-07

    ... -3B1 turbofan engines. That AD currently requires a onetime visual and tactile inspection of certain..., removing from service fan disks with electrical arc-out indications, performing tactile and enhanced visual...-A0233, Revision 04, dated October 27, 2008, do the following: Tactile and Enhanced Visual...

  14. [Maintenance of Pure Lines and Hybridization.] Student Materials. V.A. III. [IV-A-1 through IV-A-2].

    ERIC Educational Resources Information Center

    Texas A and M Univ., College Station. Vocational Instructional Services.

    Part of a series of eight student learning modules in vocational agriculture, this booklet deals with plant reproduction. Topics covered include the pure line theory and its history, pure line selection, the effect of inbreeding on vitality, the definition of and reasons for hybridization in plants, and techniques for producing hybirds; a list of…

  15. Integrated Advance Microwave Sounding Unit-A (AMSU-A). Performance Verification Report: EOS AMSU-A1 and AMSU-A2 Receivers Assemblies

    NASA Technical Reports Server (NTRS)

    2000-01-01

    This test report presents the test data of the EOS AMSU-A Flight Model No.1 (FM-1) receiver subsystem. The tests are performed per the Acceptance Test Procedure for the AMSU-A Reseiver Subsystem, AE-26002/6A. The functional performance tests are conducted either at the component or subsystem level. While the component-level tests are performed over the entire operating temperature range predicted by thermal analysis, the subsystem-level test are conducted at ambient temperature only.

  16. 75 FR 28188 - Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-20

    ...) numbers CF34-AL S/B 72 A0212, CF34-AL S/B 72 A0234, and CF34-AL S/B 72 A0235 in the regulatory section are... and eighth lines, ``CF34-AL'' is corrected to read ``CF34- BJ''. 2. On page 914, in the second column, in paragraph (k)(2)(iii), in the fifth line, ``CF34-AL'' is corrected to read ``CF34-BJ''. 3. On...

  17. Copy number and haplotype variation at the VRN-A1 and central FR-A2 loci are associated with frost tolerance in hexaploid wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Frost tolerance is a key trait to ensure winter wheat survival. Natural variation for this trait is mainly associated with allelic differences at the VERNALIZATION 1 (VRN1) and FROST RESISTANCE 2 (FR2) loci. VRN1 regulates the transition between vegetative and reproductive stages and FR2, a locus in...

  18. Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

    SciTech Connect

    Whitby, Richard J.; Stec, Jozef; Blind, Raymond D.; Dixon, Sally; Leesnitzer, Lisa M.; Orband-Miller, Lisa A.; Williams, Shawn P.; Willson, Timothy M.; Xu, Robert; Zuercher, William J.; Cai, Fang; Ingraham, Holly A.

    2011-09-27

    The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

  19. Capable Reader Program: Lesson Plan Guide. Units A1; A2; A3; A4; [and] A5. Pilot Year 1979-1980, Final Edition 1980-1981.

    ERIC Educational Resources Information Center

    Casper, Donna; And Others

    Part of a curriculum series for academically gifted elementary students in the area of reading, the five lesson plan guides are intended to provide teachers with suggested activities stressing high levels of reading comprehension as well as encouraging teachers to use their own ideas. Each guide focuses on one of the following major objectives:…

  20. Chiral dynamics of a1(1260) → 3π

    NASA Astrophysics Data System (ADS)

    Tegen, R.; Greiner, W.

    2003-06-01

    We calculate the sequential decays a1 rightarrow pisigma rightarrow 3pi and a1 rightarrow pirho rightarrow 3pi using chiral SU(2) otimes SU(2) current commutation relations. Proper vertices a1pisigma, sigmapipi, a1pirho, rhopipi are derived from Ward identities and yield energy-dependent decay widths Gammarhorightarrowpipi and Gammasigmarightarrowpipi necessary for the total Gammaa1rightarrow3pi decay width. Both sequential decays (via pisigma and pirho) are necessary to reproduce Gammatota1. We find evidence for a substantial quenching of the sigma rightarrow pipi decay width in a1 rightarrow pisigma rightarrow 3pi.

  1. Methods for Tumor Targeting with Salmonella typhimurium A1-R.

    PubMed

    Hoffman, Robert M; Zhao, Ming

    2016-01-01

    Salmonella typhimurium A1-R (S. typhimurium A1-R) has shown great preclinical promise as a broad-based anti-cancer therapeutic (please see Chapter 1 ). The present chapter describes materials and methods for the preclinical study of S. typhimurium A1-R in clinically-relevant mouse models. Establishment of orthotopic metastatic mouse models of the major cancer types is described, as well as other useful models, for efficacy studies of S. typhimurium A1-R or other tumor-targeting bacteria, as well. Imaging methods are described to visualize GFP-labeled S. typhimurium A1-R, as well as GFP- and/or RFP-labeled cancer cells in vitro and in vivo, which S. typhimurium A1-R targets. The mouse models include metastasis to major organs that are life-threatening to cancer patients including the liver, lung, bone, and brain and how to target these metastases with S. typhimurium A1-R. Various routes of administration of S. typhimurium A1-R are described with the advantages and disadvantages of each. Basic experiments to determine toxic effects of S. typhimurium A1-R are also described. Also described are methodologies for combining S. typhimurium A1-R and chemotherapy. The testing of S. typhimurium A1-R on patient tumors in patient-derived orthotopic xenograft (PDOX) mouse models is also described. The major methodologies described in this chapter should be translatable for clinical studies.

  2. 17 CFR 240.11a2-2(T) - Transactions effected by exchange members through other members.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Transactions effected by exchange members through other members. 240.11a2-2(T) Section 240.11a2-2(T) Commodity and Securities... Regulation (rule 11a-1) § 240.11a2-2(T) Transactions effected by exchange members through other members....

  3. EphA2 signaling following endocytosis: role of Tiam1.

    PubMed

    Boissier, Pomme; Chen, Jin; Huynh-Do, Uyen

    2013-12-01

    Eph receptors and their membrane-bound ligands, the ephrins, represent a complex subfamily of receptor tyrosine kinases (RTKs). Eph/ephrin binding can lead to various and opposite cellular behaviors such as adhesion versus repulsion, or cell migration versus cell-adhesion. Recently, Eph endocytosis has been identified as one of the critical steps responsible for such diversity. Eph receptors, as many RTKs, are rapidly endocytosed following ligand-mediated activation and traffic through endocytic compartments prior to degradation. However, it is becoming obvious that endocytosis controls signaling in many different manners. Here we showed that activated EphA2 are degraded in the lysosomes and that about 35% of internalized receptors are recycled back to the plasma membrane. Our study is also the first to demonstrate that EphA2 retains the capacity to signal in endosomes. In particular, activated EphA2 interacted with the Rho family GEF Tiam1 in endosomes. This association led to Tiam1 activation, which in turn increased Rac1 activity and facilitated Eph/ephrin endocytosis. Disrupting Tiam1 function with RNA interference impaired both ephrinA1-dependent Rac1 activation and ephrinA1-induced EphA2 endocytosis. In summary, our findings shed new light on the regulation of EphA2 endocytosis, intracellular trafficking and signal termination and establish Tiam1 as an important modulator of EphA2 signaling.

  4. USNO-A2.0 1200-1153830 is a binary star with a total eclipse with sharp transitions

    NASA Astrophysics Data System (ADS)

    Roy, Rene; Behrend, Raoul

    2017-02-01

    Based on their photometric observations, R. Roy (Blauvac, France) and R. Behrend (Geneva Observatory) found that USNO-A2.0 1200-1153830 is a binary star for which the lightcurve is characterized by a 0.4mag total eclipse and a rather soft secondary eclipse.

  5. A2BR Adenosine Receptor Modulates Sweet Taste in Circumvallate Taste Buds

    PubMed Central

    Yang, Dan; Shultz, Nicole; Vandenbeuch, Aurelie; Ravid, Katya; Kinnamon, Sue C.; Finger, Thomas E.

    2012-01-01

    In response to taste stimulation, taste buds release ATP, which activates ionotropic ATP receptors (P2X2/P2X3) on taste nerves as well as metabotropic (P2Y) purinergic receptors on taste bud cells. The action of the extracellular ATP is terminated by ectonucleotidases, ultimately generating adenosine, which itself can activate one or more G-protein coupled adenosine receptors: A1, A2A, A2B, and A3. Here we investigated the expression of adenosine receptors in mouse taste buds at both the nucleotide and protein expression levels. Of the adenosine receptors, only A2B receptor (A2BR) is expressed specifically in taste epithelia. Further, A2BR is expressed abundantly only in a subset of taste bud cells of posterior (circumvallate, foliate), but not anterior (fungiform, palate) taste fields in mice. Analysis of double-labeled tissue indicates that A2BR occurs on Type II taste bud cells that also express Gα14, which is present only in sweet-sensitive taste cells of the foliate and circumvallate papillae. Glossopharyngeal nerve recordings from A2BR knockout mice show significantly reduced responses to both sucrose and synthetic sweeteners, but normal responses to tastants representing other qualities. Thus, our study identified a novel regulator of sweet taste, the A2BR, which functions to potentiate sweet responses in posterior lingual taste fields. PMID:22253866

  6. Magnetic gating of a 2D topological insulator

    NASA Astrophysics Data System (ADS)

    Dang, Xiaoqian; Burton, J. D.; Tsymbal, Evgeny Y.

    2016-09-01

    Deterministic control of transport properties through manipulation of spin states is one of the paradigms of spintronics. Topological insulators offer a new playground for exploring interesting spin-dependent phenomena. Here, we consider a ferromagnetic ‘gate’ representing a magnetic adatom coupled to the topologically protected edge state of a two-dimensional (2D) topological insulator to modulate the electron transmission of the edge state. Due to the locked spin and wave vector of the transport electrons the transmission across the magnetic gate depends on the mutual orientation of the adatom magnetic moment and the current. If the Fermi energy matches an exchange-split bound state of the adatom, the electron transmission can be blocked due to the full back scattering of the incident wave. This antiresonance behavior is controlled by the adatom magnetic moment orientation so that the transmission of the edge state can be changed from 1 to 0. Expanding this consideration to a ferromagnetic gate representing a 1D chain of atoms shows a possibility to control the spin-dependent current of a strip of a 2D topological insulator by magnetization orientation of the ferromagnetic gate.

  7. Food Cravings, Food Addiction, and a Dopamine-Resistant (DRD2 A1) Receptor Polymorphism in Asian American College Students

    PubMed Central

    Yeh, Joanna; Trang, Amy; Henning, Susanne M; Wilhalme, Holly; Carpenter, Catherine; Heber, David; Li, Zhaoping

    2016-01-01

    Background/Objectives In an era where obesity remains an important public health concern, food addiction has emerged as a possible contributor to obesity. The DRD2 gene is the most studied polymorphism. The aim of this study was to investigate a relationship between food craving and food addiction questionnaires, body composition measurements, and a dopamine-resistant receptor polymorphism (DRD2 A1) among healthy Asian Americans. Subjects/Methods A total of 84 Asian American college students were recruited. Participants underwent body composition measurement via bioelectrical impedance, answered subjective questionnaires, and had blood drawn for genotyping. Results Among Asian American college students, there was no difference in body composition (BMI, percent body fat) between the A1 (A1A1 or A1A2) and A2 (A2A2) groups. There were statistically significant differences in food cravings of carbohydrates and fast food on the Food Craving Inventory between the A1 and A2 groups (p=0.03), but not for sugar or fat. Among female Asian college students, there was also a difference on the Power of Food questionnaire (p=0.04), which was not seen among males. 13 out of 55 females also had > 30% body fat at a BMI of 21.4 to 28.5 kg/m2. Conclusion Greater carbohydrate and fast food craving was associated with the DRD2 A1 versus A2 allele among Asian Americans. Further studies examining the ability of dopamine agonists to affect food craving and to reduce body fat in Asian American are warranted. More studies in food addiction among obese Asian Americans are needed with careful definition of obesity, specifically for Asian women. PMID:27222427

  8. 26 CFR 1.613A-0 - Limitations on percentage depletion in the case of oil and gas wells; table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-0 Limitations on percentage depletion in the case of oil and gas wells; table of contents... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Limitations on percentage depletion in the...

  9. 26 CFR 1.613A-0 - Limitations on percentage depletion in the case of oil and gas wells; table of contents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-0 Limitations on percentage depletion in the case of oil and gas wells; table of contents... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Limitations on percentage depletion in the...

  10. 26 CFR 1.613A-0 - Limitations on percentage depletion in the case of oil and gas wells; table of contents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-0 Limitations on percentage depletion in the case of oil and gas wells; table of contents... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Limitations on percentage depletion in the...

  11. Polarization Calibration of the Chromospheric Lyman-Alpha SpectroPolarimeter for a 0.1 % Polarization Sensitivity in the VUV Range. Part I: Pre-flight Calibration

    NASA Astrophysics Data System (ADS)

    Giono, G.; Ishikawa, R.; Narukage, N.; Kano, R.; Katsukawa, Y.; Kubo, M.; Ishikawa, S.; Bando, T.; Hara, H.; Suematsu, Y.; Winebarger, A.; Kobayashi, K.; Auchère, F.; Trujillo Bueno, J.

    2016-12-01

    The Chromospheric Lyman-Alpha SpectroPolarimeter (CLASP) is a sounding rocket experiment designed to measure for the first time the linear polarization of the hydrogen Lyman-{α} line (121.6 nm) and requires a 0.1 % polarization sensitivity, which is unprecedented for a spectropolarimeter in the vacuum UV (VUV) spectral range.

  12. Association between a Novel Mutation in SLC20A2 and Familial Idiopathic Basal Ganglia Calcification

    PubMed Central

    Zhang, Yang; Guo, Xianan; Wu, Anhua

    2013-01-01

    Familial idiopathic basal ganglia calcification (FIBGC) is a rare, autosomal dominant disorder involving bilateral calcification of the basal ganglia. To identify gene mutations related to a Chinese FIBGC lineage, we evaluated available individuals in the family using CT scans. DNA was extracted from the peripheral blood of available family members, and both exonic and flanking intronic sequences of the SLC20A2 gene were amplified by PCR and then sequenced. Non-denaturing polyacrylamide gel electrophoresis (PAGE) was used to confirm the presence of mutations. Allele imbalances of the SLC20A2 gene or relative quantity of SLC20A2 transcripts were evaluated using qRT-PCR. A novel heterozygous single base-pair deletion (c.510delA) within the SLC20A2 gene was identified. This deletion mutation was found to co-segregate with basal ganglia calcification in all of the affected family members but was not detected in unaffected individuals or in 167 unrelated Han Chinese controls. The mutation will cause a frameshift, producing a truncated SLC20A2 protein with a premature termination codon, most likely leading to the complete loss of function of the SLC20A2 protein. This mutation may also lead to a reduction in SLC20A2 mRNA expression by approximately 30% in cells from affected individuals. In conclusion, we identified a novel mutation in SLC20A2 that is linked to FIBGC. In addition to the loss of function at the protein level, decreasing the expression of SLC20A2 mRNA may be another mechanism that can regulate SLC20A2 function in IBGC individuals. We propose that the regional expression pattern of SLC20A1 and SLC20A2 might explain the unique calcification pattern observed in FIBGC patients. PMID:23437308

  13. Hemoglobin A1c in predicting progression to diabetes.

    PubMed

    Nakagami, Tomoko; Tajima, Naoko; Oizumi, Toshihide; Karasawa, Shigeru; Wada, Kiriko; Kameda, Wataru; Susa, Shinji; Kato, Takeo; Daimon, Makoto

    2010-01-01

    The predictive value of hemoglobin A1c (HbA1c) in comparison to fasting plasma glucose (FPG) is evaluated for 5-year incident diabetes (DM), as HbA1c may be more practical than FPG in the screening for DM in the future. Of 1189 non-DM subjects aged 35-89 years old from the Funagata Study, 57 subjects (4.8%) had developed DM on the WHO criteria at 5-year follow-up. The odds ratio (95% confidence interval: CI) for a one standard deviation increase in FPG/HbA1c was 3.40 (2.44-4.74)/3.49 (2.42-5.02). The area under the receiver operating characteristic curve for FPG/HbA1c was 0.786 (95% CI: 0.719-0.853)/0.785 (0.714-0.855). The HbA1c corresponding to FPG 5.56 mmol/l was HbA1c 5.3%. There was no statistical difference in sensitivity between FPG 5.56 mmol/l and HbA1c 5.3% (61.4% vs. 56.1%), while specificity was higher in HbA1c 5.3% than FPG 5.56 mmol/l (87.8% vs. 82.5%, p-value<0.001). The fraction of incident case from those with baseline IGT was similar between the groups, however the fraction of people above the cut-off was significantly lower in HbA1c 5.3% than FPG 5.56 mmol/l (14.3% vs. 19.6%, p-value<0.001). HbA1c is similar to FPG to evaluate DM risk, and HbA1c could be practical and efficient to select subjects for intervention.

  14. SLC11A1 — EDRN Public Portal

    Cancer.gov

    SLC11A1 is a membrane associated divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. SLC11A1 is a member of the solute carrier family 11 (proton-coupled divalent metal ion transporters) family. Mutations in the SLC11A1 gene are involved in susceptibility to infectious diseases such as tuberculosis and leprosy, and inflammatory diseases such as rheumatoid arthritis and Crohn disease. Several alternatively spliced variants have been identified.

  15. 26 CFR 1.56A-1 - Imposition of tax.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Imposition of tax. 1.56A-1 Section 1.56A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-1 Imposition of tax. (a) In general. Section 56(a) imposes an income tax...

  16. A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome

    PubMed Central

    Kohmoto, Tomohiro; Tsuji, Atsumi; Morita, Kei-ichi; Naruto, Takuya; Masuda, Kiyoshi; Kashimada, Kenichi; Enomoto, Keisuke; Morio, Tomohiro; Harada, Hiroyuki; Imoto, Issei

    2016-01-01

    Stickler syndrome (STL) is an autosomal, dominantly inherited, clinically variable and genetically heterogeneous connective tissue disorder characterized by ocular, auditory, orofacial and skeletal abnormalities. We conducted targeted resequencing using a next-generation sequencer for molecular diagnosis of a 2-year-old girl who was clinically suspected of having STL with Pierre Robin sequence. We detected a novel heterozygous missense mutation, NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A], in COL11A1, resulting in a Gly to Asp substitution at position 1507 [NM_001854.3(COL11A1_i001)] within one of the collagen-like domains of the triple helical region. The same mutation was detected in her 4-year-old brother with cleft palate and high-frequency sensorineural hearing loss. PMID:27081569

  17. A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome.

    PubMed

    Kohmoto, Tomohiro; Tsuji, Atsumi; Morita, Kei-Ichi; Naruto, Takuya; Masuda, Kiyoshi; Kashimada, Kenichi; Enomoto, Keisuke; Morio, Tomohiro; Harada, Hiroyuki; Imoto, Issei

    2016-01-01

    Stickler syndrome (STL) is an autosomal, dominantly inherited, clinically variable and genetically heterogeneous connective tissue disorder characterized by ocular, auditory, orofacial and skeletal abnormalities. We conducted targeted resequencing using a next-generation sequencer for molecular diagnosis of a 2-year-old girl who was clinically suspected of having STL with Pierre Robin sequence. We detected a novel heterozygous missense mutation, NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A], in COL11A1, resulting in a Gly to Asp substitution at position 1507 [NM_001854.3(COL11A1_i001)] within one of the collagen-like domains of the triple helical region. The same mutation was detected in her 4-year-old brother with cleft palate and high-frequency sensorineural hearing loss.

  18. Sulfur-Containing 1,3-Dialkylxanthine Derivatives as Selective Antagonists at A1-Adenosine Receptors

    PubMed Central

    Kiriasis, Leonidas; Barone, Suzanne; Bradbury, Barton J.; Kammula, Udai; Campagne, Jean Michel; Secunda, Sherrie; Daly, John W.; Neumeyer, John L.; Pfleiderer, Wolfgang

    2012-01-01

    Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [[3H]-N6-(phenylisopropyl) adenosine as radioligand] or striatum [[3H]-5′-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was >740-fold A1 selective. PMID:2754711

  19. Partial separation of platelet and placental adenosine receptors from adenosine A2-like binding protein

    SciTech Connect

    Zolnierowicz, S.; Work, C.; Hutchison, K.; Fox, I.H. )

    1990-04-01

    The ubiquitous adenosine A2-like binding protein obscures the binding properties of adenosine receptors assayed with 5'-N-({sup 3}H)ethylcarboxamidoadenosine (({sup 3}H)NECA). To solve this problem, we developed a rapid and simple method to separate adenosine receptors from the adenosine A2-like binding protein. Human platelet and placental membranes were solubilized with 1% 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate. The soluble platelet extract was precipitated with polyethylene glycol and the fraction enriched in adenosine receptors was isolated from the precipitate by differential centrifugation. The adenosine A2-like binding protein was removed from the soluble placental extract with hydroxylapatite and adenosine receptors were precipitated with polyethylene glycol. The specificity of the ({sup 3}H)NECA binding is typical of an adenosine A2 receptor for platelets and an adenosine A1 receptor for placenta. This method leads to enrichment of adenosine A2 receptors for platelets and adenosine A1 receptors for placenta. This provides a useful preparation technique for pharmacologic studies of adenosine receptors.

  20. Preparation, magnetic and transport properties of A 0.66Ba 0.34MnO 3 - y (A = Pr, Nd, Sm, Eu, Gd) perovskites

    NASA Astrophysics Data System (ADS)

    Troyanchuk, I. O.; Kolesova, I. M.; Szymczak, H.; Nabialek, A.

    1997-02-01

    The manganites A 0.66Ba 0.34MnO 3 - x (A = Pr, Nd, Sm, Eu, Gd) with cubic perovskite structure have been synthesized. It is found that Pr 0.66Ba 0.34MnO 3 and Nd 0.66Ba 0.34MnO 3 are ferromagnets while Sm-, Eu- and Gd-containing samples exhibit spin-glass-like behavior. The decreasing oxygen content in A 0.66Ba 0.34MnO 3- y (A = Pr, Nd) up to γ = 0.1 leads to the collapse of the long-range ferromagnetic order. The Nd 0.66Ba 0.34MnO 3 exhibits giant magneto resistance below Tc ˜ 150 K. The results can be explained in terms of the model of superexchange interactions via oxygen.