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Sample records for 1a7 1a8 1a9

  1. Differences in frequencies of UGT1A9, 1A7, and 1A1 genetic polymorphisms in Chinese Tibetan versus Han Chinese populations.

    PubMed

    Yan, W; Wang, Y W; Yang, F F; Wang, M; Zhang, X Q; Dong, J; Chen, E; Yang, J

    2013-01-01

    As part of a series of pharmacogenomics studies of the Chinese population, we investigated genetic polymorphisms of some UGT1A regions. The three genes that were analyzed were UGT1A9, 1A7, and 1A1; we sequenced their exons, together with promoters, surrounding introns and 3'-untranslated regions (3'UTR) in 100 unrelated-healthy Chinese Tibetan individuals. We compared the data with information on Han Chinese of the same region, which we downloaded from the HapMap database. We identified 40 polymorphisms; 16 of them were shared by the two populations. We then analyzed their linkage disequilibrium map. The UGT1As cluster can be divided into two linkage blocks in the Tibetan population: Block 1 (UGT1A9, UGT1A7), Block 2 (3'-UTR). Furthermore, we identified haplotypes and selected their tagSNPs. In exon 1 of UGT1A7 gene, 393G>A (Arg131Gln, rs17868324) was found at a frequency of 44.4% in the Tibetan population, compared to only 0.7% in the Han population. The linkage blocks in the Han Chinese sample differed from that of the Chinese Tibetan group; the former had Block 1 (UGT1A9, UGT1A7), Block 2 (UGT1A7), and Block 3 (3'-UTR). These findings provide fundamental information for future molecular genetic studies of the UGT1A gene cluster as well as for personalized medicine in Chinese. PMID:24390994

  2. Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone.

    PubMed

    Thibaudeau, Jean; Lépine, Johanie; Tojcic, Jelena; Duguay, Yannick; Pelletier, Georges; Plante, Marie; Brisson, Jacques; Têtu, Bernard; Jacob, Simon; Perusse, Louis; Bélanger, Alain; Guillemette, Chantal

    2006-01-01

    The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (Vmax) and affinities (Km). The -79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P < 0.001) in human endometrial carcinoma-1B cells. Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the -79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE-induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. PMID:16397224

  3. Albumin Stimulates the Activity of the Human UDP-Glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the Effects Are Enzyme and Substrate Dependent

    PubMed Central

    Svaluto-Moreolo, Paolo; Dziedzic, Klaudyna; Yli-Kauhaluoma, Jari; Finel, Moshe

    2013-01-01

    Human UDP-glucuronosyltransferases (UGTs) are important enzymes in metabolic elimination of endo- and xenobiotics. It was recently shown that addition of fatty acid free bovine serum albumin (BSA) significantly enhances in vitro activities of UGTs, a limiting factor in in vitro–in vivo extrapolation. Nevertheless, since only few human UGT enzymes were tested for this phenomenon, we have now performed detailed enzyme kinetic analysis on the BSA effects in six previously untested UGTs, using 2–4 suitable substrates for each enzyme. We also examined some of the previously tested UGTs, but using additional substrates and a lower BSA concentration, only 0.1%. The latter concentration allows the use of important but more lipophilic substrates, such as estradiol and 17-epiestradiol. In five newly tested UGTs, 1A7, 1A8, 1A10, 2A1, and 2B15, the addition of BSA enhanced, to a different degree, the in vitro activity by either decreasing reaction’s Km, increasing its Vmax, or both. In contrast, the activities of UGT2B17, another previously untested enzyme, were almost unaffected. The results of the assays with the previously tested UGTs, 1A1, 1A6, 2B4, and 2B7, were similar to the published BSA only as far as the BSA effects on the reactions’ Km are concerned. In the cases of Vmax values, however, our results differ significantly from the previously published ones, at least with some of the substrates. Hence, the magnitude of the BSA effects appears to be substrate dependent, especially with respect to Vmax increases. Additionally, the BSA effects may be UGT subfamily dependent since Km decreases were observed in members of subfamilies 1A, 2A and 2B, whereas large Vmax increases were only found in several UGT1A members. The results shed new light on the complexity of the BSA effects on the activity and enzyme kinetics of the human UGTs. PMID:23372764

  4. Cellular Asymmetric Catalysis by UDP-glucuronosyltransferase 1A8 Shows Functional Localization to the Basolateral Plasma Membrane*

    PubMed Central

    Ziegler, Kerstin; Tumova, Sarka; Kerimi, Asimina; Williamson, Gary

    2015-01-01

    UDP-glucuronosyltransferases (UGTs) are highly expressed in liver, intestine and kidney, and catalyze the glucuronic acid conjugation of both endogenous compounds and xenobiotics. Using recombinant human UGT isoforms, we show that glucuronic acid conjugation of the model substrate, (−)-epicatechin, is catalyzed mainly by UGT1A8 and UGT1A9. In HepG2 cells, pretreatment with polyunsaturated fatty acids increased substrate glucuronidation. In the intestinal Caco-2/HT29-MTX co-culture model, overall relative glucuronidation rates were much higher than in HepG2 cells, and (−)-epicatechin was much more readily conjugated when applied to the basolateral side of the cell monolayer. Under these conditions, 95% of the conjugated product was effluxed back to the site of application, and none of the other phase 2-derived metabolites followed this distribution pattern. HT29-MTX cells contained >1000-fold higher levels of UGT1A8 mRNA than Caco-2 or HepG2 cells. Gene expression of UGT1A8 increased after treatment of cells with docosahexaenoic acid, as did UGT1A protein levels. Immunofluorescence staining and Western blotting showed the presence of UGT1A in the basal and lateral parts of the plasma membrane of HT29-MTX cells. These results suggest that some of the UGT1A8 enzyme is not residing in the endoplasmic reticulum but spans the plasma membrane, resulting in increased accessibility to compounds outside the cell. This facilitates more efficient conjugation of substrate and is additionally coupled with rapid efflux by functionally associated basolateral transporters. This novel molecular strategy allows the cell to carry out conjugation without the xenobiotic entering into the interior of the cell. PMID:25586184

  5. Novel single nucleotide polymorphism of UGT1A9 gene in Japanese.

    PubMed

    Fujita, Ken-ichi; Ando, Yuichi; Nagashima, Fumio; Yamamoto, Wataru; Endo, Hisashi; Kodama, Keiji; Araki, Kazuhiro; Miya, Toshimichi; Narabayashi, Masaru; Sasaki, Yasutsuna

    2006-02-01

    We sequenced from 5'-franking region to intron 1 (to 337 bp downstream from exon 1) of the UDP-glucuronosyltransferase (UGT) 1A9 gene prepared from 55 Japanese cancer patients. Seven single nucleotide polymorphisms (SNPs) were found. Two of them were UGT1A9 -118(T)n (n=10) and UGT1A9*5, and four were reported SNPs in intron 1 of UGT1A9 gene (89540C>T, 89549G>A, 89616T>A and 89710A>C). A novel SNP (89587T>C) was found. The sequence is as follows: SNP, 050824FujitaK001; Gene Name, UGT1A9; Accession Number, AF297093; Length, 25 bases; 5'-CCTTCTTGAAGAT/CATGTATTTATAA-3'. Two patients were heterozygous for the mutant allele, resulting in the allele frequency of 1.82%. PMID:16547398

  6. Arbidol exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7.

    PubMed

    Liu, Xin; Huang, Ting; Chen, Jian-Xing; Zeng, Jia; Fan, Xu-Ran; Xu-Zhu; Yu, Zhen-Wen; Sun, Xiao-Yu; Hong, Mo; Sun, Hong-Zhi

    2013-12-01

    The aim of the present study was to investigate arbidol's inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. The nonspecific probe substrate 4-methylumbelliferone (4-MU) and recombinant UGT enzymes (UGT1A9, UGT2B7) were firstly used to evaluate the inhibition of arbidol towards UGT1A9 and UGT2B7. Furthermore, specific substrates of UGT1A9 and UGT2B7 propofol and zidovudine (AZT) were used to determine the inhibition of arbidol towards UGT1A9 and UGT2B7. Inhibition type and inhibition kinetic parameters (Ki) were determined. In vitro-in vivo extrapolation (IV-IVE) was performed to predict in vivo DDI magnitude induced by arbidol. Arbidol was demonstrated to exhibit competitive inhibition towards UGT1A9 and UGT2B7 without substate-dependent behaviour. The inhibition kinetic parameters (Ki) were calculated to be 0.5 microM, 3.5 microM, 2.8 microM, 29.7 microM for UGT2B7-mediated 4-MU glucuronidation, UGT1A9-mediated 4-MU glucuronidation, UGT2B7-mediated AZT glucuronidation, and UGT1A9-mediated propofol glucuronidation, respectively. Using these parameters, the in vivo alteration of area under of concentration-time curve (AUC) was calculated to be 156%, 22%, 28% and 2.6%, respectively. Given that arbidol exhibits strong inhibition towards UGT1A9 and UGT2B7, clinical monitoring should be given when arbidol was co-administered with drugs mainly undergoing UGT1A9, UGT2B7-mediated metabolism. PMID:24400440

  7. Neonatal Development of Hepatic UGT1A9: Implications of Pediatric Pharmacokinetics

    PubMed Central

    Miyagi, Shogo J.; Milne, Alison M.; Coughtrie, Michael W. H.

    2012-01-01

    This article reports on the development of UDP-glucuronosyltransferase 1A9 (UGT1A9) in neonatal and pediatric liver. The substrate 4-methylumbelliferone (4MU) with specific inhibition by niflumic acid was used to define specific UGT1A9 activity. Subsequently, in silico pharmacokinetic (PK) and physiology-based pharmacokinetic (PBPK) modeling was used to determine UGT1A9 maturation and hepatic clearance. Modeled maximal enzyme activity was 27.9 nmol · min−1 · mg protein−1 at 4 months of age, which had high concordance with the average Vmax in 45 individual adult (>20 years) livers of 29.0 nmol · min−1 · mg protein−1. The activity of UGT1A9 ranged 7.5-fold in the adult population (4.1–54.5 nmol · min−1 · mg protein−1). Expression of UGT1A9 correlated with age only in children younger than 1 year (Spearman r = 0.70). Activity correlated with expression up to 18 years of age (Spearman r = 0.76). Furthermore, scaling intrinsic hepatic clearance of 4MU with an allometric PK model yielded a high clearance at birth and then fell to adult levels (1.3 l · h−1 · kg−1 at 18.1 years for well stirred or 1.4 l · h−1 · kg−1 at 18.7 years for parallel tube). The Simcyp PBPK models did not converge but showed an increase in clearance at under 1 year of age and then decreased to adult levels at approximately 20 years of age. Allometric scaling may be more accurate in cases of high-extraction drugs. Enzyme activities or hepatic clearances did not differ with gender or ethnicity. The UGT1A9 isoform has higher normalized clearance for 4MU at young ages, which may explain how other UGT1A9 substrates, such as propofol, have higher clearances in children than in adults. PMID:22492655

  8. Involvement of hepatocyte nuclear factor 1 in the regulation of the UDP-glucuronosyltransferase 1A7 (UGT1A7) gene in rat hepatocytes.

    PubMed

    Metz, R P; Auyeung, D J; Kessler, F K; Ritter, J K

    2000-08-01

    UDP-glucuronosyltransferase 1A7 (UGT1A7) is a major UGT contributing to the glucuronidation of xenobiotic phenols in rats. Its expression in rat liver is tightly regulated, with low constitutive and high inducible expression in response to aryl hydrocarbon receptor ligands and oltipraz. Previously, we reported the absence of 3-methylcholanthrene- or oltipraz-responsive elements in the 1.6-kbp region flanking the UGT1A7 promoter. However, potential binding sites were noted for several liver-enriched transcription factors. Here we show that deletion of the hepatic nuclear factor (HNF)3, HNF4, and CCAAT-enhancer binding protein-like binding sites had no effect on the expression of a UGT1A7 reporter plasmid, p(-965/+56)1A7-Luc, in primary rat hepatocytes. The full activity of the promoter was contained in the region between bases -157 and +76. Two sites of binding by rat liver nuclear proteins were detected in this region by DNase footprinting. PR-1 corresponded to the HNF1-like binding site between bases -52 and -38, whereas PR-2 was located between -30 to -6. Gel retardation studies supported the presence of HNF1alpha in the PR-1 DNA-liver nuclear protein complex. Mutation of PR-1 inhibited binding in the gel shift assay, prevented activation by overexpressed HNF1 in human embryonic kidney cells, and reduced by >80% the maximal luciferase activities expressed from basal and 3-methylcholanthrene-responsive UGT1A7 gene reporter constructs in primary rat hepatocytes. These data provide evidence for an important stimulatory role of HNF1 in promoting UGT1A7 gene expression in rat liver. PMID:10908299

  9. Dimerization of human uridine diphosphate glucuronosyltransferase allozymes 1A1 and 1A9 alters their quercetin glucuronidation activities.

    PubMed

    Liu, Yan-Qing; Yuan, Ling-Min; Gao, Zhang-Zhao; Xiao, Yong-Sheng; Sun, Hong-Ying; Yu, Lu-Shan; Zeng, Su

    2016-01-01

    Uridine diphosphate glucuronosyltransferase 1A (UGT1A) is a major phase II drug-metabolism enzyme superfamily involved in the glucuronidation of endobiotics and xenobiotics in humans. Many polymorphisms in UGT1A genes are reported to inhibit or decrease UGT1A activity. In this study, two UGT1A1 allozymes, UGT1A1 wild-type and a splice mutant, as well as UGT1A9 wild-type and its three UGT1A9 allozymes, UGT1A9*2(C3Y), UGT1A9*3(M33T), and UGT1A9*5(D256N) were single- or double-expressed in a Bac-to-Bac expression system. Dimerization of UGT1A1 or UGT1A9 allozymes was observed via fluorescence resonance energy transfer (FRET) and co-immunoprecipitation analysis. SNPs of UGT1A altered the ability of protein-protein interaction, resulting in differential FRET efficiencies and donor-acceptor r distances. Dimerization changed the chemical regioselectivity, substrate-binding affinity, and enzymatic activity of UGT1A1 and UGT1A9 in glucuronidation of quercetin. These findings provide molecular insights into the consequences of homozygous and heterozygous UGT1A1 and UGT1A9 allozymes expression on quercetin glucuronidation. PMID:27025983

  10. Dimerization of human uridine diphosphate glucuronosyltransferase allozymes 1A1 and 1A9 alters their quercetin glucuronidation activities

    PubMed Central

    Liu, Yan-Qing; Yuan, Ling-Min; Gao, Zhang-Zhao; Xiao, Yong-Sheng; Sun, Hong-Ying; Yu, Lu-Shan; Zeng, Su

    2016-01-01

    Uridine diphosphate glucuronosyltransferase 1A (UGT1A) is a major phase II drug-metabolism enzyme superfamily involved in the glucuronidation of endobiotics and xenobiotics in humans. Many polymorphisms in UGT1A genes are reported to inhibit or decrease UGT1A activity. In this study, two UGT1A1 allozymes, UGT1A1 wild-type and a splice mutant, as well as UGT1A9 wild-type and its three UGT1A9 allozymes, UGT1A9*2(C3Y), UGT1A9*3(M33T), and UGT1A9*5(D256N) were single- or double-expressed in a Bac-to-Bac expression system. Dimerization of UGT1A1 or UGT1A9 allozymes was observed via fluorescence resonance energy transfer (FRET) and co-immunoprecipitation analysis. SNPs of UGT1A altered the ability of protein-protein interaction, resulting in differential FRET efficiencies and donor-acceptor r distances. Dimerization changed the chemical regioselectivity, substrate-binding affinity, and enzymatic activity of UGT1A1 and UGT1A9 in glucuronidation of quercetin. These findings provide molecular insights into the consequences of homozygous and heterozygous UGT1A1 and UGT1A9 allozymes expression on quercetin glucuronidation. PMID:27025983

  11. Stereoselective glucuronidation and hydroxylation of etodolac by UGT1A9 and CYP2C9 in man.

    PubMed

    Tougou, K; Gotou, H; Ohno, Y; Nakamura, A

    2004-05-01

    1. In vitro metabolic studies with etodolac were performed. S- and R-etodolac were converted to the acylglucuronide and hydroxylated metabolites by UDP-glucuronosyltransferase (UGT) and cytochrome P450 in microsomes. However, the stereoselectivities of UGT and P450 for the isomers were opposite. S-etodolac was glucuronidated preferentially than R-etodolac by UGT. In contrast, R-etodolac was hydroxylated preferentially than S-etodolac by P450. 2. Of several human P450 enzymes, CYP2C9 had the greatest activity for hydroxylation of R-etodolac. Sulfaphenazole, an inhibitor of CYP2C9, and anti-CYP2C9 antibody inhibited the hydroxylation of R-etodolac in human liver microsomes. CYP2C9 therefore contributes to the stereoselective hydroxylation of R-etodolac. 3. Of several human UGT enzymes, UGT1A9 had the greatest activity for glucuronidation of S-etodolac. Propofol and thyroxine, inhibitors of UGT1A9, inhibited the glucuronidation of S-etodolac in human liver microsomes. Therefore, UGT1A9 is mainly responsible for the stereoselective glucuronidation of S-etodolac. 4. Because S-etodolac was metabolized more rapidly than R-etodolac in human cryopreserved hepatocytes, the stereoselectivities of UGT1A9 for etodolac substantially influenced the overall metabolism of S- and R-etodolac in man. PMID:15370961

  12. Fission yeast dam1-A8 mutant is resistant to and rescued by an anti-microtubule agent

    SciTech Connect

    Griffiths, Karen; Masuda, Hirohisa; Dhut, Susheela; Toda, Takashi

    2008-04-11

    The Dam1/DASH outer kinetochore complex is required for high-fidelity chromosome segregation in budding and fission yeast. Unlike budding yeast, the fission yeast complex is non-essential, however it promotes bipolar microtubule attachment in conjunction with microtubule-depolymerising kinesin-8 Klp5 and Klp6. Here, we screened for dam1 temperature sensitive mutants in a klp5 null background and identified dam1-A8 that contains two amino acid substitutions in the C-terminus (H126R and E149G). dam1-A8klp5 mutant cells display massive chromosome missegregation with lagging chromosomes and monopolar attachment of sister chromatids to one SPB (spindle pole body). Unexpectedly contrary to a deletion mutant that is hypersensitive to microtubule-destabilising drugs, dam1-A8 is resistant and furthermore the temperature sensitivity of dam1-A8klp5 is rescued by addition of these drugs. This indicates that the hyper-stabilised rigidity of kinetochore-spindle mal-attachments is the primary cause of lethality. Our result shows that fine-tuning of Dam1 activity is essential for chromosome bi-orientation.

  13. Fission yeast dam1-A8 mutant is resistant to and rescued by an anti-microtubule agent.

    PubMed

    Griffiths, Karen; Masuda, Hirohisa; Dhut, Susheela; Toda, Takashi

    2008-04-11

    The Dam1/DASH outer kinetochore complex is required for high-fidelity chromosome segregation in budding and fission yeast. Unlike budding yeast, the fission yeast complex is non-essential, however it promotes bipolar microtubule attachment in conjunction with microtubule-depolymerising kinesin-8 Klp5 and Klp6. Here, we screened for dam1 temperature sensitive mutants in a klp5 null background and identified dam1-A8 that contains two amino acid substitutions in the C-terminus (H126R and E149G). dam1-A8klp5 mutant cells display massive chromosome missegregation with lagging chromosomes and monopolar attachment of sister chromatids to one SPB (spindle pole body). Unexpectedly contrary to a deletion mutant that is hypersensitive to microtubule-destabilising drugs, dam1-A8 is resistant and furthermore the temperature sensitivity of dam1-A8klp5 is rescued by addition of these drugs. This indicates that the hyper-stabilised rigidity of kinetochore-spindle mal-attachments is the primary cause of lethality. Our result shows that fine-tuning of Dam1 activity is essential for chromosome bi-orientation. PMID:18262494

  14. Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

    PubMed Central

    Ramírez, Jacqueline; Mirkov, Snezana; House, Larry K.

    2015-01-01

    OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0–21%) was observed using clinically relevant OTS167 concentrations (0.4–2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration. PMID:25870101

  15. Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain.

    PubMed

    Sakakibara, Yukiko; Katoh, Miki; Kondo, Yuya; Nadai, Masayuki

    2016-03-01

    UDP-glucuronosyltransferase (UGT), a phase II drug-metabolizing enzyme, is expressed in the brain and can catalyze glucuronidation of endogenous and exogenous substrates in the brain. Thus, changes in UGT1A expression could affect homeostasis and drug efficacy. Phenobarbital (PB), a typical inducer of drug-metabolizing enzymes, has been reported to induce oxidative stress and epigenetic changes, which could alter UGT expression in the brain. Here, we aimed to clarify the effects of PB on Ugt1a6 and Ugt1a7 gene expression in rat brains. Sprague-Dawley rats were treated intraperitoneally with PB (80 mg/kg), once daily for 7 days. Ugt1a6 and Ugt1a7 mRNA expression levels were increased in the striatum and thalamus (Ugt1a6, 3.0- and 2.9-fold, respectively; Ugt1a7, 2.6- and 2.6-fold, respectively). Acetaminophen glucuronidation was also increased in the medulla oblongata and thalamus by 1.8- and 1.2-fold, respectively. The induction rates within different brain regions were correlated with Ugt1a6 and Ugt1a7 mRNA expression, and the degree of induction also correlated with that of NF-E2-related factor-2 mRNA. Measurement of oxidative stress markers suggested that PB induced oxidative stress in brain regions in which Ugt1a6 and Ugt1a7 mRNAs were increased. Moreover, histone modifications were altered by PB treatment, resulting in increased histone H3 lysine 4 trimethylation in the striatum and thalamus and decreased histone H3 lysine 9 trimethylation in the thalamus. These results suggested that oxidative stress and histone modifications may promote transcriptional activation of Ugt1a6 and Ugt1a7 genes. In summary, Ugt1a6 and Ugt1a7 mRNA levels were increased by PB treatment, which may alter pharmacokinetics in the brain. PMID:26684499

  16. Inhibitory effects of commonly used herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6, and 1A9 enzyme activities.

    PubMed

    Mohamed, Mohamed-Eslam F; Frye, Reginald F

    2011-09-01

    The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC(50)) and the volume in which the dose could be diluted to generate an IC(50)-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC(50) value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC(50) values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC(50) values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC(50)-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

  17. Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse.

    PubMed

    Al Saabi, Alaa; Allorge, Delphine; Sauvage, François-Ludovic; Tournel, Gilles; Gaulier, Jean-Michel; Marquet, Pierre; Picard, Nicolas

    2013-03-01

    Ethyl glucuronide (EtG) determination is increasingly used in clinical and forensic toxicology to document ethanol consumption. The enzymes involved in EtG production, as well as potential interactions with common drugs of abuse, have not been extensively studied. Activities of human liver (HLM), kidney (HKM), and intestinal (HIM) microsomes, as well as of 12 major human recombinant UDP-glucuronosyltransferases (UGTs), toward ethanol (50 and 500 mM) were evaluated in vitro using liquid chromatography-tandem mass spectrometry. Enzyme kinetic parameters were determined for pooled microsomes and recombinant UGTs with significant activity. Individual contributions of UGTs were estimated using the relative activity factor approach, proposed for scaling activities obtained with cDNA-expressed enzymes to HLM. Interaction of morphine, codeine, lorazepam, oxazepam, nicotine, cotinine, cannabinol, and cannabidiol (5, 10, 15 mg/l) with ethanol (1.15, 4.6, 11.5 g/l; i.e., 25, 100, 250 mM) glucuronidation was assessed using pooled HLM. Ethanol glucuronidation intrinsic clearance (Cl(int)) was 4 and 12.7 times higher for HLM than for HKM and HIM, respectively. All recombinant UGTs, except UGT1A1, 1A6, and 1A10, produced EtG in detectable amounts. UGT1A9 and 2B7 were the most active enzymes, each accounting for 17 and 33% of HLM Cl(int), respectively. Only cannabinol and cannabidiol significantly affected ethanol glucuronidation. Cannabinol increased ethanol glucuronidation in a concentration-dependent manner, whereas cannabidiol significantly inhibited EtG formation in a noncompetitive manner (IC(50) = 1.17 mg/l; inhibition constant (K(i)) = 3.1 mg/l). UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation. In addition, our results suggest that cannabinol and cannabidiol could significantly alter ethanol glucuronidation. PMID:23230132

  18. Expression of MAGE-A1, -A9, -A11 in laryngeal squamous cell carcinoma and their prognostic significance: a retrospective clinical study.

    PubMed

    Liu, Shenghui; Sang, Meixiang; Xu, Yuru; Gu, Lina; Liu, Fei; Shan, Baoen

    2016-05-01

    Conclusion The melanoma-associated antigens A1, -A9, -A11 (MAGE-A1, -A9, -A11) are relatively tumor-specific in laryngeal squamous cell carcinoma (LSCC), and could be ideal antigens for LSCC immunotherapy. In addition, MAGE-A9 probably is a poor prognostic marker for LSCC patients. Objective The MAGE-A family belongs to Cancer/testis antigens (CTA). However, the expression pattern of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC is still unclear. This study aims to evaluate the expression and possible prognostic role of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC patients. Methods The expression of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC specimens was investigated by immunohistochemistry, and the association of their expression and the clinical parameters and the survival of LSCC patients were analyzed by chi-square test, Kaplan-Meier survival and Cox regression analysis. Results The expression rates of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC were 54.7%, 46.2%, and 51.9%, respectively. The expression of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC was correlated with clinical stage, lymph node metastasis, and tumor size. The overall survival of LSCC patients with positive MAGE-A1, MAGE-A9, or MAGE-A11 expression was lower than the patients without MAGE-A1, MAGE-A9, or MAGE-A11 expression. Cox's multivariable analysis showed that MAGE-A9 expression was an independently poor prognostic factor for LSCC patients. PMID:26766421

  19. UDP-glucuronosyltransferase (UGT) 1A9-overexpressing HeLa cells is an appropriate tool to delineate the kinetic interplay between breast cancer resistance protein (BRCP) and UGT and to rapidly identify the glucuronide substrates of BCRP.

    PubMed

    Jiang, Wen; Xu, Beibei; Wu, Baojian; Yu, Rong; Hu, Ming

    2012-02-01

    The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low bioavailability for flavonoids. To investigate the simplest interplay between one UDP-glucuronosyltransferase isoform and one efflux transporter in flavonoid disposition, engineered HeLa cells stably overexpressing UGT1A9 were developed, characterized, and further applied to investigate the metabolism of two model flavonoids (genistein and apigenin) and excretion of their glucuronides. The results indicated that the engineered HeLa cells overexpressing UGT1A9 rapidly excreted the glucuronides of genistein and apigenin. The kinetic characteristics of genistein or apigenin glucuronidation were similar with the use of UGT1A9 overexpressed in HeLa cells or the commercially available UGT1A9. Small interfering (siRNA)-mediated UGT1A9 silencing resulted in a substantial decrease in glucuronide excretion (>75%, p < 0.01). Furthermore, a potent inhibitor of breast cancer resistance protein (BCRP), 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143), caused, in a dose-dependent manner, a substantial and marked reduction of the clearance (74-94%, p < 0.01), and a substantial increase in the intracellular glucuronide levels (4-8-fold, p < 0.01), resulting in a moderate decrease in glucuronide excretion (19-59%, p < 0.01). In addition, a significant, albeit moderate, reduction in the fraction of genistein metabolized (f(met)) in the presence of Ko143 was observed. In contrast, leukotriene C₄ and siRNA against multidrug resistance protein (MRP) 2 and MRP3 did not affect excretion of flavonoid glucuronides. In conclusion, the engineered HeLa cells overexpressing UGT1A9 is an appropriate model to study the kinetic interplay between UGT1A9 and BCRP in the phase II disposition of flavonoids. This simple cell model should also be very useful to rapidly identify whether a phase II metabolite

  20. UDP-Glucuronosyltransferase (UGT) 1A9-Overexpressing HeLa Cells Is an Appropriate Tool to Delineate the Kinetic Interplay between Breast Cancer Resistance Protein (BRCP) and UGT and to Rapidly Identify the Glucuronide Substrates of BCRP

    PubMed Central

    Jiang, Wen; Xu, Beibei; Wu, Baojian; Yu, Rong

    2012-01-01

    The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low bioavailability for flavonoids. To investigate the simplest interplay between one UDP-glucuronosyltransferase isoform and one efflux transporter in flavonoid disposition, engineered HeLa cells stably overexpressing UGT1A9 were developed, characterized, and further applied to investigate the metabolism of two model flavonoids (genistein and apigenin) and excretion of their glucuronides. The results indicated that the engineered HeLa cells overexpressing UGT1A9 rapidly excreted the glucuronides of genistein and apigenin. The kinetic characteristics of genistein or apigenin glucuronidation were similar with the use of UGT1A9 overexpressed in HeLa cells or the commercially available UGT1A9. Small interfering (siRNA)-mediated UGT1A9 silencing resulted in a substantial decrease in glucuronide excretion (>75%, p < 0.01). Furthermore, a potent inhibitor of breast cancer resistance protein (BCRP), 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143), caused, in a dose-dependent manner, a substantial and marked reduction of the clearance (74–94%, p < 0.01), and a substantial increase in the intracellular glucuronide levels (4–8-fold, p < 0.01), resulting in a moderate decrease in glucuronide excretion (19–59%, p < 0.01). In addition, a significant, albeit moderate, reduction in the fraction of genistein metabolized (fmet) in the presence of Ko143 was observed. In contrast, leukotriene C4 and siRNA against multidrug resistance protein (MRP) 2 and MRP3 did not affect excretion of flavonoid glucuronides. In conclusion, the engineered HeLa cells overexpressing UGT1A9 is an appropriate model to study the kinetic interplay between UGT1A9 and BCRP in the phase II disposition of flavonoids. This simple cell model should also be very useful to rapidly identify whether a phase II

  1. Nonphotic entrainment by 5-HT1A/7 receptor agonists accompanied by reduced Per1 and Per2 mRNA levels in the suprachiasmatic nuclei.

    PubMed

    Horikawa, K; Yokota, S; Fuji, K; Akiyama, M; Moriya, T; Okamura, H; Shibata, S

    2000-08-01

    In mammals, the environmental light/dark cycle strongly synchronizes the circadian clock within the suprachiasmatic nuclei (SCN) to 24 hr. It is well known that not only photic but also nonphotic stimuli can entrain the SCN clock. Actually, many studies have shown that a daytime injection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT), a serotonin 1A/7 receptor agonist, as a nonphotic stimulus induces phase advances in hamster behavioral circadian rhythms in vivo, as well as the neuron activity rhythm of the SCN in vitro. Recent reports suggest that mammalian homologs of the Drosophila clock gene, Period (Per), are involved in photic entrainment. Therefore, we examined whether phase advances elicited by 8-OH DPAT were associated with a change of Period mRNA levels in the SCN. In this experiment, we cloned partial cDNAs encoding hamster Per1, Per2, and Per3 and observed both circadian oscillation and the light responsiveness of Period. Furthermore, we found that the inhibitory effect of 8-OH DPAT on hamster Per1 and Per2 mRNA levels in the SCN occurred only during the hamster's mid-subjective day, but not during the early subjective day or subjective night. The present findings demonstrate that the acute and circadian time-dependent reduction of Per1 and/or Per2 mRNA in the hamster SCN by 8-OH DPAT is strongly correlated with the phase resetting in response to 8-OH DPAT. PMID:10908630

  2. Preliminary Investigation of the Contribution of CYP2A6, CYP2B6, and UGT1A9 Polymorphisms on Artesunate-Mefloquine Treatment Response in Burmese Patients with Plasmodium falciparum Malaria

    PubMed Central

    Phompradit, Papichaya; Muhamad, Poonuch; Cheoymang, Anurak; Na-Bangchang, Kesara

    2014-01-01

    CYP2A6, CYP2B6, and UGT1A9 genetic polymorphisms and treatment response after a three-day course of artesunate-mefloquine was investigated in 71 Burmese patients with uncomplicated Plasmodium falciparum malaria. Results provide evidence for the possible link between CYP2A6 and CYP2B6 polymorphisms and plasma concentrations of artesunate/dihydroartemisinin and treatment response. In one patient who had the CYP2A6*1A/*4C genotype (decreased enzyme activity), plasma concentration of artesunate at one hour appeared to be higher, and the concentration of dihydroartemisinin was lower than for those carrying other genotypes (415 versus 320 ng/mL). The proportion of patients with adequate clinical and parasitologic response who had the CYP2B6*9/*9 genotype (mutant genotype) was significantly lower compared with those with late parasitologic failure (14.0% versus 19.0%). Confirmation through a larger study in various malaria-endemic areas is required before a definite conclusion on the role of genetic polymorphisms of these drug-metabolizing enzymes on treatment response after artesunate-based combination therapy can be made. PMID:24891466

  3. Refinement of the canine CD1 locus topology and investigation of antibody binding to recombinant canine CD1 isoforms.

    PubMed

    Schjaerff, Mette; Keller, Stefan M; Fass, Joseph; Froenicke, Lutz; Grahn, Robert A; Lyons, Leslie; Affolter, Verena K; Kristensen, Annemarie T; Moore, Peter F

    2016-03-01

    CD1 molecules are antigen-presenting glycoproteins primarily found on dendritic cells (DCs) responsible for lipid antigen presentation to CD1-restricted T cells. Despite their pivotal role in immunity, little is known about CD1 protein expression in dogs, notably due to lack of isoform-specific antibodies. The canine (Canis familiaris) CD1 locus was previously found to contain three functional CD1A genes: canCD1A2, canCD1A6, and canCD1A8, where two variants of canCD1A8, canCD1A8.1 and canCD1A8.2, were assumed to be allelic variants. However, we hypothesized that these rather represented two separate genes. Sequencing of three overlapping bacterial artificial chromosomes (BACs) spanning the entire canine CD1 locus revealed canCD1A8.2 and canCD1A8.1 to be located in tandem between canCD1A7 and canCD1C, and canCD1A8.1 was consequently renamed canCD1A9. Green fluorescent protein (GFP)-fused canine CD1 transcripts were recombinantly expressed in 293T cells. All proteins showed a highly positive GFP expression except for canine CD1d and a splice variant of canine CD1a8 lacking exon 3. Probing with a panel of anti-CD1 monoclonal antibodies (mAbs) showed that Ca13.9H11 and Ca9.AG5 only recognized canine CD1a8 and CD1a9 isoforms, and Fe1.5F4 mAb solely recognized canine CD1a6. Anti-CD1b mAbs recognized the canine CD1b protein, but also bound CD1a2, CD1a8, and CD1a9. Interestingly, Ca9.AG5 showed allele specificity based on a single nucleotide polymorphism (SNP) located at position 321. Our findings have refined the structure of the canine CD1 locus and available antibody specificity against canine CD1 proteins. These are important fundamentals for future investigation of the role of canine CD1 in lipid immunity. PMID:26687789

  4. UDP-glucuronosyltransferases 1A6 and 1A10 catalyze reduced menadione glucuronidation

    SciTech Connect

    Nishiyama, Takahito; Ohnuma, Tomokazu; Inoue, Yuu; Kishi, Takehiko; Ogura, Kenichiro; Hiratsuka, Akira

    2008-06-27

    Menadione (2-methyl-1,4-naphthoquine), also known as vitamin K3, has been widely used as a model compound in the field of oxidative stress-related research. The metabolism of menadione has been studied, and it is known that menadione undergoes a two-electron reduction by NAD(P)H:Quinone oxidoreductase 1 (NQO1) after which the reduced form of menadione (2-methyl-1,4-naphthalenediol, menadiol) is glucuronidated and excreted in urine. To investigate which human UDP-glucuronosyltransferase (UGT) isoforms participate in the glucuronidation of menadiol reduced by NQO1 from menadione, we first constructed heterologously expressed NQO1 in Sf9 cells and tested the menadiol glucuronidating activity of 16 human recombinant UGT isoforms. Of the 16 UGT isoforms, UGTs 1A6, 1A7, 1A8, 1A9, and 1A10 catalyzed menadiol glucuronidation, and, of these, UGTs 1A6 and 1A10 catalyzed menadiol glucuronidation at much higher rates than the other UGTs. Menadiol was regioselectively glucuronidated in the manner of 4-position > 1-position by UGTs 1A7, 1A8, 1A9, and 1A10. In contrast to these UGTs, only UGT1A6 exhibited 1-menadiol-preferential glucuronidating activity. The results suggest possible detoxification pathways for quinones via NQO1 reduction followed by UGT glucuronidation.

  5. Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases.

    PubMed

    Xin, Hong; Qi, Xiao-Yi; Wu, Jing-Jing; Wang, Xin-Xin; Li, Yan; Hong, James Y; He, Wei; Xu, Wei; Ge, Guang-Bo; Yang, Ling

    2016-04-01

    Licochalcone A (LCA) is a major bioactive compound in Licorice, a widely used herbal medicine. In this study, the inhibitory effects of LCA against human UDP-glucuronosyltransferases (UGTs) and LCA associated herb-drug interactions were systematically investigated. Our results demonstrated that LCA displayed broad-spectrum inhibition against human UGTs. LCA exhibited strong inhibitory effects against UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 2B7 (both IC50 and Ki values lower than 5 μM), while showing moderate inhibitory effects against UGT1A8, 1A10, 2B4, 2B15, and 2B17. The inhibitory effects of LCA against two major UGTs, including UGT1A1 and 1A9, were further investigated in human liver microsomes (HLMs), where the potential risks of LCA via inhibition of UGT1A1 and 1A9 were predicted by combining the in vitro inhibitory data and physiological data. The results from this study also showed that several LCA-containing products were able to increase the area under the curve (AUC) of the substrates that were predominantly metabolized by UGT1A1 or 1A9. These findings together demonstrate that LCA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose LCA is co-administered with UGT substrates. PMID:26875642

  6. Glucuronidation of anabolic androgenic steroids by recombinant human UDP-glucuronosyltransferases.

    PubMed

    Kuuranne, Tiia; Kurkela, Mika; Thevis, Mario; Schänzer, Wilhelm; Finel, Moshe; Kostiainen, Risto

    2003-09-01

    A multidimensional study on the glucuronidation of anabolic androgenic steroids and their phase I metabolites by 11 recombinant human UDP-glucuronosyltransferases (UGTs) was carried out using liquid chromatographic-tandem mass spectrometric analyses. Large differences between the enzymes with respect to the conjugation profiles of the 11 tested aglycones were detected. Two UGTs, 1A6 and 1A7, did not exhibit measurable activity toward any of the aglycones that were examined in this study. Regioselectivity was demonstrated by UGTs 1A8, 1A9, and 2B15 that preferentially catalyzed hydroxyl glucuronidation at the 17beta-position. Most of the other enzymes glucuronidated hydroxyl groups at both the 3alpha- and the 17beta-positions. Clear stereoselectivity was observed in glucuronidation of diastereomeric nandrolone metabolites (5alpha-estran-3alpha-ol-17-one and 5beta-estran-3alpha-ol-17-one), whereas such specificity was not seen when analogous methyltestosterone metabolites were assayed. UGTs 1A1, 1A3, 1A4, 1A8, 1A9, 1A10, 2B4, 2B7, and 2B15 readily glucuronidated 5alpha-androstane-3alpha,17beta-diol, but none of them exhibited methyltestosterone glucuronidation activity. In agreement with the latter observations, we found that the methyltestosterone glucuronidation activity of human liver microsomes is extremely low, whereas in induced rat liver microsomes it was significantly higher. The homology among UGTs 1A7 to 1A10 at the level of amino acid sequence is very high, and it was thus surprising to find large differences in their activity toward this set of aglycones. Furthermore, the high activity of UGT1A8 and 1A10 toward some of the substrates indicates that extrahepatic enzymes might play a role in the metabolism of anabolic androgenic steroids. PMID:12920167

  7. UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for puerarin metabolism in human liver microsomes.

    PubMed

    Luo, Cheng-Feng; Cai, Bin; Hou, Ning; Yuan, Mu; Liu, Shi-Ming; Ji, Hong; Xiong, Long-Gen; Xiong, Wei; Luo, Jian-Dong; Chen, Min-Sheng

    2012-11-01

    Puerarin has multiple pharmacological effects and is widely prescribed for patients with cardiovascular diseases, including hypertension, cerebral ischemia, myocardial ischemia, diabetes mellitus, and arteriosclerosis. While puerarin is a useful therapeutic agent, its mechanisms of action have not been well defined. Understanding puerarin metabolism, in particular its interactions with metabolizing enzymes, will contribute to our understanding of its toxic and therapeutic effects and may help to elucidate potential negative drug-drug interactions. In this study, the major metabolite of puerarin was obtained from the urine of rats administered puerarin, by a semi-preparative high-performance liquid chromatography method. The major metabolite was identified as puerarin-7-O-glucuronide. In vitro, we used a UDP-glucuronosyltransferase (UGT) reaction screening method with 12 recombinant human UGTs to demonstrate that formation of puerarin-7-O-glucuronide was catalyzed by UGT1A1, 1A9, 1A10, 1A3, 1A6, 1A7, and 1A8. UGT1A1, 1A9, and 1A10 significantly catalyzed puerarin-7-O-glucuronide formation, and the activity of UGT1A1 was significantly higher than those of 1A9 and 1A10. The V (max) of UGT1A1 was two- to threefold higher than the levels of UGT1A9 or 1A10, with a lower K ( m ) value and a higher V (max)/K ( m ) value. The kinetics of puerarin-7-O-glucuronide formation catalyzed by UGT1A1 were similar to those of the pooled human liver microsomes (HLMs), with V (max) values of 186.3 and 149.2 pmol/min/mg protein, and K ( m ) values of 811.3 and 838.9 μM, respectively. Furthermore, bilirubin and β-estradiol, probe substrates for UGT1A1, significantly inhibited the formation of puerarin-7-O-glucuronide in HLMs. PMID:22648071

  8. Optimized methods for targeted peptide-based quantification of human uridine 5'-diphosphate-glucuronosyltransferases in biological specimens using liquid chromatography-tandem mass spectrometry.

    PubMed

    Sato, Yuichiro; Nagata, Masanori; Tetsuka, Kazuhiro; Tamura, Kouichi; Miyashita, Aiji; Kawamura, Akio; Usui, Takashi

    2014-05-01

    The aim of this study was to optimize methods for quantifying 13 uridine 5'-diphosphate-glucuronosyltransferase (UGT) isoforms (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17) in human liver, intestinal, and kidney microsomes, and in recombinant human UGT-expressing insect cell membranes (rhUGTs) by targeted peptide-based quantification using liquid chromatography-tandem mass spectrometry. Production of targeted peptides was compared by combining three denaturing agents (urea, sodium deoxycholate, and octyl glucoside) and three denaturing temperatures (37°C, 60°C, and 95°C) followed by tryptic digestion for 2-20 hours. Denaturing conditions and digestion times yielding high production efficiency varied markedly among isoforms and specimens, indicating the importance of specific optimization. Each UGT isoform was quantified using the methods found to be optimal. The expression of 10 (1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B15, and 2B17), 6 (1A1, 1A3, 1A4, 1A10, 2B7, and 2B17), and 3 (1A6, 1A9, and 2B7) isoforms was detected in human liver, intestinal, and kidney microsomes, respectively, and levels were reproducible using multiple protocols. All isoforms were quantified in rhUGTs. Determining the levels of UGTs in human tissue specimens and those in rhUGTs is important for estimating the contribution of glucuronidation to body clearance based on in vitro-in vivo extrapolation. PMID:24595681

  9. In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis.

    PubMed

    Liang, Si-Cheng; Ge, Guang-Bo; Xia, Yang-Liu; Zhang, Jiang-Wei; Qi, Xiao-Yi; Tu, Cai-Xia; Yang, Ling

    2015-10-01

    The C-8 phenol group is essential to exert the bioactivities of daphnetin, but it is readily conjugated with glucuronic acid prior to excretion. In this study, daphnetin-7-methylether (7M-DNP) was used to investigate the effect of 7-methyl substitution on daphnetin glucuronidation in human/rat liver (HLM/RLM) and intestine (HIM/RIM) microsomes, and recombinant UDP-glucuronosyltransferases (UGTs). Compared with daphnetin, the Vmax /Km values of 7M-DNP via 8-O-glucuronidation were 2.1-fold lower in HLM, 1.7-fold lower in HIM, and 2.4-fold lower in RLM, suggesting an improvement in metabolic stability. Different from daphnetin 8-O-glucuronidation exclusively catalyzed by UGT1A6 and UGT1A9, UGT1A1, -1A3, -1A7, -1A8, and -1A9 showed glucuronidation activity toward 7M-DNP. Kinetics studies, chemical inhibition, and the relative activity factor approach were used to demonstrate that UGT1A9 was mainly responsible for the reaction in HLM, whereas UGT1A1 was a primary contributor in HIM. The Vmax /Km values of 7M-DNP glucuronidation in HLM and HIM were 0.61-0.74-fold lower than those of rat, suggesting the differences between the two species. The bioactivity analysis demonstrated that 7M-DNP had an anti-inflammatory activity comparable to that of daphnetin. These findings indicated that the outcomes of 7-methyl substitution on daphnetin might be positive, but this should be confirmed in future in vivo studies. PMID:26104686

  10. In Vitro Glucuronidation of the Antibacterial Triclocarban and Its Oxidative MetabolitesS⃞

    PubMed Central

    Schebb, N. H.; Franze, B.; Maul, R.; Ranganathan, A.

    2012-01-01

    Triclocarban (3,4,4′-trichlorocarbanilide; TCC) is widely used as an antibacterial in bar soaps. During use of these soaps, a significant portion of TCC is absorbed by humans. For the elimination from the body, glucuronidation plays a key role in both biliary and renal clearance. To investigate this metabolic pathway, we performed microsomal incubations of TCC and its hydroxylated metabolites 2′-OH-TCC, 3′-OH-TCC, and 6-OH-TCC. Using a new liquid chromatography-UV-mass spectrometry method, we could show a rapid glucuronidation for all OH-TCCs by the uridine-5′-diphosphate-glucuronosyltransferases (UGT) present in liver microsomes of humans (HLM), cynomolgus monkeys (CLM), rats (RLM), and mice (MLM). Among the tested human UGT isoforms, UGT1A7, UGT1A8, and UGT1A9 showed the highest activity for the conjugation of hydroxylated TCC metabolites followed by UGT1A1, UGT1A3, and UGT1A10. Due to this broad pattern of active UGTs, OH-TCCs can be efficiently glucuronidated in various tissues, as shown for microsomes from human kidney (HKM) and intestine (HIM). The major renal metabolites in humans, TCC-N-glucuronide and TCC-N′-glucuronide, were formed at very low conversion rates (<1%) by microsomal incubations. Low amounts of N-glucuronides were generated by HLM, HIM, and HKM, as well as by MLM and CLM, but not by RLM, according to the observed species specificity of this metabolic pathway. Among the human UGT isoforms, only UGT1A9 had activity for the N-glucuronidation of TCC. These results present an anomaly where in vivo the predominant urinary metabolites of TCC are N and N′-glucuronides, but these compounds are slowly produced in vitro. PMID:21953915

  11. In vitro glucuronidation of the antibacterial triclocarban and its oxidative metabolites.

    PubMed

    Schebb, N H; Franze, B; Maul, R; Ranganathan, A; Hammock, B D

    2012-01-01

    Triclocarban (3,4,4'-trichlorocarbanilide; TCC) is widely used as an antibacterial in bar soaps. During use of these soaps, a significant portion of TCC is absorbed by humans. For the elimination from the body, glucuronidation plays a key role in both biliary and renal clearance. To investigate this metabolic pathway, we performed microsomal incubations of TCC and its hydroxylated metabolites 2'-OH-TCC, 3'-OH-TCC, and 6-OH-TCC. Using a new liquid chromatography-UV-mass spectrometry method, we could show a rapid glucuronidation for all OH-TCCs by the uridine-5'-diphosphate-glucuronosyltransferases (UGT) present in liver microsomes of humans (HLM), cynomolgus monkeys (CLM), rats (RLM), and mice (MLM). Among the tested human UGT isoforms, UGT1A7, UGT1A8, and UGT1A9 showed the highest activity for the conjugation of hydroxylated TCC metabolites followed by UGT1A1, UGT1A3, and UGT1A10. Due to this broad pattern of active UGTs, OH-TCCs can be efficiently glucuronidated in various tissues, as shown for microsomes from human kidney (HKM) and intestine (HIM). The major renal metabolites in humans, TCC-N-glucuronide and TCC-N'-glucuronide, were formed at very low conversion rates (<1%) by microsomal incubations. Low amounts of N-glucuronides were generated by HLM, HIM, and HKM, as well as by MLM and CLM, but not by RLM, according to the observed species specificity of this metabolic pathway. Among the human UGT isoforms, only UGT1A9 had activity for the N-glucuronidation of TCC. These results present an anomaly where in vivo the predominant urinary metabolites of TCC are N and N'-glucuronides, but these compounds are slowly produced in vitro. PMID:21953915

  12. Placental profiling of UGT1A enzyme expression and activity and interactions with preeclampsia at term.

    PubMed

    Collier, Abby C; Thévenon, Audrey D; Goh, William; Hiraoka, Mark; Kendal-Wright, Claire E

    2015-12-01

    Placental UDP-glucuronosyltransferase (UGT) enzymes have critical roles in hormone, nutrient, chemical balance and fetal exposure during pregnancy. Placental UGT1A isoforms were profiled and differences between preeclamptic (PE) and non-PE placental UGT expression determined. In third trimester villous placenta, UGT1A1, 1A4, 1A6 and 1A9 were expressed and active in all specimens (n = 10), but UGT1A3, 1A5, 1A7, 1A8 and 1A10 were absent. The UGT1A activities were comparable to human liver microsomes per milligram, but placental microsome yields were only 2 % of liver (1 mg/g of tissue vs. 45 mg/g of tissue). For successful PCR, placental collection and processing within 60 min from delivery, including DNAse and ≥300 ng of RNA in reverse transcription were essential and snap freezing in liquid nitrogen immediately was the best preservation method. Although UGT1A6 mRNA was lower in PE (P < 0.001), there were no other significant effects on UGT mRNA, protein or activities. A more comprehensive tissue sample set is required for confirmation of PE interactions with UGT. Placental UGT1A enzyme expression patterns are similar to the liver and a detoxicative role for placental UGT1A is inferred. PMID:25465229

  13. Human UDP-Glucuronosyltransferase 1A1 is the Primary Enzyme Responsible for the N-glucuronidation of N-hydroxy-PhIP in vitro

    SciTech Connect

    Malfatti, M A; Felton, J S

    2004-04-06

    UDP-Glucuronosyltransferase 1A proteins (UGT1A) catalyze the glucuronidation of many endogenous and xenobiotic compounds including heterocyclic amines and their hydroxylated metabolites (the main topic of this study). Studies have shown that in humans UGT1A mediated glucuronidation is an important pathway in the detoxification of food-borne carcinogenic heterocyclic amines. The biotransformation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most mass abundant heterocyclic amine found in cooked meats, is highly dependent on cytochrome P4501A2 hydroxylation followed by UGT catalyzed glucuronidation of the N-hydroxy-PhIP reactive intermediate. To determine which UGT1A proteins are involved in the glucuronidation of N-hydroxy-PhIP, microsomal preparations from baculovirus infected insect cells that express all of the known functional human UGT1A isozymes (UGT1A1, -1A3, -1A4, -1A6, -1A7, -1A8, -1A9, -1A10) were exposed to N-hydroxy-PhIP and the reaction products were isolated by HPLC. All UGT1A proteins except UGT1A6 showed some degree of activity towards N-hydroxy-PhIP. The formation of both N-hydroxy-PhIP-N{sup 2}-glucuronide and N-hydroxy-PhIP-N3-glucuronide was both time and substrate concentration dependent in all the microsomal incubations that showed appreciable activity. UGT1A1 was the most efficient in converting N-hydroxy-PhIP to both conjugates producing 5 times more of the N{sup 2}-conjugate than UGT1A4, the next active UGT, and 286 times more than UGT1A7, the least active UGT. With an apparent Km of 52 {micro}M and a K{sub cat} of 114 min-1, UGT1A1 was also the most catalytically efficient in forming N-hydroxy-PhIP-N{sup 2}-glucuronide. Catalytic constants for UGT1A4, UGT1A8 and UGT1A9 were 52 min-1, 35 min{sup -1} and 3.7 min{sup -1}, respectively. The catalytic efficiency for N-hydroxy-PhIP-N3-glucuronide formation was 8, 10, and 6 times lower for UGT1A1, -1A4, and -1A8, respectively, when compared to the k{sub cat} values for N

  14. Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes.

    PubMed

    Kuehl, Gwendolyn E; Bigler, Jeannette; Potter, John D; Lampe, Johanna W

    2006-02-01

    Acetylsalicylic acid (aspirin) is a common nonsteroidal anti-inflammatory drug used for treatment of pain and arthritis. In the body, acetylsalicylic acid is rapidly deacetylated to form salicylic acid. Both compounds have been proposed as anti-inflammatory agents. Major metabolites of salicylic acid are its acyl and phenolic glucuronide conjugates. Formation of these conjugates, catalyzed by UDP-glucuronosyltransferases (UGTs), decreases the amount of pharmacologically active salicylic acid present. We aimed to identify the UGTs catalyzing the glucuronidation of salicylic acid using both heterologously expressed enzymes and pooled human liver microsomes (HLMs) and to develop a liquid chromatography-tandem mass spectrometry method to quantify glucuronidation activity of UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17 Supersomes. All UGTs tested, except 1A4, 2B15, and 2B17, catalyzed salicylic acid phenolic and acyl glucuronidation. Ratios of salicylic acid phenolic to acyl glucuronide formation varied more than 12-fold from 0.5 for UGT1A6 to 6.1 for UGT1A1. These results suggest that all UGTs except 1A4, 2B15, and 2B17 might be involved in the glucuronidation of salicylic acid in vivo. From comparisons of apparent Km values determined in pooled HLMs and in expressed UGTs, UGT2B7 was suggested as a likely catalyst of salicylic acid acyl glucuronidation, whereas multiple UGTs were suggested as catalysts of phenolic glucuronidation. The results of this UGT screening may help target future evaluation of the effects of UGT polymorphisms on response to aspirin in clinical and population-based studies. PMID:16258079

  15. Comparison of the Inhibitory Potential of Bavachalcone and Corylin against UDP-Glucuronosyltransferases.

    PubMed

    Shan, Lina; Yang, Shuman; Zhang, Gang; Zhou, Dun; Qiu, Zhenyu; Tian, Lei; Yuan, Hongxia; Feng, Yujun; Shi, Xianbao

    2014-01-01

    Bavachalcone and corylin are two major bioactive compounds isolated from Psoralea corylifolia L., which has been widely used as traditional Chinese medicine for many years. As two antibiotic or anticancer drugs, bavachalcone and corylin are used in combination with other drugs; thus it is necessary to evaluate potential pharmacokinetic herb-drug interactions (HDI) of the two bioactive compounds. The aim of the present study was to compare the effects of liver UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT1A7, UGT1A8, UGT 1A10, and UGT2B4 inhibited by bavachalcone and corylin. 4-Methylumbelliferone (4-MU) was used as a nonspecific "probe" substrate. Bavachalcone had stronger inhibition on UGT1A1 and UGT1A7 than corylin which did not inhibit UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A10, and UGT2B4. Data fitting using Dixon and Lineweaver-Burk plots demonstrated the noncompetitive inhibition of bavachalcone against UGT1A1 and UGT1A7-mediated 4-MU glucuronidation reaction. The values of inhibition kinetic parameters (Ki) were 5.41  μ M and 4.51  μ M for UGT1A1 and UGT1A7, respectively. The results of present study suggested that there was a possibility of UGT1A1 and UGT1A7 inhibition-based herb-drug interaction associated with bavachalcone and provided the basis for further in vivo studies to investigate the HDI potential between bavachalcone and UGT substrates. PMID:24829606

  16. Tissue and species differences in the glucuronidation of glabridin with UDP-glucuronosyltransferases.

    PubMed

    Guo, Bin; Fang, Zhongze; Yang, Lu; Xiao, Ling; Xia, Yangliu; Gonzalez, Frank J; Zhu, Liangliang; Cao, Yunfeng; Ge, Guangbo; Yang, Ling; Sun, Hongzhi

    2015-04-25

    Glabridin (GA) has gained wide application in the cosmetics and food industry. This study was performed to investigate its metabolic inactivation and elimination by glucuronidation by use of liver and intestine microsomes from humans (HLM and HIM) and rats (RLM and RIM), and liver microsomes from cynomolgus monkeys and beagle dogs (CyLM and DLM). Both hydroxyl groups at the C2 and C4 positions of the B ring are conjugated to generate two mono-glucuronides (M1 and M2). HIM, RIM and RLM showed the most robust activity in catalyzing M2 formation with intrinsic clearance values (Clint) above 2000 μL/min/mg, with little measurable M1 formation activity. DLM displayed considerable activity both in M1 and M2 formation, with Clint values of 71 and 214 μL/min/mg, respectively, while HLM and CyLM exhibited low activities in catalyzing M1 and M2 formation, with Clint values all below 20 μL/min/mg. It is revealed that UGT1A1, 1A3, 1A9, 2B7, 2B15 and extrahepatic UGT1A8 and 1A10 are involved in GA glucuronidation. Nearly all UGTs preferred M2 formation except for UGT1A1. Notably, UGT1A8 displayed the highest activity with a Clint value more than 5-fold higher than the other isoforms. Chemical inhibition studies, using selective inhibitors of UGT1A1, 1A9, 2B7 and 1A8, further revealed that UGT1A8 contributed significantly to intestinal GA glucuronidation in humans. In summary, this in vitro study demonstrated large species differences in GA glucuronidation by liver and intestinal microsomes, and that intestinal UGTs are important for the pathway in humans. PMID:25765239

  17. Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation.

    PubMed

    Basu, Nikhil K; Kubota, Shigeki; Meselhy, Meselhy R; Ciotti, Marco; Chowdhury, Bhabadeb; Hartori, Masao; Owens, Ida S

    2004-07-01

    Among gastrointestinal distributed isozymes encoded at the UGT1 locus, UDP-glucuronosyltransferase 1A10 (UGT1A10) metabolizes a number of important chemicals. Similar to broad conversion of phytoestrogens (Basu, N. K., Ciotti, M., Hwang, M. S., Kole, L., Mitra, P. S., Cho, J. W., and Owens, I. S. (2004) J. Biol. Chem. 279, 1429-1441), UGT1A10 metabolized estrogens and their derivatives, whereas UGT1A1, -1A3, -1A7, and -1A8 differentially exhibited reduced activity toward the same. UGT1A10 compared with UGT1A7, -1A8, and -1A3 generally exhibited high activity toward acidic nonsteroidal anti-inflammatory drugs and natural benzaldehyde derivatives, while UGT1A3 metabolized most efficiently aromatic transcinnamic acids known to be generated from flavonoid glycosides by microflora in the lower gastrointestinal tract. Finally UGT1A10, -1A7, -1A8, and -1A3 converted plant-based salicylic acids; methylsalicylic acid was transformed at high levels, and acetylsalicylic (aspirin) and salicylic acid were transformed at moderate to low levels. Atypically UGT1A10 transformed estrogens between pH 6 and 8 but acidic structures preferentially at pH 6.4. Furthermore evidence indicates UGT1A10 expressed in COS-1 cells depends upon phosphorylation; UGT1A10 versus its single, double, and triple mutants at three predicted protein kinase C phosphorylation sites incorporated [(33)P]-orthophosphate and showed a progressive decrease with no detectable label or activity for the triple T73A/T202A/S432G-1A10 mutant. Single and double mutants revealed either null/full activity or null/additive activity, respectively. Additionally UGT1A10-expressing cultures glucuronidated 17beta-[(14)C]estradiol, whereas cultures containing null mutants at protein kinase C sites showed no estrogen conversion. Importantly UGT1A10 in cells supported 10-fold higher glucuronidation of 17beta-estradiol than UGT1A1. In summary, our results suggest gastrointestinally distributed UGT1A10 is important for detoxifying

  18. Characterization of N-glucuronidation of 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor.

    PubMed

    Omura, Koichi; Nakazawa, Takashi; Sato, Takahiro; Iwanaga, Takashi; Nagata, Osamu

    2007-12-01

    In humans, orally administered 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051) is excreted mainly as triazole N(1)- and N(2)-glucuronides in urine. It is important to determine the enzyme(s) that catalyze the metabolism of a new drug to estimate individual differences and/or drug-drug interactions. Therefore, the characterization and mechanism of these glucuronidations were investigated using human liver microsomes (HLMs), human intestinal microsomes (HIMs), and recombinant human UDP-glucuronosyltransferase (UGT) isoforms to determine the UGT isoform(s) responsible for FYX-051 N(1)- and N(2)-glucuronidation. FYX-051 was metabolized to its N(1)- and N(2)-glucuronide forms by HLMs, and their K(m) values were 64.1 and 72.7 microM, respectively; however, FYX-051 was scarcely metabolized to its glucuronides by HIMs. Furthermore, among the recombinant human UGT isoforms, UGT1A1, UGT1A7, and UGT1A9 catalyzed the N(1)- and N(2)-glucuronidation of FYX-051. To estimate their contribution to FYX-051 glucuronidation, inhibition analysis with pooled HLMs was performed. Mefenamic acid, a UGT1A9 inhibitor, decreased FYX-051 N(1)- and N(2)-glucuronosyltransferase activities, whereas bilirubin, a UGT1A1 inhibitor, did not affect these activities. Furthermore, in the experiment using microsomes from eight human livers, the N(1)- and N(2)-glucuronidation activity of FYX-051 was found to significantly correlate with the glucuronidation activity of propofol, a specific substrate of UGT1A9 (N(1): r(2) = 0.868, p < 0.01; N(2): r(2) = 0.775, p < 0.01). These results strongly suggested that the N(1)- and N(2)-glucuronidation of FYX-051 is catalyzed mainly by UGT1A9 in human livers. PMID:17761779

  19. Structure–inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs)

    SciTech Connect

    Fang, Zhong-Ze; Cao, Yun-Feng; Hu, Cui-Min; Hong, Mo; Sun, Xiao-Yu; Ge, Guang-Bo; Liu, Yong; Zhang, Yan-Yan; Yang, Ling; Sun, Hong-Zhi

    2013-03-01

    The wide utilization of ginseng provides the high risk of herb–drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb–drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb–drug interaction induced by this kind of inhibition, the ginsenoside Rg{sub 3} was selected as an example, and the inhibition kinetic type and parameters (K{sub i}) were determined. Rg{sub 3} competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K{sub i} values) were calculated to be 22.6, 7.9, 1.9, and 2.0 μM for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg{sub 3} (400 ng/ml (0.5 μM)) after intramuscular injection of 60 mg Rg{sub 3}, the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 2.2%, 6.3%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng–drug interaction. - Highlights: ► Structure-dependent inhibition of

  20. Metabolism of chamaechromone in vitro with human liver microsomes and recombinant human drug-metabolizing enzymes.

    PubMed

    Lou, Yan; Hu, Haihong; Qiu, Yunqing; Zheng, Jinqi; Wang, Linrun; Zhang, Xingguo; Zeng, Su

    2014-04-01

    Chamaechromone is a major component in the dried roots of Stellera chamaejasme with antihepatitis B virus and insecticidal activity. In this study, metabolic profiles of chamaechromone were investigated in human liver microsomes. One monohydroxide and two monoglucuronides of chamaechromone were identified. The enzyme kinetics for both hydroxylation and glucuronidation were fitted to the Michaelis-Menten equation. The hydroxylation of chamaechromone was inhibited by α-naphthoflavone, and predominantly catalyzed by recombinant human cytochrome P450 1A2, whereas the glucuronidation was inhibited by quercetin, 1-naphthol, and fluconazole, and mainly catalyzed by recombinant human UDP-glucuronosyltransferase 1A3, 1A7, 1A9, and 2B7. PMID:24687737

  1. Study of five haemogenetic markers (Gc, C3, Bf, Ag, and GALT) in six Indonesian populations and in 12 subgroups of Balinese.

    PubMed

    Scherz, R; Breguet, G; Ney, R; Pflugshaupt, R; Bütler, R

    1988-08-01

    In various ethnic groups of the Indonesian archipelago and of Bali, the polymorphisms of the serum proteins Gc globulin (vitamin D-binding protein), C3 (complement component 3), Bf (complement factor B), Ag x,y (lipoprotein allotypes), and of the red cell enzyme system GALT (galactose-1P-uridyltransferase) were analysed. Among the studied proteins, the Gc system was the most informative one for the anthropologist. Besides considerable differences of frequencies of the common alleles Gc*1F, Gc*1S and Gc*2, a number of rare alleles (1A1, 1A3, 1A8, 1A9, 1A12, 1C2, 1C21, 1C24, and 2C8) and some new ones (1C28, 1C29, 1C30, 2C9) were observed. The presence of Gc*1A1 demonstrates the relationship to the Australo-Melanesian populations, but Mongolian variants (1A3, 1A8, 1A9, 1C2) were also encountered. Within the C3 system a very high frequency of the C3*S allele was observed in all populations. The rare alleles C3*F0.55, C3S1, and C3*S0.5 were observed in some groups. A new allele (C3*F0.35) was detected in a Chinese individual and in a nobleman from Bali. The frequency of the Bf*F allele was rather low in general, and the Bf*S0.7 allele was found in three Indonesian individuals only. The Ag*(x) frequencies were rather high, as it is known for Asiatic populations. Variability among subgroups was not very pronounced. The GALT*2 allele (Duarte variant of the enzyme) was observed very rarely; however, it was present in several populations. Enzyme activities could not be determined, and therefore we cannot tell whether the galactosaemia gene (GALT*0) was present or not. PMID:2851268

  2. Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases.

    PubMed

    Lv, Xia; Wang, Xin-Xin; Hou, Jie; Fang, Zhong-Ze; Wu, Jing-Jing; Cao, Yun-Feng; Liu, Shu-Wen; Ge, Guang-Bo; Yang, Ling

    2016-06-15

    Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68μM and 30.82μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1. PMID:27089846

  3. Microsomal Quercetin Glucuronidation in Rat Small Intestine Depends on Age and Segment

    PubMed Central

    Bolling, Bradley W.; Court, Michael H.; Blumberg, Jeffrey B.

    2011-01-01

    UDP-glucuronosyltransferase (UGT) activity toward the flavonoid quercetin and UGT protein were characterized in three equidistant small intestine (SI) segments from 4-, 12-, 18-, and 28-month-old male Fischer 344 rats (n = 8/age) using villin to control for enterocyte content. SI microsomal intrinsic clearance of quercetin was increased 3- to 9-fold from 4 months in the proximal and distal SI at 12 and 18 months. Likewise, at 30 μM quercetin, SI microsomal glucuronidation activity was increased with age: 4.8- and 3.9-fold greater at 18 months than at 4 months. Quercetin UGT regioselectivity was not changed by age. The distal SI preferentially catalyzed glucuronidation at the 7-position, whereas the proximal SI produced the greatest proportion of 4′- and 3′-conjugates. Enterocyte UGT content in different SI segments was not consistently changed with age. In the proximal SI, UGT1A increased 64 and 150% at 12 and 18 months and UGT1A1, UGT1A7, and UGT1A8 were also increased at 12 and 18 months. However, age-related changes in expression were inconsistent in the medial and distal segments. Microsomal rates of quercetin glucuronidation and UGT expression were positively correlated with UGT1A1 content for all pooled samples (r = 0.467) and at each age (r = 0.538–0.598). UGT1A7 was positively correlated with total, 7-O- and 3-O-quercetin glucuronidation at 18 months. Thus, age-related differences in UGT quercetin glucuronidation depend on intestinal segment, are more pronounced in the proximal and distal segments and may be partially related to UGT1A1 and UGT1A7 content. PMID:21543555

  4. UDP-glucuronosyltransferase (UGT) 1A1 mainly contributes to the glucuronidation of trovafloxacin.

    PubMed

    Fujiwara, Ryoichi; Sumida, Kyohei; Kutsuno, Yuki; Sakamoto, Masaya; Itoh, Tomoo

    2015-02-01

    Identification of drug-metabolizing enzyme(s) responsible for the metabolism of drugs is an important step to understand not only interindividual variability in pharmacokinetics but also molecular mechanisms of metabolite-related toxicity. While it was reported that the major metabolic pathway of trovafloxacin, which is an antibiotic, was glucuronidation, the UDP-glucuronosyltransferase (UGT) isoform(s) responsible for the trovafloxacin glucuronidation has not been identified yet. In the present study, among the functional human UGT members, UGT1A1, UGT1A3, and UGT1A9 exhibited higher trovafloxacin acyl-glucuronidation activities. While other UGT members such as UGT1A8, UGT2B7, and UGT2B15 showed glucuronidation activity toward trovafloxacin, the metabolic velocity was extremely low. In human liver microsomes, trovafloxacin acyl-glucuronidation followed the Hill equation with S50 value of 95 μM, Vmax value of 243 pmol/min per mg, and a Hill coefficient of 2.0, while the UGT1A1-expressing system displayed Michaelis-Menten kinetics with a substrate inhibition, with Km value of 759 μM and Vmax value of 1160 pmol/min per mg. In human liver microsomes prepared from poor metabolizers (UGT1A1*28/*28), significantly reduced trovafloxacin acyl-glucuronide formation activity was observed, indicating that UGT1A1 mainly, while other UGT members such as UGT1A3 and UGT1A9 partially, contributes to the glucuronidation of trovafloxacin. PMID:25760534

  5. UDP-glucuronosyltransferase expression in mouse liver is increased in obesity- and fasting-induced steatosis.

    PubMed

    Xu, Jialin; Kulkarni, Supriya R; Li, Liya; Slitt, Angela L

    2012-02-01

    UDP-glucuronosyltransferases (Ugt) catalyze phase II conjugation reactions with glucuronic acid, which enhances chemical polarity and the elimination from the body. Few studies have addressed whether Ugt expression and activity are affected by liver disease, such as steatosis. The purpose of this study was to determine whether steatosis induced by obesity or fasting could affect liver Ugt mRNA expression and activity. Male C57BL/6J and Lep(ob/ob) (ob/ob) mice were fed ad libitum or food was withheld for 24 h. In steatotic livers of ob/ob mice, Ugt1a1, -1a6, -1a9, -2a3, -3a1, and -3a2 mRNA expression increased. Fasting, which also induced steatosis, increased hepatic Ugt1a1, -1a6, -1a7, -1a9, -2b1, -2b5, -2a3, -3a1, and -3a2 mRNA expression in mouse liver. Likewise, acetaminophen glucuronidation increased by 47% in hepatic microsomes from ob/ob mice compared with that in C57BL/6J mice, but not after fasting. In both steatosis models, Ugt induction was accompanied by increased aryl hydrocarbon receptor, constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPAR)-α, pregnane X receptor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and peroxisome proliferator-activated receptor-γ coactivator-1α mRNA expression. In addition, fasting increased CAR, PPAR, and Nrf2 binding activity. The work points to hepatic triglyceride concentrations corresponding with nuclear receptor and Ugt expression. The findings indicate that steatosis significantly alters hepatic Ugt expression and activity, which could have a significant impact on determining circulating hormone levels, drug efficacy, and environmental chemical clearance. PMID:22031624

  6. Differences in the Glucuronidation of Resveratrol and Pterostilbene: Altered Enzyme Specificity and Potential Gender Differences

    PubMed Central

    Dellinger, Ryan W.; Gomez Garcia, Angela M.; Meyskens, Frank L.

    2015-01-01

    Summary Resveratrol, a natural polyphenol found in grapes, berries and other plants, has been proposed as an ideal chemopreventative agent due to its plethora of health promoting activities. However, despite its lofty promise as a cancer prevention agent its success in human clinical trials has been limited due to its poor bioavailability. Thus, interest in other natural polyphenols is intensifying including the naturally occurring dimethylated analog of resveratrol, pterostilbene. The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the metabolism of both resveratrol and pterostilbene. The current study sought to elucidate the UGT family members responsible for the metabolism of pterostilbene and to examine gender differences in the glucuronidation of resveratrol and pterostilbene. We demonstrate that UGT1A1 and UGT1A3 are mainly responsible for pterostilbene glucuronidation although UGT1A8, UGT1A9 and UGT1A10 also had detectable activity. Intriguingly, UGT1A1 exhibits the highest activity against both resveratrol and pterostilbene despite altered hydroxyl group specificity. Using pooled human liver microsomes, enzyme kinetics were determined for pterostilbene and resveratrol glucuronides. In all cases females were more efficient than males, indicating potential gender differences in stilbene metabolism. Importantly, the glucuronidation of pterostilbene is much less efficient than that of resveratrol, indicating that pterostilbene will have dramatically decreased metabolism in humans. PMID:23965644

  7. Metabolic fate of desomorphine elucidated using rat urine, pooled human liver preparations, and human hepatocyte cultures as well as its detectability using standard urine screening approaches.

    PubMed

    Richter, Lilian H J; Kaminski, Yeda Rumi; Noor, Fozia; Meyer, Markus R; Maurer, Hans H

    2016-09-01

    Desomorphine is an opioid misused as "crocodile", a cheaper alternative to heroin. It is a crude synthesis product homemade from codeine with toxic byproducts. The aim of the present work was to investigate the metabolic fate of desomorphine in vivo using rat urine and in vitro using pooled human liver microsomes and cytosol as well as human liver cell lines (HepG2 and HepaRG) by Orbitrap-based liquid chromatography-high resolution-tandem mass spectrometry or hydrophilic interaction liquid chromatography. According to the identified metabolites, the following metabolic steps could be proposed: N-demethylation, hydroxylation at various positions, N-oxidation, glucuronidation, and sulfation. The cytochrome P450 (CYP) initial activity screening revealed CYP3A4 to be the only CYP involved in all phase I steps. UDP-glucuronyltransferase (UGT) initial activity screening showed that UGT1A1, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, and UGT2B17 formed desomorphine glucuronide. Among the tested in vitro models, HepaRG cells were identified to be the most suitable tool for prediction of human hepatic phase I and II metabolism of drugs of abuse. Finally, desomorphine (crocodile) consumption should be detectable by all standard urine screening approaches mainly via the parent compound and/or its glucuronide assuming similar kinetics in rats and humans. PMID:27372715

  8. Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-Null Mice

    PubMed Central

    Aleksunes, Lauren M.

    2012-01-01

    The transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor α (PPARα), and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate genes encoding drug-metabolizing enzymes and transporters in livers of mice after chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drug-metabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor-null mice. Chemical activators were administered intraperitoneally to mice once daily for 4 days. Livers were collected 24 h after the final dose, and total RNA was isolated for mRNA quantification of cytochromes P450, NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion-transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35, Sult5a1, Gstm3, and Mrp4), CAR (Cyp2b10, Aldh1a1, Aldh1a7, Ugt1a1, Ugt2b34, Sult1e1, Sult3a1, Sult5a1, Papps2, Gstt1, Gsta1, Gsta4, Gstm1–4, and Mrp2–4), PXR (Cyp3a11, Ugt1a1, Ugt1a5, Ugt1a9, Gsta1, Gstm1–m3, Oatp1a4, and Mrp3), PPARα (Cyp4a14, Aldh1a1, mGst3, Gstm4, and Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, Gsta4, Gstm1–m4, mGst3, and Mrp3–4). Taken together, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase I, phase II, and transport genes by

  9. Biotransformation of Bisphenol AF to Its Major Glucuronide Metabolite Reduces Estrogenic Activity

    PubMed Central

    Yin, Jie; Zhang, Jing; Feng, Yixing; Shao, Bing

    2013-01-01

    Bisphenol AF (BPAF), an endocrine disrupting chemical, can induce estrogenic activity through binding to estrogen receptor (ER). However, the metabolism of BPAF in vivo and the estrogenic activity of its metabolites remain unknown. In the present study, we identified four metabolites including BPAF diglucuronide, BPAF glucuronide (BPAF-G), BPAF glucuronide dehydrated and BPAF sulfate in the urine of Sprague-Dawley (SD) rats. BPAF-G was further characterized by nuclear magnetic resonance (NMR). After treatment with a single dose of BPAF, BPAF was metabolized rapidly to BPAF-G, as detected in the plasma of SD rats. Biotransformation of BPAF to BPAF-G was confirmed with human liver microsomes (HLM), and Vmax of glucuronidation for HLM was 11.6 nmol/min/mg. We also found that BPAF glucuronidation could be mediated through several human recombinant UDP-glucuronosyltransferases (UGTs) including UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, among which UGT2B7 showed the highest efficiency of glucuronidation. To explain the biological function of BPAF biotransformation, the estrogenic activities of BPAF and BPAF-G were evaluated in ER-positive breast cancer T47D and MCF7 cells. BPAF significantly stimulates ER-regulated gene expression and cell proliferation at the dose of 100 nM and 1 μM in breast cancer cells. However, BPAF-G did not show any induction of estrogenic activity at the same dosages, implying that formation of BPAF-G is a potential host defense mechanism against BPAF. Based on our study, biotransformation of BPAF to BPAF-G can eliminate BPAF-induced estrogenic activity, which is therefore considered as reducing the potential threat to human beings. PMID:24349450

  10. Biotransformation of bisphenol AF to its major glucuronide metabolite reduces estrogenic activity.

    PubMed

    Li, Ming; Yang, Yunjia; Yang, Yi; Yin, Jie; Zhang, Jing; Feng, Yixing; Shao, Bing

    2013-01-01

    Bisphenol AF (BPAF), an endocrine disrupting chemical, can induce estrogenic activity through binding to estrogen receptor (ER). However, the metabolism of BPAF in vivo and the estrogenic activity of its metabolites remain unknown. In the present study, we identified four metabolites including BPAF diglucuronide, BPAF glucuronide (BPAF-G), BPAF glucuronide dehydrated and BPAF sulfate in the urine of Sprague-Dawley (SD) rats. BPAF-G was further characterized by nuclear magnetic resonance (NMR). After treatment with a single dose of BPAF, BPAF was metabolized rapidly to BPAF-G, as detected in the plasma of SD rats. Biotransformation of BPAF to BPAF-G was confirmed with human liver microsomes (HLM), and Vmax of glucuronidation for HLM was 11.6 nmol/min/mg. We also found that BPAF glucuronidation could be mediated through several human recombinant UDP-glucuronosyltransferases (UGTs) including UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, among which UGT2B7 showed the highest efficiency of glucuronidation. To explain the biological function of BPAF biotransformation, the estrogenic activities of BPAF and BPAF-G were evaluated in ER-positive breast cancer T47D and MCF7 cells. BPAF significantly stimulates ER-regulated gene expression and cell proliferation at the dose of 100 nM and 1 μM in breast cancer cells. However, BPAF-G did not show any induction of estrogenic activity at the same dosages, implying that formation of BPAF-G is a potential host defense mechanism against BPAF. Based on our study, biotransformation of BPAF to BPAF-G can eliminate BPAF-induced estrogenic activity, which is therefore considered as reducing the potential threat to human beings. PMID:24349450

  11. A pilot study of leukocyte expression patterns for drug metabolizing enzyme and transporter transcripts in autoimmune glomerulonephritis

    PubMed Central

    Joy, Melanie S.; Roberts, Brittney V.; Wang, Jinzhao; Hu, Yichun; Hogan, Susan L.; Falk, Ronald J.

    2014-01-01

    Objective: Leukocyte mRNA expression patterns of drug metabolizing enzyme genes and transporter genes that are relevant for the disposition of cyclophosphamide and mycophenolate were studied. The relationships between expression and patient-level data and pharmacokinetics were evaluated. Methods: The study included patients with glomerulonephritis secondary to lupus nephritis (SLE, n = 36), small vessel vasculitis (SVV, n = 35), healthy controls (HC, n = 10), and disease controls (VC, n = 5; LC, n = 5). Transcript assays targeted metabolizing enzymes (UGT1A7, UGT1A9, UGT2B7, CYP3A4, CYP2C9, CYP2B6) and transporters (ABCB1, ABCC2, ABCG2, SLCO1A2). Genotyping for specific variants was conducted. Group transcript fold-changes were evaluated. Patient level data was evaluated for transcript fold-change and disease, treatment, gender, race, and genotype. Results: Significant differences were noted in expression of UGT1A7, ABCB1, and ABCC2; for UGT1A7, SVV (0.17 ± 0.42; p < 0.05) and SLE (0.03 ± 0.1; p < 0.05) groups had lower expression than HC (0.79 ± 2.02). For ABCB1, SLE had a lower expression (0.33 ± 0.21; p < 0.05) than HCs (1 ± 0.82). For ABCG2, SVV group had a lower expression (0.17 ± 0.14; p < 0.05) than HCs (1 ± 1.82). Differences in expression of ABCC2 approached statistical significance with VC patients (2.02 ± 1.13) exhibiting higher expression than SVV patients (1.06 ± 1.11; p = 0.05). The relationships between transcript expression and patient-level data demonstrated; ABCC2 expression was different by race (1.26 ± 1.82 Caucasian versus 1.37 ± 0.86 non-Caucasian; p = 0.049) and CYP2B6 expression was different by treatment (2.07 ± 2.94 cyclophosphamide versus 0.45 ± 0.5 mycophenolate; p = 0.01). Conclusions: The current study showed differential expression of drug metabolizing enzyme and transporter transcripts and contributes to the literature on transcript expression of drug transporters in

  12. Organochlorines inhibit acetaminophen glucuronidation by redirecting UDP-glucuronic acid towards the D-glucuronate pathway

    SciTech Connect

    Chan, Tom S. Wilson, John X.; Selliah, Subajini; Bilodeau, Marc; Zwingmann, Claudia; Poon, Raymond; O'Brien, Peter J.

    2008-11-01

    Industry-derived organochlorines are persistent environmental pollutants that are a continuing health concern. The effects of these compounds on drug metabolism are not well understood. In the current study we present evidence that the inhibition of acetaminophen (APAP) glucuronidation by minute concentrations of organochlorines correlates well with their ability to stimulate the D-glucuronate pathway leading to ascorbate synthesis. A set of 6 arylated organochlorines, including 5 PCB (polychlorinated biphenyl) congeners, were assessed for their effects on APAP glucuronidation in isolated hepatocytes from male Sprague-Dawley rats. The capacity of each organochlorine to inhibit APAP glucuronidation was found to be directly proportional to its capacity to stimulate ascorbate synthesis. PCB153, PCB28 and bis-(4-chlorophenyl sulfone) (BCPS) in increasing order were the most effective organochlorines for inhibiting APAP glucuronidation and stimulating the D-glucuronate pathway. None of the 3 inhibitors of APAP glucuronidation were able to alter the expression of UGT1A6, UGT1A7 and UGT1A8 (the major isoforms responsible for APAP glucuronidation in the rat), however, their efficacy at inhibiting APAP glucuronidation was proportional to their capacity to deplete UDP-glucuronic acid (UDPGA). BCPS-mediated inhibition of APAP glucuronidation in isolated hepatocytes had non-competitive characteristics and was insensitive to the inactivation of cytochrome P450. The effective organochlorines were also able to selectively stimulate the hydrolysis of UDPGA to UDP and glucuronate in isolated microsomes, but could not inhibit APAP glucuronidation in microsomes when UDPGA was in excess. We conclude that organochlorines are able to inhibit APAP glucuronidation in hepatocytes by depleting UDPGA via redirecting UDPGA towards the D-glucuronate pathway. Because the inhibition is non-competitive, low concentrations of these compounds could have long term inhibitory effects on the

  13. Extending framework based on the linear coordination polymers: Alternative chains containing lanthanum ion and acrylic acid ligand

    SciTech Connect

    Li Hui . E-mail: lihui@bit.edu.cn; Guo Ming; Tian Hong; He Feiyue; Lee, G.-H.; Peng, S.-M.

    2006-11-15

    One-dimensional alternative chains of two lanthanum complexes: [La(L{sup 1}){sub 3}(CH{sub 3}OH)(H{sub 2}O){sub 2}].5H{sub 2}O (L{sup 1}=anion of {alpha}-cyano-4-hydroxycinnamic acid ) 1 and [La(L{sup 2}){sub 3}(H{sub 2}O){sub 2}].3H{sub 2}O (L{sup 2}=anion of trans-3-(4-methyl-benzoyl)-acrylic acid) 2 were synthesized and structurally characterized by single-crystal X-ray diffraction, element analysis, IR and thermogravimetric analysis. The crystal structure data are as follows for 1: C{sub 31}H{sub 36}LaN{sub 3}O{sub 17}, triclinic, P-1, a=9.8279(4)A, b=11.8278(5)A, c=17.8730(7)A, {alpha}=72.7960(10){sup o}, {beta}=83.3820(10){sup o}, {gamma}=67.1650(10)-bar , Z=2, R{sub 1}=0.0377, wR{sub 2}=0.0746; for 2: C{sub 33}H{sub 37}LaO{sub 14}, triclinic, P-1, a=8.7174(5)A, b=9.9377(5)A, c=21.153(2)A, {alpha}=81.145(2){sup o}, {beta}=87.591(2){sup o}, {gamma}=67.345(5){sup o}, Z=2, R{sub 1}=0.0869, wR{sub 2}=0.220. 1 is a rare example of the alternative chain constructed by syn-syn and anti-syn coordination mode of carboxylato ligand arranged along the chain alternatively. La(III) ions in 2 are linked by two {eta}{sup 3}-O bridges and four bridges (two {eta}{sup 2}-O and two {eta}{sup 3}-O) alternatively. Both of the linear coordination polymers grow into two- and three-dimensional networks by packing through extending hydrogen-bond network directed by ligands.

  14. The History of Slavs Inferred from Complete Mitochondrial Genome Sequences

    PubMed Central

    Mielnik-Sikorska, Marta; Daca, Patrycja; Malyarchuk, Boris; Derenko, Miroslava; Skonieczna, Katarzyna; Perkova, Maria; Dobosz, Tadeusz; Grzybowski, Tomasz

    2013-01-01

    To shed more light on the processes leading to crystallization of a Slavic identity, we investigated variability of complete mitochondrial genomes belonging to haplogroups H5 and H6 (63 mtDNA genomes) from the populations of Eastern and Western Slavs, including new samples of Poles, Ukrainians and Czechs presented here. Molecular dating implies formation of H5 approximately 11.5–16 thousand years ago (kya) in the areas of southern Europe. Within ancient haplogroup H6, dated at around 15–28 kya, there is a subhaplogroup H6c, which probably survived the last glaciation in Europe and has undergone expansion only 3–4 kya, together with the ancestors of some European groups, including the Slavs, because H6c has been detected in Czechs, Poles and Slovaks. Detailed analysis of complete mtDNAs allowed us to identify a number of lineages that seem specific for Central and Eastern Europe (H5a1f, H5a2, H5a1r, H5a1s, H5b4, H5e1a, H5u1, some subbranches of H5a1a and H6a1a9). Some of them could possibly be traced back to at least ∼4 kya, which indicates that some of the ancestors of today's Slavs (Poles, Czechs, Slovaks, Ukrainians and Russians) inhabited areas of Central and Eastern Europe much earlier than it was estimated on the basis of archaeological and historical data. We also sequenced entire mitochondrial genomes of several non-European lineages (A, C, D, G, L) found in contemporary populations of Poland and Ukraine. The analysis of these haplogroups confirms the presence of Siberian (C5c1, A8a1) and Ashkenazi-specific (L2a1l2a) mtDNA lineages in Slavic populations. Moreover, we were able to pinpoint some lineages which could possibly reflect the relatively recent contacts of Slavs with nomadic Altaic peoples (C4a1a, G2a, D5a2a1a1). PMID:23342138

  15. Adaptive hepatic and intestinal alterations in mice after deletion of NADPH-cytochrome P450 Oxidoreductase (Cpr) in hepatocytes.

    PubMed

    Cheng, Xingguo; Gu, Jun; Klaassen, Curtis D

    2014-11-01

    Cytochrome P450 enzymes (P450) play an important role in first-pass metabolism in both the intestine and liver. NADPH-cytochrome P450 oxidoreductase (Cpr) is an essential electron transfer protein required for microsomal P450 activity. Mice with conditional knockout of Cpr in hepatocytes develop normally and survive even with complete loss of liver microsomal P450 activity. Our current studies were performed to determine whether alternative drug-metabolizing pathways increase in an attempt to maintain whole-body homeostasis. In addition to the liver, Cpr is mainly expressed in tissues such as lung, kidney, and gastrointestinal tract. In livers of H-Cpr-null mice, there is a marked increase in mRNA expression of phase I enzymes (Aldh1a1, 1a7, 3a2; Ces1b2, 2a6, and 2a12), antioxidant enzymes (Ho-1, Nqo1, and epoxide hydrolase), phase II enzymes (Ugt1a9; Gsta1/2, m3, m4, m6, t1, and t3; and Sult1a1 and 1d1), and drug transporters (Oatp1a4, Oct3, Mate1, Mdr1a, and Mrp3 and 4). In addition, glucuronide-conjugated bilirubin concentrations are doubled in serum of H-Cpr-null mice. Both constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein in nuclei are higher in the livers of H-Cpr-null mice, indicating that CAR and Nrf2 are activated. In the small intestine of H-Cpr-null mice, mRNA expression of Cyp3a11 and Mdr1a, two genes critical for intestinal first-pass metabolism, are markedly up-regulated. In addition, nutrient (Pept1) and cholesterol (Npc1l1) transporters are induced in the small intestine of H-Cpr-null mice. In conclusion, in H-Cpr-null mice, adaptive regulation of alternative detoxification genes in liver and small intestine appear to partially compensate for the loss of microsomal P450 function in liver. PMID:25147274

  16. Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors.

    PubMed

    Li, Cindy Yanfei; Renaud, Helen J; Klaassen, Curtis D; Cui, Julia Yue

    2016-07-01

    The xenobiotic-sensing transcription factors (xeno-sensors) AhR, CAR, and PXR upregulate the expression of many drug-processing genes (DPGs) in liver. Previous studies have unveiled profound changes in the basal expression of DPGs during development; however, knowledge on the ontogeny of the inducibility of DPGs in response to pharmacological activation of xeno-sensors is still limited. The goal of this study was to investigate the age-specific regulation of DPGs by prototypical xeno-sensor ligands: 2,3,7,8-tetrachlorodibenzodioxin (TCDD) for AhR; 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) for CAR; and pregnane-16α-carbonitrile (PCN) for PXR during mouse liver development. The basal mRNAs of most DPGs were low during neonatal age, but gradually increased to adult levels, whereas some DPGs (Cyp1a2, Cyp2b10, Cyp3a11, Gstm2, Gstm3, Papss2, and Oatp1a4) exhibited an adolescent-predominant expression pattern. The inducibility of DPGs was age-specific: 1) during neonatal age, the highest fold increase in the mRNA expression was observed for Cyp1a2, Sult5a1, and Ugt1a9 by TCDD; Cyp3a11 and Mrp2 by TCPOBOP; as well as Gstm2 and Gstm3 by PCN; 2) during adolescent age, the highest fold increase in the mRNA expression was observed for Ugt1a6 and Mrp4 by TCDD, Cyp2b10, Ugt2b34, and Ugt2b35 by TCPOBOP, as well as Gsta1, Gsta4, Sult1e1, Ugt1a1, Mrp3, and Mrp4 by PCN; 3) in adults, the highest fold increase in the mRNA expression was observed for Aldh1a1, Aldh1a7, and Ugt2b36 by TCPOBOP, as well as Papss2 and Oatp1a4 by PCN. In conclusion, the inducibility of hepatic DPGs following the pharmacological activation of xeno-sensors is age specific. PMID:26577535

  17. The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyltransferase (UGT) and cytochrome p450 (CYP450) enzymes.

    PubMed

    Shi, Xianbao; Yang, Shuman; Zhang, Gang; Song, Yonggui; Su, Dan; Liu, Yali; Guo, Feng; Shan, Lina; Cai, Jiqun

    2016-05-01

    1. The aim of this study was to investigate the inhibitory effect of morusin on Glucuronosyltransferase (UGT) isoforms and cytochrome P450 enzymes (CYP450s). We also investigated the metabolism of morusin in human, rat, dog, monkey, and minipig liver microsomes. 2. 100 μM of morusin exhibited strong inhibition on all UGTs and CYP450s. The half inhibition concentration (IC50) values for CYP3A4, CYP1A2, CYP2C9, CYP2E1, UGT1A6, UGT1A7, and UGT1A8 were 2.13, 1.27, 3.18, 9.28, 4.23, 0.98, and 3.00 μM, and the inhibition kinetic parameters (Ki) were 1.34, 1.16, 2.98, 6.23, 4.09, 0.62, and 2.11 μM, respectively. 3. Metabolism of morusin exhibited significant species differences. The quantities of M1 from minipig, monkey, dog, and rat were 7.8, 11.9, 2.0, and 6.3-fold of human levels. The Km values in HLMs, RLMs, MLMs, DLMs, and PLMs were 7.84, 22.77, 14.32, 9.13, and 22.83 μM, and Vmax for these species were 0.09, 1.23, 1.43, 0.15, and 0.75 nmol/min/mg, respectively. CLint (intrinsic clearance) values (Vmax/Km) for morusin obeyed the following order: monkey > rat > minipig > dog > human. CLH (hepatic clearance) values for humans, dogs, and rats were calculated to be 8.28, 17.38, and 35.12 mL/min/kg body weight, respectively. 4. This study provided vital information to understand the inhibitory potential and metabolic behavior of morusin among various species. PMID:26372370

  18. 17 CFR 270.17e-1 - Brokerage transactions on a securities exchange.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... transactions on a securities exchange. For purposes of section 17(e)(2)(A) of the Act , a commission, fee or... the fund governance standards defined in § 270.0-1(a)(7); and (d) The investment company: (1)...

  19. 17 CFR 270.17e-1 - Brokerage transactions on a securities exchange.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... transactions on a securities exchange. For purposes of section 17(e)(2)(A) of the Act , a commission, fee or... the fund governance standards defined in § 270.0-1(a)(7); and (d) The investment company: (1)...

  20. 17 CFR 270.17e-1 - Brokerage transactions on a securities exchange.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... transactions on a securities exchange. For purposes of section 17(e)(2)(A) of the Act , a commission, fee or... the fund governance standards defined in § 270.0-1(a)(7); and (d) The investment company: (1)...

  1. 17 CFR 270.17e-1 - Brokerage transactions on a securities exchange.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... transactions on a securities exchange. For purposes of section 17(e)(2)(A) of the Act , a commission, fee or... the fund governance standards defined in § 270.0-1(a)(7); and (d) The investment company: (1)...

  2. Antifungal Activity of Wickerhamomyces anomalus and Lactobacillus plantarum during Sourdough Fermentation: Identification of Novel Compounds and Long-Term Effect during Storage of Wheat Bread ▿

    PubMed Central

    Coda, Rossana; Cassone, Angela; Rizzello, Carlo G.; Nionelli, Luana; Cardinali, Gianluigi; Gobbetti, Marco

    2011-01-01

    This study aimed at investigating the antifungal activity of Wickerhamomyces anomalus and sourdough lactic acid bacteria to extend the shelf life of wheat flour bread. The antifungal activity was assayed by agar diffusion, growth rate inhibition, and conidial germination assays, using Penicillium roqueforti DPPMAF1 as the indicator fungus. Sourdough fermented by Lactobacillus plantarum 1A7 (S1A7) and dough fermented by W. anomalus LCF1695 (D1695) were selected and characterized. The water/salt-soluble extract of S1A7 was partially purified, and several novel antifungal peptides, encrypted into sequences of Oryza sativa proteins, were identified. The water/salt-soluble extract of D1695 contained ethanol and, especially, ethyl acetate as inhibitory compounds. As shown by growth inhibition assays, both water/salt-soluble extracts had a large inhibitory spectrum, with some differences, toward the most common fungi isolated from bakeries. Bread making at a pilot plant was carried out with S1A7, D1695, or a sourdough started with a combination of both strains (S1A7-1695). Slices of the bread manufactured with S1A7-1695 did not show contamination by fungi until 28 days of storage in polyethylene bags at room temperature, a level of protection comparable to that afforded by 0.3% (wt/wt) calcium propionate. The effect of sourdough fermentation with W. anomalus LCF1695 was also assessed based on rheology and sensory properties. PMID:21441340

  3. Effect of hypoxia on UDP-glucuronosyl transferase mRNA expression in human hepatocarcinoma functional liver celL4 cell line.

    PubMed

    Kato, R; Matsura, A; Kamiya, R; Oishi, C; Kagawa, Y; Tanaka, F; Matsumoto, N; Ijiri, Y; Hayashi, T

    2016-03-01

    Although hypoxic conditions have been reported to affect the expression levels of various enzymes like cytochrome P450, the effect of hypoxia for UDP-glucuronosyl transferase (UGT) expression has been unclear. We evaluated the mRNA expression of UGTs (UGT1A1·1A6·1A9·2B7) in a functional liver cell-4 (FLC-4) cell line by three-dimensional culture under hypoxic conditions (37 °C, 1% O₂, 5% CO₂) fo 7 days. The mRNA expression of UGT1A1·1A6·1A9·2B7 decreased significantly after 3 days and that of UGT1A1·1A6·1A9 decreased significantly after 7 days. Hypoxic conditions affect the expression levels of UGT enzymes, thus the adjustment of dosage and interval should be considered in drug therapy that metabolized by UGT. PMID:27183710

  4. High School Puente Program. What Works Clearinghouse Intervention Report

    ERIC Educational Resources Information Center

    What Works Clearinghouse, 2009

    2009-01-01

    The "High School Puente Program" aims to help disadvantaged students graduate from high school, become college eligible, and enroll in four-year colleges and universities. The program consists of three components: (1) a 9th- and 10th-grade college preparatory English class that incorporates Mexican-American/Latino and other multicultural…

  5. 75 FR 59706 - Medicine Bow Hydro, LLC; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-28

    ...' express permission. The proposed project will consist of the following: (1) A 9,200- foot-circumference, 60-foot-high earth or rockfilled embankment; creating an 88-acre upper reservoir with a storage...-foot-high earth and rockfill or concrete-face rockfill dam; creating an 121-acre lower reservoir with...

  6. Photocopy of drawing located at National Archives, San Bruno California ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Photocopy of drawing located at National Archives, San Bruno California (Navy# H-1-A-9). Additions to Naval Hospital Mare Island Cal basement and first floor plan; November 25, 1909. - Mare Island Naval Shipyard, Hospital Headquarters, Johnson Lane, west side at intersection of Johnson Lane & Cossey Street, Vallejo, Solano County, CA

  7. Photocopy of drawing located at National Archives, San Bruno, California ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Photocopy of drawing located at National Archives, San Bruno, California (Navy # H-1-A-8). Additions to Naval Hospital Mare Island Cal foundations plans; 1909. - Mare Island Naval Shipyard, Hospital Headquarters, Johnson Lane, west side at intersection of Johnson Lane & Cossey Street, Vallejo, Solano County, CA

  8. 26 CFR 1.664-3 - Charitable remainder unitrust.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... sale of unmarketable assets as defined in § 1.664-1(a)(7)(ii), or the marriage, divorce, death, or birth of a child with respect to any individual will not be considered discretionary with, or within the... unitrust amount will occur as of the first day of the year following the year of the divorce. Y...

  9. 26 CFR 1.664-3 - Charitable remainder unitrust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... sale of unmarketable assets as defined in § 1.664-1(a)(7)(ii), or the marriage, divorce, death, or... unitrust amount will occur as of the first day of the year following the year of the divorce. Y provides... father dies. Y provides for a combination of methods that satisfies paragraph (a)(1)(i)(c) of...

  10. In vitro glucuronidation of the primary metabolite of 10-chloromethyl-11-demethyl-12-oxo-calanolide A by human liver microsomes and its interactions with UDP-glucuronosyltransferase substrates.

    PubMed

    Liu, Xin; Sheng, Li; Zhao, Manman; Mi, Jiaqi; Liu, Zhihao; Li, Yan

    2015-02-01

    F18 (10-chloromethyl-11-demethyl-12-oxo-calanolide), an analog of (+)-Calanolide A, is a novel small-molecule nonnucleoside reverse transcriptase inhibitor for the therapy of human immunodeficiency virus (HIV) infection. M3, the most abundant primary metabolite of F18 in human liver microsomes (HLMs) and rat liver microsomes (RLMs), is mainly excreted in bile as a glucuronide conjugate in rats after oral administration. The aim of this study was to identify the UDP glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of M3 by HLMs and recombinant human UGTs and investigate the metabolic interactions of M3 with the substrates of UGTs in HLMs. As a result, UGT1A1 was the major isozyme responsible for the glucuronidation of M3, followed by UGT1A4, UGT1A9 and UGT2B7. M3 exhibited significant inhibition against UGT1A9 and UGT2B7 in both HLMs and recombinant human UGTs. In addition, M3 inhibited UGT1A9 catalyzed mycophenolic acid (MPA) glucuronidation with Ki of 0.39 μM, and M3 also inhibited the glucuronidation of 3'-azido-3'-deoxythymidine (AZT) by a "mixed-type" mechanism with Ki of 16.8 μM. The results suggest that UGT1A1 provides the major contribution to M3 glucuronidation in vitro and M3 has the potential to interact with xenobiotics and endogenous chemicals that are UGT1A9 and UGT 2B7 substrates. PMID:25760535

  11. 16 CFR 1611.2 - General description of products covered.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... sections 2 and 4 of the Flammable Fabrics Act of 1953, as amended in 1954, set out at 16 CFR part 1609 for... at §§ 1611.31(i) and 1611.33(b) (formerly 16 CFR 302.1(a)(9) and 302.3(b)). ... REGULATIONS STANDARD FOR THE FLAMMABILITY OF VINYL PLASTIC FILM The Standard § 1611.2 General description...

  12. 16 CFR 1611.2 - General description of products covered.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... sections 2 and 4 of the Flammable Fabrics Act of 1953, as amended in 1954, set out at 16 CFR part 1609 for... at §§ 1611.31(i) and 1611.33(b) (formerly 16 CFR 302.1(a)(9) and 302.3(b)). ... REGULATIONS STANDARD FOR THE FLAMMABILITY OF VINYL PLASTIC FILM The Standard § 1611.2 General description...

  13. 16 CFR 1611.2 - General description of products covered.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... sections 2 and 4 of the Flammable Fabrics Act of 1953, as amended in 1954, set out at 16 CFR part 1609 for... at §§ 1611.31(i) and 1611.33(b) (formerly 16 CFR 302.1(a)(9) and 302.3(b)). ... REGULATIONS STANDARD FOR THE FLAMMABILITY OF VINYL PLASTIC FILM The Standard § 1611.2 General description...

  14. 16 CFR 1611.2 - General description of products covered.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... sections 2 and 4 of the Flammable Fabrics Act of 1953, as amended in 1954, set out at 16 CFR part 1609 for... at §§ 1611.31(i) and 1611.33(b) (formerly 16 CFR 302.1(a)(9) and 302.3(b)). ... REGULATIONS STANDARD FOR THE FLAMMABILITY OF VINYL PLASTIC FILM The Standard § 1611.2 General description...

  15. The expression of the Sprouty 1 protein inversely correlates with growth, proliferation, migration and invasion of ovarian cancer cells

    PubMed Central

    2014-01-01

    Background Our recent study on a panel of human ovarian cancer cells revealed that SKOV-3 cells barely express the Sprouty isoform 1 (Spry1) while 1A9 cells maintain it at a level similar to normal ovarian cells. Here we investigated the functional outcomes of induced alterations in the expression of Spry1 in the two cell lines in vitro. Methods Using the Spry1 specific plasmid and siRNA, the expression of Spry1 was induced and conversely silenced in SKOV-3 and 1A9 cells, respectively. The functional outcome was investigated by means of proliferation, MTT, scratch-wound, migration and invasion assays and selection of the stable clones. Mechanism of the effect was explored by Western blot. Results In the Spry1-transfected SKOV-3 cells, a significant reduction in growth and proliferation was evident. Stable clones of the Spry1-transfected SKOV-3 were almost undetectable after day 14. The number of migrated and invaded cells and the percentage of the scratch closure were significantly lower in the Spry1-transfected group. Spry1 silencing in 1A9 cells, on the other hand, led to a significant increase in cell growth and proliferation. The number of migrated and invaded cells and the percentage of the scratch closure significantly increased in Spry1-silenced 1A9 group. Mechanistically, overexpression of Bax, activation of caspases 3, 7, 8 and 9, cleavage of PARP and attenuation of Bcl-2 and Bcl-xl were observed along with reduced activation of Erk and Akt and increased amount and activity of PTEN in the Spry1-transfected SKOV-3 cells. Conclusions Here, we report the inverse correlation between the expression of Spry1 and growth, proliferation, invasion and migration of ovarian cancer cells. PMID:24932220

  16. 16 CFR 1611.2 - General description of products covered.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... sections 2 and 4 of the Flammable Fabrics Act of 1953, as amended in 1954, set out at 16 CFR part 1609 for... at §§ 1611.31(i) and 1611.33(b) (formerly 16 CFR 302.1(a)(9) and 302.3(b)). ... REGULATIONS STANDARD FOR THE FLAMMABILITY OF VINYL PLASTIC FILM The Standard § 1611.2 General description...

  17. Neutropenia exacerbates infection by Acinetobacter baumannii clinical isolates in a murine wound model

    PubMed Central

    Grguric-Smith, Laryssa M.; Lee, Hiu H.; Gandhi, Jay A.; Brennan, Melissa B.; DeLeon-Rodriguez, Carlos M.; Coelho, Carolina; Han, George; Martinez, Luis R.

    2015-01-01

    The Gram negative coccobacillus Acinetobacter baumannii has become an increasingly prevalent cause of hospital-acquired infections in recent years. The majority of clinical A. baumannii isolates display high-level resistance to antimicrobials, which severely compromises our capacity to care for patients with A. baumannii disease. Neutrophils are of major importance in the host defense against microbial infections. However, the contribution of these cells of innate immunity in host resistance to cutaneous A. baumannii infection has not been directly investigated. Hence, we hypothesized that depletion of neutrophils increases severity of bacterial disease in an experimental A. baumannii murine wound model. In this study, the Ly-6G-specific monoclonal antibody (mAb), 1A8, was used to generate neutropenic mice and the pathogenesis of several A. baumannii clinical isolates on wounded cutaneous tissue was investigated. We demonstrated that neutrophil depletion enhances bacterial burden using colony forming unit determinations. Also, mAb 1A8 reduces global measurements of wound healing in A. baumannii-infected animals. Interestingly, histological analysis of cutaneous tissue excised from A. baumannii-infected animals treated with mAb 1A8 displays enhanced collagen deposition. Furthermore, neutropenia and A. baumannii infection alter pro-inflammatory cytokine release leading to severe microbial disease. Our findings provide a better understanding of the impact of these innate immune cells in controlling A. baumannii skin infections. PMID:26528277

  18. Autoimmunity in type 1 diabetes mellitus: a rat model

    SciTech Connect

    Liu, Z.

    1987-01-01

    In this study, we have sought to isolate in vitro, from acutely diabetic BB rats, cytotoxic T lymphocytes, which exhibit specific cytotoxicity toward islet cells. Thoracic duct lymphocytes (TDL) from acutely diabetic BB rats cultured with irradiated MHC matched (RT1.u) islet cells and dendritic cells in vitro were shown to be specifically cytotoxic to MHC matched and mismatched allogeneic (RT1.1) and xenogeneic (hamster) islet target cells in a /sup 3/H-leucine release assay. Two cell lines (V1A8 and V1D11) derived from the TDL culture showed similar patterns of non-MHC restricted islet cell killing which could be blocked by islet cells and cultured rat insulinoma cells (RIN5mF) but not by non-islet cells of various tissue origins. Both V1A8 and V1D11 were not cytotoxic to Natural Killer (NK) sensitive target cells, G1TC and YAC-1. Conventional surface markers for rat helper and suppressor/cytotoxic T cells were not detectable on either cell lines. The V1D11 cell line was positive for W 3/13 (rat T/NK marker) on OX-19 (rat T/macrophage marker), whereas the V1A8 cell line was only positive for W 3/13.

  19. 39 CFR 320.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Definitions. 320.1 Section 320.1 Postal Service UNITED STATES POSTAL SERVICE RESTRICTIONS ON PRIVATE CARRIAGE OF LETTERS SUSPENSION OF THE PRIVATE EXPRESS STATUTES § 320.1 Definitions. The definitions in § 310.1 apply to part 320 as well. 1 1 Several of the items enumerated in § 310.1(a)(7) do...

  20. Hepatic UDP-glucuronosyltransferase is responsible for eslicarbazepine glucuronidation.

    PubMed

    Loureiro, Ana I; Fernandes-Lopes, Carlos; Bonifácio, Maria J; Wright, Lyndon C; Soares-da-Silva, Patricio

    2011-09-01

    Eslicarbazepine acetate (ESL) is a once-daily novel antiepileptic drug approved in Europe for use as adjunctive therapy for refractory partial-onset seizures with or without secondary generalization. Metabolism of ESL consists primarily of hydrolysis to eslicarbazepine, which is then subject to glucuronidation followed by renal excretion. In this study, we have identified that human liver microsomes (HLM) enriched with uridine 5'-diphosphoglucuronic acid give origin to a single Escherichia coli β-glucuronidase-sensitive eslicarbazepine glucuronide (most likely the O-glucuronide). The kinetics of eslicarbazepine glucuronidation in HLM was investigated in the presence and absence of bovine serum albumin (BSA). The apparent K(m) were 412.2 ± 63.8 and 349.7 ± 74.3 μM in the presence and absence of BSA, respectively. Incubations with recombinant human UDP glucuronosyltransferases (UGTs) indicated that UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 appear to be involved in eslicarbazepine conjugation. The UGT with the highest affinity for conjugation was UGT2B4 (K(m) = 157.0 ± 31.2 and 28.7 ± 10.1 μM, in the absence and presence of BSA, respectively). There was a significant correlation between eslicarbazepine glucuronidation and trifluoperazine glucuronidation, a typical UGT1A4 substrate; however, no correlation was found with typical substrates for UGT1A1 and UGT1A9. Diclofenac inhibited eslicarbazepine glucuronidation in HLM with an IC(50) value of 17 μM. In conclusion, glucuronidation of eslicarbazepine results from the contribution of UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, but the high-affinity component of the UGT2B4 isozyme may play a major role at therapeutic plasma concentrations of unbound eslicarbazepine. PMID:21673130

  1. Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response.

    PubMed

    Cesca, Marta; Morosi, Lavinia; Berndt, Alexander; Fuso Nerini, Ilaria; Frapolli, Roberta; Richter, Petra; Decio, Alessandra; Dirsch, Olaf; Micotti, Edoardo; Giordano, Silvia; D'Incalci, Maurizio; Davoli, Enrico; Zucchetti, Massimo; Giavazzi, Raffaella

    2016-01-01

    The antitumor activity of angiogenesis inhibitors is reinforced in combination with chemotherapy. It is debated whether this potentiation is related to a better drug delivery to the tumor due to the antiangiogenic effects on tumor vessel phenotype and functionality. We addressed this question by combining bevacizumab with paclitaxel on A2780-1A9 ovarian carcinoma and HT-29 colon carcinoma transplanted ectopically in the subcutis of nude mice and on A2780-1A9 and IGROV1 ovarian carcinoma transplanted orthotopically in the bursa of the mouse ovary. Paclitaxel concentrations together with its distribution by MALDI mass spectrometry imaging (MALDI MSI) were measured to determine the drug in different areas of the tumor, which was immunostained to depict vessel morphology and tumor proliferation. Bevacizumab modified the vessel bed, assessed by CD31 staining and dynamic contrast enhanced MRI (DCE-MRI), and potentiated the antitumor activity of paclitaxel in all the models. Although tumor paclitaxel concentrations were lower after bevacizumab, the drug distributed more homogeneously, particularly in vascularized, non-necrotic areas, and was cleared more slowly than controls. This happened specifically in tumor tissue, as there was no change in paclitaxel pharmacokinetics or drug distribution in normal tissues. In addition, the drug concentration and distribution were not influenced by the site of tumor growth, as A2780-1A9 and IGROV1 growing in the ovary gave results similar to the tumor growing subcutaneously. We suggest that the changes in the tumor microenvironment architecture induced by bevacizumab, together with the better distribution of paclitaxel, may explain the significant antitumor potentiation by the combination. PMID:26494857

  2. Early Sorafenib-Induced Toxicity Is Associated with Drug Exposure and UGTIA9 Genetic Polymorphism in Patients with Solid Tumors: A Preliminary Study

    PubMed Central

    Golmard, Jean Louis; Thomas-Schoemann, Audrey; Mir, Olivier; Taieb, Fabrice; Durand, Jean-Philippe; Coriat, Romain; Dauphin, Alain; Vidal, Michel; Tod, Michel; Loriot, Marie-Anne; Goldwasser, François; Blanchet, Benoit

    2012-01-01

    Background Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. Methods Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. Results Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUCcum) was independently associated with any grade ≥3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥2 diarrhea (p = 0.015) and female gender with grade ≥2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUCcum value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥3 toxicity (p = 0.018). Conclusion In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results. PMID:22912756

  3. Resistance of novel mouse strains different in MHC class I and the NKC domain to the development of experimental tumors.

    PubMed

    Fišerová, Anna; Richter, Jan; Čapková, Katarína; Bieblová, Jana; Mikyšková, Romana; Reiniš, Milan; Indrová, Marie

    2016-08-01

    To elucidate the immunological mechanisms critical for tumor progression, we bred novel mouse strains, different in the NKC and H-2D domains. We used inbreeding to generate hybrids of Balb/c and C57BL/6 of stable H-2Db+d-NK1.1neg and H-2Db-d+NK1.1high phenotypes. We analyzed the growth of three established MHC class I-deficient tumor cell lines: TC-1/A9 tumor (HPV-associated) and B16F10 melanoma, both syngeneic to C57BL/6, and the MCB8 (3-methycholanthrene-induced tumor) syngeneic to Balb/c. Furthermore, we induced colorectal carcinoma by azoxymethane-DSS treatment to test the susceptibility to chemically-induced primary cancer. We found that the novel strains spontaneously regressed the tumor transplants syngeneic to both Balb/c (MCB8) and C57BL/6 (B16F10 and TC-1/A9) mice. The H2-Db+d-NK1.1neg, but not the H2-Db-d+NK1.1high strain was also highly resistant to chemically-induced colorectal cancer in comparison to the parental mice. The immune changes during TC-1/A9 cancer development involved an increase of the NK cell distribution in the peripheral blood and spleen along with higher expression of NKG2D activation antigen; this was in correlation with the time-dependent rise of cytotoxic activity in comparison to C57BL/6 mice. The TC-1/A9 cancer regression was accompanied by higher proportion of B cells in the spleen and B220+/CD86+ activated antigen-presenting B cells distributed in the lymphoid organs, as well as in the periphery. The changes in the T-cell population were represented mainly by the prevalence of T helper cells reflected by grown CD4/CD8 ratio, most prominent in the b+d-NK1.1neg strain. The results of the present study imply usefulness of the two novel mouse strains as an experimental model for further studies of tumor resistance mechanisms. PMID:27279019

  4. In vitro assay of six UDP-glucuronosyltransferase isoforms in human liver microsomes, using cocktails of probe substrates and liquid chromatography-tandem mass spectrometry.

    PubMed

    Seo, Kyung-Ah; Kim, Hyo-Ji; Jeong, Eun Sook; Abdalla, Nagi; Choi, Chang-Soo; Kim, Dong-Hyun; Shin, Jae-Gook

    2014-11-01

    UDP-glucuronosyltransferase (UGT)-mediated drug-drug interactions are commonly evaluated during drug development. We present a validated method for the simultaneous evaluation of drug-mediated inhibition of six major UGT isoforms, developed in human liver microsomes through the use of pooled specific UGT probe substrates (cocktail assay) and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The six probe substrates used in this assay were estradiol (UGT1A1), chenodeoxycholic acid (UGT1A3), trifluoperazine (UGT1A4), 4-hydroxyindole (UGT1A6), propofol (UGT1A9), and naloxone (UGT2B7). In a cocktail incubation, UGT1A1, UGT1A9, and UGT2B7 activities were substantially inhibited by other substrates. This interference could be eliminated by dividing substrates into two incubations: one containing estradiol, trifluoperazine, and 4-hydroxyindole, and the other containing chenodeoxycholic acid, propofol, and naloxone. Incubation mixtures were pooled for the simultaneous analysis of glucuronyl conjugates in a single LC-MS/MS run. The optimized cocktail method was further validated against single-probe substrate assays using compounds known to inhibit UGTs. The degree of inhibition of UGT isoform activities by such known inhibitors in this cocktail assay was not substantially different from that in single-probe assays. This six-isoform cocktail assay may be very useful in assessing the UGT-based drug-interaction potential of candidates in a drug-discovery setting. PMID:25122565

  5. Population pharmacokinetic analysis of sorafenib in patients with solid tumours

    PubMed Central

    Jain, Lokesh; Woo, Sukyung; Gardner, Erin R; Dahut, William L; Kohn, Elise C; Kummar, Shivaani; Mould, Diane R; Giaccone, Giuseppe; Yarchoan, Robert; Venitz, Jürgen; Figg, William D

    2011-01-01

    AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h−1 (3.6–22.3 l h−1), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified. PMID:21392074

  6. Comparison of inhibition capability of scutellarein and scutellarin towards important liver UDP-glucuronosyltransferase (UGT) isoforms.

    PubMed

    Ma, Guang-You; Cao, Yun-Feng; Hu, Cui-Min; Fang, Zhong-Ze; Sun, Xiao-Yu; Hong, Mo; Zhu, Zhi-Tu

    2014-03-01

    Scutellarin is an important bioactive flavonoid extracted from Erigeron breviscapus (Vant.) Hand-Mazz, and scutellarein is the corresponding aglycone of scutellarin. The present study aims to compare the inhibition potential of scutellarin and scutellarein towards several important UDP-glucuronosyltransferase (UGT) isoforms, including UGT1A1, UGT1A6, UGT1A9 and UGT2B7. It was demonstrated that scutellarein exerted stronger inhibition towards the tested UGT isoforms than scutellarin. Furthermore, the inhibition kinetic type and parameters (Ki ) were determined for the scutellarein's inhibition towards these UGT isoforms. Competitive inhibition of scutellarein towards all these UGT isoforms was demonstrated, and the Ki values were calculated to be 0.02, 5.0, 5.8 and 35.9 μM for UGT1A1, 1A6, 1A9 and 2B7, respectively. Using in vivo maximum plasma concentration of scutellarein in rat, the in vitro-in vivo extrapolation was performed to predict in vivo situation, indicating the most possible in vivo adverse effects due to the inhibition of scutellarein towards UGT1A1. All these results remind us to monitor the utilization of scutellarin and scutellarein, and the herbs containing these two components. PMID:23620377

  7. In vitro alkylating of alpha, beta-unsaturated amidoesters, diethyl pyridylmethylphosphonates and their cis-Pt(II)complexes.

    PubMed

    Najman-Bronzewska, L; Ochocki, J

    1997-03-01

    The alkylating ability of alpha,beta-unsaturated amidoesters 1a-8d, diethyl pyridylmethylphosphonate esters and their cis-platinum(II) complexes has been investigated based on the test with 4-(4'-nitrobenzyl)pyridine (NBP) (Preussmann Test). Of the compounds tested for alkylating activity, only cis-platinum(II) phosphonate complexes were found to possess activity. The highest activity was found for CiS-[PtCl2(4-pmpe)2] where 4-pmpe is diethyl 4-pyridylmethylphosphonate. The results show a correlation between alkylating activity in vitro and cytotoxic activity in vivo for platinum(II) complexes. PMID:9157465

  8. Structure and absolute configuration of 9-desoxy-9-chloroquinine, C/sub 20/H/sub 23/N/sub 2/OCl

    SciTech Connect

    Mazhar-Ul-Haque; Ahmed, J.; Horne, W.; Miana, G.A.; Al-Hazimi, H.M.G.; Amin, H.B.

    1986-04-01

    The title compound crystallizes in the orthorhombic space group p2/sub 1/2/sub 1/2/sub 1/: a = 8.674(1), b = 8.944(1), c = 23.255(4) A, Z = 4. The structure was solved by direct methods, and refined by full-matrix least squares to R = 0.047 for 1472 observed reflections. Determination of the absolute configuration (S at C(9))enabled a discrepancy in the literature concerning the stereochemical outcome of the reaction between SOCl/sub 2/ and quinine to be resolved.

  9. Human hepatocarcinoma functional liver cell-4 cell line exhibits high expression of drug-metabolizing enzymes in three-dimensional culture.

    PubMed

    Kato, Ryuji; Shigemoto, Kota; Akiyama, Hiromasa; Ieda, Asaka; Ijiri, Yoshio; Hayashi, Tetsuya

    2014-01-01

    The expression levels of CYP and uridine diphosphate-glucuronosyl transferase (UGT) are lower in hepatocellular carcinoma cell lines than in human primary hepatocytes. However, a functional liver cell (FLC)-4 cell line that has a greater capacity to secrete liver-specific proteins than other hepatocellular carcinoma cells has recently been established. A three-dimensional culture using Engelbreth-Holm-Swan (EHS) gel induces the secretion of liver-specific proteins via the induction of hepatocyte nuclear factor-4α (HNF-4α). The aim of this study was to evaluate the mRNA expression of the enzymes CYP and UGT in FLC-4 and HepG2 cells in monolayer and three-dimensional cultures using EHS gel. The mRNA levels of HNF-4α, albumin, pregnane X receptor (PXR), constitutive androstane receptor (CAR), CYPs (1A2, 2E1, 2C8, 2C9, 2C19, 2D6, and 3A4) and UGTs (1A1, 1A6, 1A9, and 2B7) were determined using real-time reverse transcription (RT) PCR. In a monolayer culture, the mRNA expression levels of HNF-4α, albumin, PXR, CAR, CYPs (2E1, 2C9, 2C19, 2D6, and 3A4) and UGTs (1A1, 1A6, and 1A9) were higher in FLC-4 cells than in HepG2 cells. In FLC-4 cells, the mRNA expression levels of HNF-4α, albumin, PXR, CAR, CYPs (2E1, 2C8, 2C19, and 3A4) and UGTs (1A1, 1A6, 1A9, and 2B7) significantly increased in three-dimensional culture. FLC-4 cells cultured in EHS gel showed significantly increased expression levels of CYPs and UGTs. The results of this study suggest that human hepatocellular carcinoma FLC-4 cells cultured in EHS gel show potential for use in studying in vitro drug metabolism. PMID:25366484

  10. Stromal-cell and cytokine-dependent lymphocyte clones which span the pre-B- to B-cell transition.

    PubMed

    Ishihara, K; Medina, K; Hayashi, S; Pietrangeli, C; Namen, A E; Miyake, K; Kincade, P W

    1991-01-01

    Five stromal-cell-dependent lymphocyte clones are described that correspond to late pre-B or early B-cell stages of differentiation. They are useful for determining the molecular requirements for pre-B replication, for studying the stromal cells that supply those factors, and for delineating the final sequence of differentiation events as newly formed lymphocytes prepare to exit the bone marrow. The efficiency of lymphocyte growth at limiting dilution varied substantially on different stromal-cell clones and may reflect functional heterogeneity of stromal cells. Most lymphocyte clones were similar to uncloned lymphocytes from Whitlock-Witte cultures in that they responded only transiently to interleukin-7 (IL-7) and then died, unless maintained on a stromal-cell clone. One unusual lymphocyte clone (2E8) was propagated for more than 1 year in IL-7 alone and was selectively responsive to that cytokine. Most of the lymphocyte clones were not tumorigenic in immunodeficient mice. However, one pre-B clone (1A9) grew autonomously in culture when held at high density, responded to conditioned medium from a number of cell lines, and was tumorigenic. Tumors derived from this clone were infiltrated by stromal cells and lymphocytes taken from the tumors' retained characteristics of the original clone. Ly-6 antigens were inducible on 2E8 and 1A9 cells, but the lymphocytes were otherwise arrested in differentiation. The 2E8 cells had rearranged and expressed kappa light-chain genes but displayed them on the surface along with surrogate light chains and mu heavy chains. Thus, expression of authentic light chain need not coincide with termination of surrogate light-chain utilization in newly formed B cells. Several glycoproteins have recently been demonstrated to be associated with surface immunoglobulin (Ig) on mature B-lineage cells and plasma-cell tumors. We now show that one member of this family (approximately 33 kD) was associated with the mu+surrogate light-chain complex on

  11. Selectivity for inhibition of nilotinib on the catalytic activity of human UDP-glucuronosyltransferases.

    PubMed

    Ai, Limei; Zhu, Liangliang; Yang, Lu; Ge, Guangbo; Cao, Yunfeng; Liu, Yong; Fang, Zhongze; Zhang, Yanyan

    2014-04-01

    1. Nilotinib, a tyrosine kinase inhibitor, could potently inhibit SN-38 glucuronidation mainly catalyzed by UDP-glucuronosyltransferase (UGT) 1A1. This study was designed to investigate whether nilotinib can be used as a selective inhibitor of UGT1A1 in human liver. 2. Assays with recombinant UGTs indicated that nilotinib could strongly inhibit the activity of UGT1A1 and decreased the activity of extra-hepatic UGT1A7 to a much lesser extent. The inhibition on 4-methylumbelliferone (4Mu) glucuronidation by recombinant UGT1A1 obeyed competitive inhibition mechanism, with a kinetic constants (Ki) value of 0.17 μM. Assays with human liver microsomes (HLM) demonstrated that nilotinib could selectively inhibit estradiol-3-O-glucuronidation (E2-3-O-glucuronidation), a probe reaction of UGT1A1. Kinetic studies displayed that the inhibition on E2-3-O-glucuronidation followed non-competitive inhibition model, different from the inhibition on 4Mu glucuronidation. The Ki values were calculated to be 0.14 and 0.53 μM, depending on the enzyme sources of recombinant UGT1A1 or HLM, respectively. 3. Given that UGT1A7 is an extra-hepatic enzyme, this study indicates that nilotinib can be used as a selective inhibitor of UGT1A1 in human liver. PMID:24066723

  12. Observation of edge turbulence spread by ECEI on the ELM-crash-suppressed plasmas in the KSTAR

    NASA Astrophysics Data System (ADS)

    Lee, Jaehyun; Choi, Minjun; Yun, Gunsu; Lee, Woochang; Park, Hyeon K.; Luhmann, Neville C., Jr.

    2015-11-01

    The structure and dynamics of the ELM and edge turbulence modified by n = 1 RMP have been studied during the ELM-crash-suppression phase by applying correlation analysis techniques on the measured ECEI signals. The ECEI shows that filamentary modes remained at theedge with frequent bursts during ELM-crash-suppression phase. The filamentary mode fluctuates in the range of 20 kHz and the dynamics of the mode seems to be violent and complex compared to the ELMing H-mode phase. Correlation analysis shows corresponding fluctuations have long poloidal wavelength (or small poloidal wavenumber kθ < 1 cm-1) with smaller size compared to the filamentary mode, and average group velocity of ~ 3 km/s along the electron diamagnetic direction, parallel wavelengths in the range of 2 <λ| | < 8 m. The characteristic size in the order of kθρs ~ 0 . 1 and velocimetry analysis suggest the resistive ballooning mode is a strong candidate for edge fluctuation in the ELM-crash-suppression phase. This work is supported by the NRF of Korea under Contract No. NRF-2014M1A7A1A03029881 and NRF-2014M1A7A1A03029865 and U.S. DoE grant No. DE-FG02-99ER54524.

  13. 2-D/3-D ECE imaging data for validation of turbulence simulations

    NASA Astrophysics Data System (ADS)

    Choi, Minjun; Lee, Jaehyun; Yun, Gunsu; Lee, Woochang; Park, Hyeon K.; Park, Young-Seok; Sabbagh, Steve A.; Wang, Weixing; Luhmann, Neville C., Jr.

    2015-11-01

    The 2-D/3-D KSTAR ECEI diagnostic can provide a local 2-D/3-D measurement of ECE intensity. Application of spectral analysis techniques to the ECEI data allows local estimation of frequency spectra S (f) , wavenumber spectra S (k) , wavernumber and frequency spectra S (k , f) , and bispectra b (f1 ,f2) of ECE intensity over the 2-D/3-D space, which can be used to validate turbulence simulations. However, the minimum detectable fluctuation amplitude and the maximum detectable wavenumber are limited by the temporal and spatial resolutions of the diagnostic system, respectively. Also, the finite measurement area of the diagnostic channel could introduce uncertainty in the spectra estimation. The limitations and accuracy of the ECEI estimated spectra have been tested by a synthetic ECEI diagnostic with the model and/or fluctuations calculated by GTS. Supported by the NRF of Korea under Contract No. NRF-2014M1A7A1A03029881 and NRF-2014M1A7A1A03029865 and by U.S. DOE grant DE-FG02-99ER54524.

  14. Design of a collective scattering system for electron gyroscale turbulence study in KSTAR

    NASA Astrophysics Data System (ADS)

    Lee, Woochang; Park, Hyeon; Lee, Dongjae; Leem, Juneeok; Nam, Yongun

    2015-11-01

    The design characteristics of a multi-channel collective (or coherent) scattering system for electron scale turbulence study in KSTAR, which is planned to be installed in 2016, are investigated. A few critical issues are discussed in depth such as effect of the Faraday rotation of the electric field polarization of probing and scattered, the probing wave frequency which is related to the optics for measurement of electron gyro scale turbulence, the wave polarization to minimize absorption of the probing power by electron cyclotron resonant layers, and the probing power. A proper and feasible optics with 300 GHz probing wave, which is based on these issues, provides a simultaneous measurement of electron density fluctuations at four discrete poloidal wave numbers up to 21 cm-1. The upper limit corresponds to the normalized wave number k⊥ρe of 0.2 in KSTAR plasmas. To detect scattered wave power and extract phase information, a quadrature detection system consisting of four-channel antenna/detector array and electronics will be employed. Work supported by NRF Korea under grant numbers NRF-2015M1A7A1A02002627 and NRF-2014M1A7A1A03029865.

  15. Corrective Action Plan for Corrective Action Unit 453: Area 9 UXO Landfill, Tonopah Test Range, Nevada

    SciTech Connect

    Bechtel Nevada

    1998-09-30

    This corrective action plan proposes the closure method for the area 9 unexploded Ordnance landfill, corrective action unit 453 located at the Tonopah Test Range. The area 9 UXO landfill consists of corrective action site no. 09-55-001-0952 and is comprised of three individual landfill cells designated as A9-1, A9-2, and A9-3. The three landfill cells received wastes from daily operations at area 9 and from range cleanups which were performed after weapons testing. Cell locations and contents were not well documented due to the unregulated disposal practices commonly associated with early landfill operations. However, site process knowledge indicates that the landfill cells were used for solid waste disposal, including disposal of UXO.

  16. NMR spectral and structural studies on some xanthenones and their thiosemicarbazone derivatives: Crystal and molecular structure of 12-(2-chlorophenyl)-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one

    NASA Astrophysics Data System (ADS)

    Sethukumar, A.; Vithya, V.; Udhaya Kumar, C.; Arul Prakasam, B.

    2012-01-01

    A series of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones [ 1a- 9a] were prepared employing a three component one-pot reaction of aryl aldehyde, 2-naphthol and 1,3-cyclohexanedione using BF 3·OEt 2 as catalyst. Thiosemicarbazone derivatives [ 1b- 5b] were also prepared in the presence of acid catalyst. All the synthesized compounds have been characterized by IR and NMR. The structure of 5b was confirmed by HSQC spectral analysis. Single crystal X-ray structural analysis of 12-(2-chlorophenyl)-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one evidences the envelope and flattened-boat conformations of cyclohexenone and pyran rings respectively.

  17. Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs.

    PubMed

    Yuan, Yuan; Zheng, Jiyue; Wang, Meiyu; Li, Yuan; Ruan, Jianqing; Zhang, Hongjian

    2016-07-20

    Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human. PMID:27362917

  18. Genotype and allele frequencies of drug-metabolizing enzymes and drug transporter genes affecting immunosuppressants in the Spanish white population.

    PubMed

    Bosó, Virginia; Herrero, María J; Buso, Enrique; Galán, Juan; Almenar, Luis; Sánchez-Lázaro, Ignacio; Sánchez-Plumed, Jaime; Bea, Sergio; Prieto, Martín; García, María; Pastor, Amparo; Sole, Amparo; Poveda, José Luis; Aliño, Salvador F

    2014-04-01

    Interpatient variability in drug response can be widely explained by genetically determined differences in metabolizing enzymes, drug transporters, and drug targets, leading to different pharmacokinetic and/or pharmacodynamic behaviors of drugs. Genetic variations affect or do not affect drug responses depending on their influence on protein activity and the relevance of such proteins in the pathway of the drug. Also, the frequency of such genetic variations differs among populations, so the clinical relevance of a specific variation is not the same in all of them. In this study, a panel of 33 single nucleotide polymorphisms in 14 different genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, MTHFR, NOD2/CARD15, SLCO1A2, SLCO1B1, TPMT, and UGT1A9), encoding for the most relevant metabolizing enzymes and drug transporters relating to immunosuppressant agents, was analyzed to determine the genotype profile and allele frequencies in comparison with HapMap data. A total of 570 Spanish white recipients and donors of solid organ transplants were included. In 24 single nucleotide polymorphisms, statistically significant differences in allele frequency were observed. The largest differences (>100%) occurred in ABCB1 rs2229109, ABCG2 rs2231137, CYP3A5 rs776746, NOD2/CARD15 rs2066844, TPMT rs1800462, and UGT1A9 rs72551330. In conclusion, differences were recorded between the Spanish and other white populations in terms of allele frequency and genotypic distribution. Such differences may have implications in relation to dose requirements and drug-induced toxicity. These data are important for further research to help explain interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy. PMID:24232128

  19. Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

    PubMed Central

    Hardwick, Rhiannon N.; Ferreira, Daniel W.; More, Vijay R.; Lake, April D.; Lu, Zhenqiang; Manautou, Jose E.; Slitt, Angela L.

    2013-01-01

    The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 3′-phosphoadenosine-5′-phosphosulfate synthase 1 were increased in NASH (not fatty/cirrhosis) only. UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD. PMID:23223517

  20. Evaluation of the in vitro/in vivo potential of five berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) commonly used as herbal supplements to inhibit uridine diphospho-glucuronosyltransferase.

    PubMed

    Choi, Eu Jin; Park, Jung Bae; Yoon, Kee Dong; Bae, Soo Kyung

    2014-10-01

    In this study, we evaluated inhibitory potentials of popularly-consumed berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) as herbal supplements on UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in vitro. We also investigated the potential herb-drug interaction via UGT1A1 inhibition by blueberry in vivo. We demonstrated that these berries had only weak inhibitory effects on the five UGTs. Bilberry and elderberry had no apparent inhibitions. Blueberry weakly inhibited UGT1A1 with an IC50 value of 62.4±4.40 μg/mL and a Ki value of 53.1 μg/mL. Blueberry also weakly inhibited UGT2B7 with an IC50 value of 147±11.1 μg/mL. In addition, cranberry weakly inhibited UGT1A9 activity (IC50=458±49.7 μg/mL) and raspberry ketones weakly inhibited UGT2B7 activity (IC50=248±28.2 μg/mL). Among tested berries, blueberry showed the lowest IC50 value in the inhibition of UGT1A1 in vitro. However, the co-administration of blueberry had no effect on the pharmacokinetics of irinotecan and its active metabolite, SN-38, which was mainly eliminated via UGT1A1, in vivo. Our data suggests that these five berries are unlikely to cause clinically significant herb-drug interactions mediated via inhibition of UGT enzymes involved in drug metabolism. These findings should enable an understanding of herb-drug interactions for the safe use of popularly-consumed berries. PMID:24997313

  1. Diabetes Mellitus Reduces Activity of Human UDP-Glucuronosyltransferase 2B7 in Liver and Kidney Leading to Decreased Formation of Mycophenolic Acid Acyl-Glucuronide Metabolite

    PubMed Central

    Dostalek, Miroslav; Court, Michael H.; Hazarika, Suwagmani

    2011-01-01

    Mycophenolic acid (MPA) is an immunosuppressive agent commonly used after organ transplantation. Altered concentrations of MPA metabolites have been reported in diabetic kidney transplant recipients, although the reason for this difference is unknown. We aimed to compare MPA biotransformation and UDP-glucuronosyltransferase (UGT) expression and activity between liver (n = 16) and kidney (n = 8) from diabetic and nondiabetic donors. Glucuronidation of MPA, as well as the expression and probe substrate activity of UGTs primarily responsible for MPA phenol glucuronide (MPAG) formation (UGT1A1 and UGT1A9), and MPA acyl glucuronide (AcMPAG) formation (UGT2B7), was characterized. We have found that both diabetic and nondiabetic human liver microsomes and kidney microsomes formed MPAG with similar efficiency; however, AcMPAG formation was significantly lower in diabetic samples. This finding is supported by markedly lower glucuronidation of the UGT2B7 probe zidovudine, UGT2B7 protein, and UGT2B7 mRNA in diabetic tissues. UGT genetic polymorphism did not explain this difference because UGT2B7*2 or *1c genotype were not associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore, mRNA expression and probe activities for UGT1A1 or UGT1A9, both forming MPAG but not AcMPAG, were comparable between diabetic and nondiabetic tissues, suggesting the effect may be specific to UGT2B7-mediated AcMPAG formation. These findings suggest that diabetes mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and enzymatic activity of human liver and kidney, explaining in part the relatively low circulating concentrations of AcMPAG in diabetic patients. PMID:21123165

  2. Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib.

    PubMed

    Nishiya, Yumi; Nakai, Daisuke; Urasaki, Yoko; Takakusa, Hideo; Ohsuki, Satoru; Iwano, Yuji; Yasukochi, Takanori; Takayama, Tomoko; Bazyo, Shohei; Oza, Chikahiro; Kurihara, Atsushi; Savage, Ronald E; Izumi, Takashi

    2016-11-01

    1. In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites. 2. The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer of M5), whereas CYP3A4/5 catalyzed the formation of both metabolites. For the elimination of M4, M5 and M8 (keto-metabolite), CYP3A4/5 was the major cytochrome P450 isoform and UGT1A9 was mainly involved in the glucuronidation of M4 and M5. 3. ADH4 was identified as one of the major alcohol dehydrogenase isoforms contributing to the formation of M6 (sequential keto-metabolite of M4 and M5) and M8. The substrate preference of ADH for M4, and not M5, was observed in the formation of M6. 4. In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites. The stereoselective hydroxylation by CYP2C19 and substrate stereoselectivity of ADH4-catalyzed oxidation in the in vitro metabolism of tivantinib was discovered. PMID:26899628

  3. Rotavirus vaccine: a review.

    PubMed

    Kumar, Goel Manish; Arun, Kumar; Bilas, Jain Ram; Ruchi, Jain; Pardeep, Khanna; Pradeep, Siwach

    2012-12-01

    Worldwide, large proportion i.e., 37% of deaths due to diarrhea in young children is attributed to rotavirus. A monovalent P1A[8] G1 vaccine and a pentavalent bovine-human reassortant vaccine human rotavirus vaccine had shown good clinical efficacy without any increase in intussusception among vaccine recipients. WHO recommends that the first dose of rotavirus vaccine should be administered to infants up to age of 6-15 weeks irrespective of the prior history of rotavirus infection and the maximum age for administering the last dose of the vaccine should be 32 weeks. Booster doses are not recommended. The current update reviews the issues related to rotavirus vaccines and their usages like milestones in the development of rotavirus vaccines, concerns regarding their efficacy and cost-effectiveness, immunity after natural infection, potential for changes in virus strains, current recommendations, post marketing surveillance, and future challenges and scope for further research regarding rotavirus vaccines. PMID:25145068

  4. Whole-genome analyses reveals the animal origin of a rotavirus G4P[6] detected in a child with severe diarrhea.

    PubMed

    Martinez, Magaly; Galeano, Maria E; Akopov, Asmik; Palacios, Ruth; Russomando, Graciela; Kirkness, Ewen F; Parra, Gabriel I

    2014-10-01

    Group A rotaviruses are a major cause of severe gastroenteritis in children worldwide. Currently, two rotavirus vaccines are being used in vaccination programs, and one of the factors involved in lower vaccine efficacy is the mismatch among the circulating strains and the vaccine strains. Thus, the emergence of animal strains in the human population could affect the efficacy of vaccination programs. Here we report the presence of a G4P[6] strain in a Paraguayan child presenting acute gastroenteritis in 2009. Genomic analyses revealed that the strain presents a porcine-like genome (G4-P[6]-I1-R1-C1-M1-A8-N1-T7-E1-H1), suggesting a direct animal-to-human transmission. Continuous surveillance of rotaviruses in humans and animals will help us to better understand rotavirus epidemiology and evolution. PMID:25075468

  5. Effects of co-treatment with sulforaphane and autophagy modulators on uridine 5′-diphospho-glucuronosyltransferase 1A isoforms and cytochrome P450 3A4 expression in Caco-2 human colon cancer cells

    PubMed Central

    WANG, MIN; ZHU, JING-YU; CHEN, SHUO; QING, YING; WU, DONG; LIN, YING-MIN; LUO, JI-ZHUANG; HAN, WEI; LI, YAN-QING

    2014-01-01

    Sulforaphane (SFN), which is highly enriched in cruciferous vegetables, has been investigated for its cancer chemopreventive properties and ability to induce autophagy. Uridine 5′-diphospho (UDP)-glucuronosyltransferase (UGT)1A induction is one of the mechanisms that is responsible for the cancer chemopreventive activity of SFN. The current study demonstrates that rapamycin may enhance the chemopreventive effects of SFN on Caco-2 cells; this may be partially attributed to nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2)- and human pregnane X receptor (hPXR)-mediated UGT1A1, UGT1A8 and UGT1A10 induction. These results indicate that targeting autophagy modulation may be a promising strategy for increasing the chemopreventive effects of SFN in cases of colon cancer. PMID:25364403

  6. Platelet activating factor antagonist design. 2. X-ray structure of dimethyl 2,3,4,5-tetrahydro-5 beta-(3,4-methylenedioxyphenyl)-2-oxo-3 beta-(3,4,5-trimethoxybenzoyl)-3 alpha,4 alpha-furandicarboxylate.

    PubMed

    Peterson, J R; Do, H D; Rogers, R D

    1989-07-15

    C25H24O12, Mr = 516.46, triclinic, P-1, a = 8.780 (3), b = 11.298 (4), c = 13.271 (6) A, alpha = 71.77 (4), beta = 70.31 (3), gamma = 72.66 (3) degrees, V = 1189 A3, Z = 2, Dx = 1.44 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.74 cm-1, F(000) = 540, T = 293 K, final R = 0.046 for 2495 observed [Fo greater than or equal to 5 sigma (Fo)] reflections. The observed structure reveals a trans disposition for the methoxycarbonyl and aryl substituents at positions 4 and 5 of the heterocycle and a cis-3,4-bis(methoxycarbonyl) relationship. There is no crystallographically imposed symmetry. Several intermolecular van der Waals interactions occur in the cell lattice of this compound. PMID:2610989

  7. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

    PubMed

    Gufford, Brandon T; Chen, Gang; Vergara, Ana G; Lazarus, Philip; Oberlies, Nicholas H; Paine, Mary F

    2015-09-01

    Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention. PMID:26070840

  8. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

    PubMed Central

    Gufford, Brandon T.; Chen, Gang; Vergara, Ana G.; Lazarus, Philip; Oberlies, Nicholas H.

    2015-01-01

    Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4′- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27–66 µM; UGT1A1, 3.2–8.3 µM; UGT1A8, 19–73 µM; and UGT1A10, 65–120 µM) encompassed reported intestinal tissue concentrations (20–310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product–drug interactions in the context of cancer prevention. PMID:26070840

  9. Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751

    PubMed Central

    Innocenti, Federico; Ramírez, Jacqueline; Obel, Jennifer; Xiong, Julia; Mirkov, Snezana; Chiu, Yi-Lin; Katz, David A.; Carr, Robert A.; Zhang, Wei; Das, Soma; Adjei, Araba; Moyer, Ann M.; Chen, Pei Xian; Krivoshik, Andrew; Medina, Diane; Gordon, Gary B.; Ratain, Mark J.; Sahelijo, Leonardo; Weinshilboum, Richard M.; Fleming, Gini F.; Bhathena, Anahita

    2013-01-01

    Objective ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. Methods UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. Results UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (> 2) was associated with an average 34% increase in ABT-751 clearance (P= 0.044), an 18% reduction in ABT-751 AUC (P = 0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P =0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 Ctrough (P = 0.009). Conclusion These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability. PMID:23670235

  10. Combinatorial synthesis, lead identification, and antitumor study of a chalcone-based positional-scanning library.

    PubMed

    Ullah, Ahsan; Ansari, Farzana Latif; Nazir, Samina; Mirza, Bushra

    2007-02-01

    A 175-member chalcone library was designed and synthesized from seven differently substituted acetophenones (A(1)-A(7)) and 25 differently substituted aryl or heteroaryl aldehydes (B(1)-B(25)). Potential lead compounds were identified by deconvolution of a two-dimensional library matrix via positional scanning, and the members of the most-active sub-libraries were synthesized and screened against crown-gall tumors with the aid of the potato-disc assay. The resulting hits gave rise to significant antitumor activities, with no antibacterial effect on the tumor-producing bacterium Agrobacterium tumefaciens. Two identified lead structures, (2E)-3-(2-chlorophenyl)-1-phenylprop-2-en-1-one (A(1)B(9)) and the hydroxy analogue (2E)-3-(2-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (A(2)B(9)), are promising candidates to be developed into highly effective anticancer chemotherapeutics. PMID:17311221

  11. Ion kinetic instabilities and turbulence of a parallel shearing flow of a plasma with hot ions

    NASA Astrophysics Data System (ADS)

    Mykhaylenko, Volodymyr St.; Mykhaylenko, Volodymyr; Lee, Hae June

    2015-11-01

    The results of the analytical and numerical investigations of the shear flow driven ion kinetic instabilities, excited due to the inverse ion Landau damping in the parallel shearing flow of plasmas with comparable ion and electron temperatures, that is the case relevant to a tokamak and space plasma, are presented. The levels of turbulence and the turbulent heating rates of ions and ion turbulent viscosity, resulted from the development of the electrostatic ion-temperature gradient and electromagnetic drift-Alfven turbulence, are determined and their consequences are discussed. This work was funded by National R&D Program through the National Research Foundation of Korea.Grants NRF-2014M1A7A1A03029878, NRF-2013R1A1A2005758.

  12. Synthesis of hemslecin A derivatives: a new class of hepatitis B virus inhibitors.

    PubMed

    Guo, Rui-Hua; Geng, Chang-An; Huang, Xiao-Yan; Ma, Yun-Bao; Zhang, Quan; Wang, Li-Jun; Zhang, Xue-Mei; Zhang, Rong-Ping; Chen, Ji-Jun

    2013-03-01

    A series of hemslecin A derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely, inhibiting the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA replication on HepG 2.2.15 cells. Most of the derivatives showed enhanced anti-HBV activities, of which compounds A1-A7, B5, C and E exhibited significant activities inhibiting HBV DNA replication with IC(50) values of 2.8-11.6 μM, comparable to that of the positive control, tenofovir. Compounds A1-A3, A5, B5, and C displayed low cytotoxicities, which resulted in high SI values of 89.7, 55.6, 77.8, >83.4, >55.8, and >150.5, respectively. PMID:23385212

  13. Synthesis, structure, and spectroscopic characterization of three uranyl phosphates with unique structural units

    NASA Astrophysics Data System (ADS)

    Wylie, Ernest M.; Dawes, Colleen M.; Burns, Peter C.

    2012-12-01

    Single crystals of Zn4(OH)2[(UO2)(PO4)2(OH)2(H2O)] (UZnP), Cs[(UO2)(HPO4)NO3] (UCsP), and In3[(UO2)2(PO4)4OH(H2O)6].2H2O (UInP) were obtained from hydrothermal reactions and have been structurally and chemically characterized. UZnP crystallizes in space group Pbcn, a=8.8817(7), b=6.6109(5), c=19.569(1) Å; UCsP crystallizes in P-1, a=7.015(2), b=7.441(1), c=9.393(2) Å, α=72.974(2), β=74.261(2), γ=79.498(2); and UInP crystallizes in P-1, a=7.9856(5), b=9.159(1), c=9.2398(6) Å α=101.289(1), β=114.642(1), γ=99.203(2). The U6+ cations are present as (UO2)2+ uranyl ions coordinated by five O atoms to give pentagonal bipyramids. The structural unit in UZnP is a finite cluster containing a uranyl pentagonal bipyramid that shares corners with two phosphate tetrahedra. The structural unit in UCsP is composed of uranyl pentagonal bipyramids with one chelating nitrate group that are linked into chains by three bridging hydrogen phosphate tetrahedra. In UInP, the structural unit contains pairs of edge-sharing uranyl pentagonal bipyramids with two chelating phosphate tetrahedra that are linked into chains through two bridging phosphate tetrahedra. Indium octahedra link these uranyl phosphate chains into a 3-dimensional framework. All three compounds exhibit unique structural units that deviate from the typical layered structures observed in uranyl phosphate solid-state chemistry.

  14. Bioactivation of Heterocyclic Aromatic Amines by UDP Glucuronosyltransferases.

    PubMed

    Cai, Tingting; Yao, Lihua; Turesky, Robert J

    2016-05-16

    2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAA) that arise during the burning of tobacco and cooking of meats. UDP-glucuronosyltransferases (UGT) detoxicate many procarcinogens and their metabolites. The genotoxic N-hydroxylated metabolite of AαC, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC), undergoes glucuronidation to form the isomeric glucuronide (Gluc) conjugates N(2)-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON(2)-Gluc) and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN(2)-O-Gluc). AαC-HON(2)-Gluc is a stable metabolite but AαC-HN(2)-O-Gluc is a biologically reactive intermediate, which covalently adducts to DNA at levels that are 20-fold higher than HONH-AαC. We measured the rates of formation of AαC-HON(2)-Gluc and AαC-HN(2)-O-Gluc in human organs: highest activity occurred with liver and kidney microsomes, and lesser activity was found with colon and rectum microsomes. AαC-HN(2)-O-Gluc formation was largely diminished in liver and kidney microsomes, by niflumic acid, a selective inhibitor UGT1A9. In contrast, AαC-HON(2)-Gluc formation was less affected and other UGT contribute to N(2)-glucuronidation of HONH-AαC. UGT were reported to catalyze the formation of isomeric Gluc conjugates at the N(2) and N3 atoms of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), the genotoxic metabolite of PhIP. However, we found that the N3-Gluc of HONH-PhIP also covalently bound to DNA at higher levels than HONH-PhIP. The product ion spectra of this Gluc conjugate acquired by ion trap mass spectrometry revealed that the Gluc moiety was linked to the oxygen atom of HONH-PhIP and not the N3 imidazole atom of the oxime tautomer of HONH-PhIP as was originally proposed. UGT1A9, an abundant UGT isoform expressed in human liver and kidney, preferentially forms the O-linked Gluc conjugates of HONH

  15. Syntheses, structures, and properties of the bis(cyclopentadienyl) rare-earth imidodiphosphinochalocogenido compounds Cp2Ln[N(QPPh2)2] (Ln = La, Gd, Er, or Yb for Q = Se; Ln = Yb for Q = S).

    PubMed

    Pernin, C G; Ibers, J A

    2000-03-20

    The compounds Cp2Ln[N(QPPh2)2] (Ln = La (1), Gd (2), Er (3), or Yb (4) for Q = Se, Ln = Yb (5) for Q = S) have been synthesized from the corresponding rare-earth tris(cyclopentadienyl) compound and H[N(QPPh2)2]. The structures of compounds 1, 2, 3, and 5, as determined by X-ray crystallography, consist of a Cp2Ln fragment, coordinated eta 3 through two chalcogen atoms and an N atom of the imidodiphosphinochalcogenido ligand [N(QPPh2)2]-. In compound 4, the Cp2Yb moiety is coordinated eta 2 through the two Se atoms of the [N(SePPh2)2]-ligand. 31P and 77Se (for 1) NMR spectroscopies lend insight into the solution nature of these species. Crystal data: 1, C34H30LaNP2Se2, triclinic, P1, a = 9.7959(10) A, b = 12.4134(13) A, c = 13.9077(14) A, alpha = 88.106(2) degrees, beta = 88.327(2) degrees, gamma = 68.481(2) degrees, V = 1572.2(3) A3, T = 153 K, Z = 2, and R1(F) = 0.0257 for the 5947 reflections with I > .2 sigma(I); 2, C34H30GdNP2Se2, triclinic, P1, a = 9.7130(14) A, b = 12.2659(17) A, c = 13.953(2) A, alpha = 88.062(2) degrees, beta = 87.613(2) degrees, gamma = 69.041(2) degrees, V = 1550.7(4) A3, T = 153 K, Z = 2, and R1(F) = 0.0323 for the 5064 reflections with I > 2 sigma(I); 3, C34H30ErNP2Se2, triclinic, P1, a = 9.704(2) A, b = 12.222(3) A, c = 13.980(4) A, alpha = 88.230(4) degrees, beta = 87.487(4) degees, gamma = 69.107(4) degrees, V = 1547.4(7) A3, T = 153 K, Z = 2, and R1(F) = 0.0278 for the 6377 reflections with I > 2 sigma(I); 4, C34H30NP2Se2Yb.C4H8O, triclinic, P1, a = 12.087(4) A, b = 12.429(4) A, c = 23.990(7) A, alpha = 89.406(5) degrees, beta = 86.368(5) degrees, gamma = 81.664(5) degrees, V = 3558.8(18) A3, T = 153 K, Z = 4, and R1(F) = 0.0321 for the 11,883 reflections with I > 2 sigma(I); and 5, C34H30NP2S2Yb, monoclinic, P21/n, a = 13.8799(18) A, b = 12.6747(16) A, c = 17.180(2) A, beta = 91.102(3) degrees, V = 3021.8(7) A3, T = 153 K, Z = 4, and R1(F) = 0.0218 for the 6698 reflections with I > 2 sigma(I). PMID:12526413

  16. Drug-Metabolizing Activity, Protein and Gene Expression of UDP-Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients

    PubMed Central

    Lu, Linlin; Zhou, Juan; Shi, Jian; Peng, Xiao-juan; Qi, Xiao-xiao; Wang, Ying; Li, Fang-yuan; Zhou, Fu-Yuan; Liu, Liang; Liu, Zhong-Qiu

    2015-01-01

    UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV-positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either Vmax (maximum reaction rate, Rmax for UGT1A1) or the clearance rates (Vmax/Km, Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV-positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which would

  17. Drug-Metabolizing Activity, Protein and Gene Expression of UDP-Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients.

    PubMed

    Lu, Linlin; Zhou, Juan; Shi, Jian; Peng, Xiao-juan; Qi, Xiao-xiao; Wang, Ying; Li, Fang-Yuan; Zhou, Fu-Yuan; Liu, Liang; Liu, Zhong-Qiu

    2015-01-01

    UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV-positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either V(max) (maximum reaction rate, R(max) for UGT1A1) or the clearance rates (V(max)/K(m), Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV-positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which

  18. An antimitotic and antivascular agent BPR0L075 overcomes multidrug resistance and induces mitotic catastrophe in paclitaxel-resistant ovarian cancer cells.

    PubMed

    Wang, Xiaolei; Wu, Erxi; Wu, Jun; Wang, Tian-Li; Hsieh, Hsing-Pang; Liu, Xinli

    2013-01-01

    Paclitaxel plays a major role in the treatment of ovarian cancer; however, resistance to paclitaxel is frequently observed. Thus, new therapy that can overcome paclitaxel resistance will be of significant clinical importance. We evaluated antiproliferative effects of an antimitotic and antivascular agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50 = 2-7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III β-tubulin or mutation of β-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induces cell death by a dual mechanism in parental and paclitaxel-resistant ovarian cancer cells. In the parental cells (OVCAR-3 and SKOV-3), BPR0L075 induced apoptosis, evidenced by poly(ADP-ribose) polymerase (PARP) cleavage and DNA ladder formation. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage. Immunoblotting analysis shows that BPR0L075 treatment induced up-regulation of cyclin B1, BubR1, MPM-2, and survivin protein levels and Bcl-XL phosphorylation in parental cells; however, in resistant cells, the endogenous expressions of BubR1 and survivin were depleted, BPR0L075 treatment failed to induce MPM-2 expression and phosphorylation of Bcl-XL. BPR0L075 induced cell death in both parental and paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel

  19. Study of anti-angiogenic drugs by fluorescence imaging and spectroscopy of a contrast agent in mice

    NASA Astrophysics Data System (ADS)

    Valentini, G.; D'Andrea, C.; Ferrari, R.; Pifferi, A.; Cubeddu, R.; Caronia, D.; Martinelli, M.; Giavazzi, R.

    2007-07-01

    We used two fluorescence techniques based on the Indocyanine Green contrast agent to study the effectiveness of antiangionenic drugs in mice. To this purpose, the volume of the active vasculature in different tumor models implanted in mice was assessed by means of a low noise fluorescence imaging setup and by a photon counting system working in transmittance geometry. Using a first tumor model (carcinoma MDA-MB-435) we observed that mice treated with a Vascular Disrupting Agent (ZD6126) showed a reduction in fluorescence emission of the contrast agent with respect to control mice. This was a clear indication of the vascular shutdown that took place in tumors. The effectiveness of the treatment was also confirmed by histological sections. Then, in a second experiment we considered a second tumor model (carcinoma 1A9-VS1) overexpressing the Vascular Endotelial Growth Factor (VEGF121), which is used by tumor cells to promote angiogenesis. We measured the Indocyanine Green fluorescence in mice treated with an antioangiogenic drug (Avastin TM) and in control mice. In tumors of treated mice we observed an ICG emission lower than the one detected in control mice. This demonstrated that VEGF activity was effectively blocked by the treatment with Avastin. In conclusion, ICG fluorescence provides a simple and reliable way to assess the effectiveness of vascular targeting therapies. Measurements of the fluorescence signal can be repeated every 24 hours, thus allowing oncologists to perform longitudinal studies on the same animals.

  20. Metabolism studies on prim-O-glucosylcimifugin and cimifugin in human liver microsomes by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry.

    PubMed

    Jia, Peipei; Zhang, Yuqian; Zhang, Qiaoyue; Sun, Yupeng; Yang, Haotian; Shi, He; Zhang, Xiaoxu; Zhang, Lantong

    2016-09-01

    Prim-O-glucosylcimifugin (PGCN) and cimifugin (CN) are major constituents of Radix Saposhnikoviae that have antipyretic, analgesic and anti-inflammatory pharmacological activities. However, there were few reports with respect to the metabolism of PGCN and CN in vitro. In this paper, we describe a strategy using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) for fast analysis of the metabolic profile of PGCN and CN in human liver microsomes. In total, five phase I metabolites of PGCN, seven phase I metabolites and two phase II metabolites of CN were identified in the incubation of human liver microsomes. The results revealed that the main phase I metabolic pathways of PGCN were hydroxylation and hydrolysis reactions. The phase I metabolic pathways of CN were found to be hydroxylation, demethylation and dehydrogenation. Meanwhile, the results indicated that O-glucuronidation was the major metabolic pathway of CN in phase II metabolism. The specific UDP-glucuronosyltransferase (UGT) enzymes responsible for CN glucuronidation metabolites were identified using recombinant UGT enzymes. The results indicated that UGT1A1, UGT1A9, UGT2B4 and UGT2B7 might play major roles in the glucuronidation of CN. Overall, this study may be useful for the investigation of metabolic mechanism of PGCN and CN, and it can provide reference and evidence for further pharmacodynamic experiments. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26910368

  1. Resolving Bovine viral diarrhea virus subtypes from persistently infected U.S. beef calves with complete genome sequence.

    PubMed

    Workman, Aspen M; Heaton, Michael P; Harhay, Gregory P; Smith, Timothy P L; Grotelueschen, Dale M; Sjeklocha, David; Brodersen, Bruce; Petersen, Jessica L; Chitko-McKown, Carol G

    2016-09-01

    Bovine viral diarrhea virus (BVDV) is classified into 2 genotypes, BVDV-1 and BVDV-2, each of which contains distinct subtypes with genetic and antigenic variation. To effectively control BVDV by vaccination, it is important to know which subtypes of the virus are circulating and how their prevalence is changing over time. Accordingly, the purpose of our study was to estimate the current prevalence and diversity of BVDV subtypes from persistently infected (PI) beef calves in the central United States. Phylogenetic analysis of the 5'-UTR (5' untranslated region) for 119 virus strains revealed that a majority (82%) belonged to genotype 1b, and the remaining strains were distributed between genotypes 1a (9%) and 2 (8%); however, BVDV-2 subtypes could not be confidently resolved. Therefore, to better define the variability of U.S. BVDV isolates and further investigate the division of BVDV-2 isolates into subtypes, complete genome sequences were obtained for these isolates as well as representatives of BVDV-1a and -1b. Phylogenetic analyses of the complete coding sequence provided more conclusive genetic classification and revealed that U.S. BVDV-2 isolates belong to at least 3 distinct genetic groups that are statistically supported by both complete and individual coding gene analyses. These results show that a more complex set of BVDV-2 subtypes has been circulating in this region than was previously thought. PMID:27400958

  2. Crystal structures and magnetic properties of the honeycomb-lattice antiferromagnet M2(pymca)3(ClO4), (M = Fe, Co, Ni)

    NASA Astrophysics Data System (ADS)

    Honda, Zentaro; Kodama, Takafumi; Hagiwara, Masayuki; Kida, Takanori; Okutani, Akira; Sakai, Masamichi; Fukuda, Takeshi; Kamata, Norihiko

    2016-09-01

    We report on the syntheses, crystal structures, and magnetic properties of a series of transition metal coordination polymers M2(pymca)3(ClO4), (pymca = pyrimidine-2-carboxylic acid, M = Fe (1), Co (2), and Ni (3)). These compounds are found to crystallize in a trigonal crystal system, space group P31m, with the lattice constants a = 9.727 Å and c = 5.996 Å for 1, a = 9.608 Å and c = 5.996 Å for 2, and a = 9.477 Å and c = 5.958 Å for 3 at room temperature. In these compounds, each pymca ligand connects to two M2+ ions, forming a honeycomb network in the ab plane. The temperature dependences of magnetic susceptibilities in these compounds show broad maxima, indicating antiferromagnetic interactions within two-dimensional honeycomb layers. We also observed an antiferromagnetic phase transition at low temperatures by magnetic susceptibility and heat capacity measurements. From the crystal structures and magnetic properties, we conclude that the compounds 1, 2, and 3 are good realizations of honeycomb-lattice antiferromagnets.

  3. Studies of Intercellular Communication and Intracellular Metabolic Responses by Bone Cells to Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Doty, Stephen B.

    1997-01-01

    Spaceflight affects the weight bearing skeletal tissues by reducing the rate of new bone formation. This effect on the long bones of flown rats has been quantitated but the effect at the cellular level and the mechanism(s) involved are not understood. We are applying electron microscopy, coupled with histochemistry and immunocytochemistry to determine the cellular functions most affected by spaceflight. The emphasis for study of these samples from SLS-1, a 9-day mission, is on the histochemical and structural changes of the endosteal and perivascular osteoblasts found in diaphyseal bone of femur and tibia. Work is still in progress but some findings are described: (1) An expected decrease in alkaline phosphatase activity in osteoblasts from flight animals, but an increase in enzyme activity in the stromal stem cells adjacent to the osteoblast. (2) An increase in osteoclastic TRAP activity in the trabecular bone region in response to spaceflight. (3) A large increase in procollagen containing secretory granules in osteoblasts in the recovery group, and a significant decrease in granule numbers in the flight group.

  4. Household, hotel and market waste audits for composting in Vietnam and Laos.

    PubMed

    Byer, Philip H; Hoang, Chi Phuong; Nguyen, Thi Thuc Thuy; Chopra, Sangeeta; Maclaren, Virginia; Haight, Murray

    2006-10-01

    In Da Nang and Ha Long, Vietnam and in Vientiane, Laos, there was interest by local authorities in separating and composting waste in order to reduce environmental and health problems at the local landfills and to produce a soil conditioner for local agricultural use. To assist in the planning of composting projects, three studies were carried out to estimate waste quantities and composition. 1. A 9-day audit of waste from 45 vendors in a market in Vientiane, the capital of Laos. The total quantity of waste and the quantity in each of nine categories were estimated for each of six different types of vendors. 2. A 7-day audit of waste disposed by three hotels in the tourist area of Ha Long, Vietnam. Waste quantities were estimated in total, on a per guest basis, and in three main categories: compostables, recyclables and miscellaneous. 3. A 7-day audit of waste collected from 74 households in Da Nang, the fourth largest city in Vietnam. Waste from each household was separated into compostable and non-compostable waste. Over 60% of each waste source comprised compostable waste and this was considered significant enough to warrant further planning of composting operations. PMID:17121118

  5. Inhibition screening method of microsomal UGTs using the cocktail approach.

    PubMed

    Gradinaru, Julieta; Romand, Stéphanie; Geiser, Laurent; Carrupt, Pierre-Alain; Spaggiari, Dany; Rudaz, Serge

    2015-04-25

    A rapid method for the simultaneous determination of the in vitro activity of the 10 major human liver UDP-glucuronosyltransferase (UGT) enzymes was developed based on the cocktail approach. Specific substrates were first selected for each UGT: etoposide for UGT1A1, chenodeoxycholic acid for UGT1A3, trifluoperazine for UGT1A4, serotonin for UGT 1A6, isoferulic acid for UGT1A9, codeine for UGT2B4, azidothymidine for UGT2B7, levomedetomidine for UGT2B10, 4-hydroxy-3-methoxymethamphetamine for UGT2B15 and testosterone for UGT2B17. Optimal incubation conditions, including time-based experiments on cocktail metabolism in pooled HLMs that had been performed, were then investigated. A 45-min incubation period was found to be a favorable compromise for all the substrates in the cocktail. Ultra-high pressure liquid chromatography coupled to an electrospray ionization time-of-flight mass spectrometer was used to separate the 10 substrates and their UGT-specific glucuronides in less than 6 min. The ability of the cocktail to highlight the UGT inhibitory potential of xenobiotics was initially proven by using well-known UGT inhibitors (selective and nonselective) and then by relating some of the screening results obtained by using the cocktail approach with morphine glucuronidation (substrate highly glucuronidated by UGT 2B7). All the results were in agreement with both the literature and with the expected effect on morphine glucuronidation. PMID:25684194

  6. Synthesis and structure of the first organic-inorganic hybrid tin (II) chlorosulfate: [C 6N 2H 14][SnCl 2SO 4

    NASA Astrophysics Data System (ADS)

    Wang, Ying; Xu, Jia-ning; Sun, Jin-yu; Wang, Li; Sun, Fu-xing; Fan, Yong; Xin, Ming-hong; Shi, Su-hua; Zhu, Guang-shan

    2006-09-01

    The first organic-inorganic hybrid tin (II) chlorosulfate [C 6N 2H 14][SnCl 2SO 4] ( I) has been synthesized hydrothermally in the presence of organic amine 1,4-diazobicyclo[2,2,2]octane (DABCO) and characterized by single-crystal X-ray diffraction, IR, ICP and elemental analysis and thermogravimetric analysis and its structure solved by single-crystal X-ray diffraction. The structure of I consists of [SnCl 2SO 4] 2- anions and diprotonated DABCO cations resulting in the formation of a 2D supramolecular network based on hydrogen bonds which contact between diprotonated DABCO cations and [SnCl 2SO 4] 2- anions. Crystal data for compound I, orthorhombic space group C222 1, a = 9.354(6) Å, b = 9.6880(7) Å, c = 13.2888(9) Å, V = 1204.32(14) Å 3, Z = 4, M = 399.84(1), Dcalc = 2.205 g cm -3, Mo Kα, R1 = 0.0254, wR2 = 0.0616, GOF = 1.092.

  7. Peloruside A, a microtubule-stabilizing agent, induces aneuploidy in ovarian cancer cells.

    PubMed

    Chan, Ariane; Singh, A Jonathan; Northcote, Peter T; Miller, John H

    2016-08-01

    To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-stabilizing agents can induce aneuploid populations of cells in the absence of G2/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-stabilizing agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation and Western blotting were used to probe the cell cycle kinetics of MAD2 and BUBR1 dissociation from p55CDC. Using confocal microscopy, we investigated whether premature dissociation of MAD2 and BUBR1 at low (40 nM) but not high (100 nM) concentrations of peloruside A was caused by defects in the attachment of chromosomes to the mitotic spindle. An increased frequency of polar chromosomes was observed at low concentrations of peloruside A, suggesting that an increased frequency of pseudo-metaphase cells, which are not detected by the spindle assembly checkpoint, may be underlying the induction of aneuploidy. PMID:27155614

  8. Synthesis and crystal structures of two nickel coordination polymers generated from asymmetric malate ligand

    SciTech Connect

    Guo Yaqin; Xiao Dongrong; Wang Enbo . E-mail: wangenbo@public.cc.jl.cn; Lu Ying; Lue Jian; Xu Xinxin; Xu Lin

    2005-03-15

    Two nickel coordination polymers [Ni(H{sub 2}O)(C{sub 4}H{sub 4}O{sub 5})].H{sub 2}O 1 and [Ni(H{sub 2}O)(mal)(phen)] 2, have been hydrothermally synthesized and structurally characterized by single crystal X-ray diffraction. Crystal data for 1: C{sub 4}H{sub 8}O{sub 7}Ni, monoclinic Cc, a=13.156(3)A, b=7.5436(15)A, c=9.6982(19)A, {beta}=130.96(3){sup o}, Z=4. Crystal data for 2: C{sub 16}H{sub 14}N{sub 2}O{sub 6}Ni, orthorhombic Pna2{sub 1}, a=9.6113(19)A, b=19.691(4)A, c=8.0944(16)A, Z=4. Compound 1 is constructed from [Ni(H{sub 2}O)(C{sub 4}H{sub 4}O{sub 5})] sheets pillared through {beta}-carboxylate groups into a 3D framework, which exhibits a diamond-like network. Compound 2 exhibits a 3D supramolecular network. To our knowledge, compound 1 represents the first diamond-like topology in the system of metal-malate. Other characterizations by elemental analysis, IR and TG are also described. The magnetic behavior of compound 1 has been studied.

  9. The Synthesis and Crystal Structure of Doped Uranium Brannerite Phases U 1- xM xTi 2O 6 ( M=Ca 2+, La 3+, and Gd 3+)

    NASA Astrophysics Data System (ADS)

    James, M.; Watson, J. N.

    2002-05-01

    Doped uranium brannerite phases (U1-xMxTi2O6; M=Ca2+, La3+ and Gd3+; x<0.5) were synthesized at 1400°C; the range of solid solution was found to vary depending on whether sintering took place in argon or air. Powder X-ray diffraction revealed that these phases crystallized to form monoclinic (C2/m) structures. In particular, the crystal structures of U0.74Ca0.26 Ti2O6 (1) (a=9.8008(2); b=3.7276(1); c=6.8745(1); β=118.38(1); V=220.97(1); Z=2; RP=7.3%; RB=4.6%) and U0.55La0.45Ti2O6 (2) (a=9.8002(7); b=3.7510(3); c=6.9990(5); β=118.37(4); V=226.40(3); Z=2; RP=4.5%; RB=2.9%) were refined from powder neutron diffraction data, revealing planes of corner and edge-sharing TiO6 octahedra separated by 8-fold coordinate U/M atoms. The oxygen sites within these structures were found to be fully occupied, confirming that the doping of lower valence M atoms occurs in conjunction with the oxidation of U(IV) to U(V).

  10. UDP-glucuronosyltransferase 1a enzymes are present and active in the mouse blastocyst.

    PubMed

    Collier, Abby C; Yamauchi, Yasuhiro; Sato, Brittany L M; Rougée, Luc R A; Ward, Monika A

    2014-11-01

    The UDP-glucuronosyltransferase (UGT) enzymes are critical for regulating nutrients, hormones, and endobiotics, as well as for detoxifying xenobiotics. Human and murine fetuses are known to express glucuronidation enzymes, but there are currently no data prior to implantation. Here we addressed this gap in knowledge and tested whether Ugt enzymes are already present in preimplantation-stage embryos. Blastocysts were obtained after in vitro fertilization with gametes from B6D2F1 hybrid mice and from embryo culture. Protein expression and localization were determined using pan-specific UGT1A and UGT2B, as well as anti-human isoform-specific antibodies. Immunofluorescence analysis showed that blastocysts expressed Ugt1a globally, in the cytoplasm and nuclei of all of the cells. Western blots demonstrated the presence of Ugt1a6 but not Ugt1a1, Ugt1a3, Ugt1a4, or Ugt1a9. The Ugt2b proteins were not detected by either assay. The level of Ugt activity in murine blastocysts was comparable with that of the adult human liver (per milligram of protein), but the activity of β-glucuronidase, an Ugt-partnering enzyme responsible for substrate regeneration, was lower. Altogether, these data confirm that Ugt1a proteins are present and active in preimplantation murine embryos and point to a potential role for these proteins in implantation and early embryonic and fetal development. PMID:25200869

  11. UDP-Glucuronosyltransferase 1a Enzymes Are Present and Active in the Mouse Blastocyst

    PubMed Central

    Yamauchi, Yasuhiro; Sato, Brittany L.M.; Rougée, Luc R.A.; Ward, Monika A.

    2014-01-01

    The UDP-glucuronosyltransferase (UGT) enzymes are critical for regulating nutrients, hormones, and endobiotics, as well as for detoxifying xenobiotics. Human and murine fetuses are known to express glucuronidation enzymes, but there are currently no data prior to implantation. Here we addressed this gap in knowledge and tested whether Ugt enzymes are already present in preimplantation-stage embryos. Blastocysts were obtained after in vitro fertilization with gametes from B6D2F1 hybrid mice and from embryo culture. Protein expression and localization were determined using pan-specific UGT1A and UGT2B, as well as anti-human isoform-specific antibodies. Immunofluorescence analysis showed that blastocysts expressed Ugt1a globally, in the cytoplasm and nuclei of all of the cells. Western blots demonstrated the presence of Ugt1a6 but not Ugt1a1, Ugt1a3, Ugt1a4, or Ugt1a9. The Ugt2b proteins were not detected by either assay. The level of Ugt activity in murine blastocysts was comparable with that of the adult human liver (per milligram of protein), but the activity of β-glucuronidase, an Ugt-partnering enzyme responsible for substrate regeneration, was lower. Altogether, these data confirm that Ugt1a proteins are present and active in preimplantation murine embryos and point to a potential role for these proteins in implantation and early embryonic and fetal development. PMID:25200869

  12. Diagnostics development for the PEP-II B factory

    SciTech Connect

    Fisher, A.S.; Alzofon, D.; Arnett, D.; Bong, E.; Daly, E.; Gioumousis, A.; Kulikov, A.; Kurita, N.; Langton, J.; Reuter, E.; Seeman, J.T.; Wienands, H.U.; Wright, D.; Chin, M.; Hinkson, J.; Hunt, D.; Kennedy, K.

    1997-01-01

    PEP-II is a 2.2-km collider with a 2.1-A, 3.1-GeV positron ring 1 m above a 1-A, 9-GeV electron ring; both are designed for a maximum of 3 A. Several diagnostics are now in preparation for commissioning the rings. The beam size and pulse duration are measured using visible synchrotron radiation from arc dipoles. Grazing-incidence, water-cooled mirrors that must withstand up to 200 W/cm extract the light. The sum signal from a set of four pickup buttons, normalized to a DC current transformer{close_quote}s measurement of the ring current, is processed to measure the charge in each bunch. This enables us to fill 1658 of the 3492 buckets per ring to a charge that must be equal within {plus_minus}2{percent}. For diagnostics and machine protection, 100 photomultiplier-based Cherenkov detectors measure the beam-loss distribution. {copyright} {ital 1997 American Institute of Physics.}

  13. Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Venitz, Jürgen; Zack, Julia; Gillies, Hunter; Allard, Martine; Regnault, Jean; Dufton, Christopher

    2012-12-01

    The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects. PMID:22205719

  14. Two coordination polymers of manganese(II) isophthalate and their preparation, structures, and magnetic properties

    SciTech Connect

    Chen Jinxi; Wang Jingjing; Ohba, Masaaki

    2012-01-15

    Two manganese coordination polymers, [Mn{sub 2}(ip){sub 2}(dmf)]{center_dot}dmf (1) and [Mn{sub 4}(ip){sub 4}(dmf){sub 6}]{center_dot}2dmf (2) (ip=isophthalate; dmf=N,N-dimethylformamide), have been synthesized and characterized. X-ray crystal structural data reveal that compound 1 crystallizes in triclinic space group P-1, a=9.716(3) A, b=12.193(3) A, c=12.576(3) A, {alpha}=62.19(2) Degree-Sign , {beta}=66.423(17) Degree-Sign , {gamma}=72.72(2) Degree-Sign , Z=2, while compound 2 crystallizes in monoclinic space group Cc, a=19.80(3) A, b=20.20(2) A, c=18.01(3) A, {beta}=108.40(4) Degree-Sign , Z=4. Variable-temperature magnetic susceptibilities of compounds 1 and 2 exhibit overall weak antiferromagnetic coupling between the adjacent Mn(II) ions. - Graphical abstract: Three-dimensional porous and two-dimensional layered manganese isophthalates have been prepared. Magnetic susceptibility measurements exhibit overall weak antiferromagnetic interactions between the Mn(II) ions in both compounds. Highlights: Black-Right-Pointing-Pointer Two manganese isophthalates have been prepared. Black-Right-Pointing-Pointer Compound 1 adopts a three-dimensional porous structure. Black-Right-Pointing-Pointer Compound 2 adopts a two-dimensional layered structure. Black-Right-Pointing-Pointer Magnetic properties of both compounds are investigated.

  15. Isoform-selective probe substrates for in vitro studies of human UDP-glucuronosyltransferases.

    PubMed

    Court, Michael H

    2005-01-01

    The majority of UDP-glucuronosyltransferases (UGT), like other drug-metabolizing enzymes, display broad and often overlapping substrate specificities, complicating evaluation of the function of individual UGT isoforms within human tissues. Despite this, there have been recent advances in identifying UGT-selective probes--UGT substrates that are primarily glucuronidated by a single isoform. Such probes can be used to (1) facilitate identification of UGT isoforms mediating a particular glucuronidation activity in human liver through activity correlation analysis; (2) evaluate the role of particular UGTs in drug-drug interactions through either enzyme induction or inhibition; and (3) elucidate the functional significance of genetic polymorphisms associated with the gene encoding the UGT of interest. UGT-selective probes currently being used in our laboratory for the evaluation of glucuronidation activities in human liver tissues include estradiol (3OH-glucuronidation; UGT1A1), trifluoperazine (UGT1A4) serotonin (UGT1A6), propofol (UGT1A9), 3'-azidothymidine (UGT2B7), and S-oxazepam (UGT2B15). In vitro incubation protocols and the HPLC analysis methods used to determine each of these activities are described in detail. Future work is needed to elucidate more highly selective probes than those in current usage, as well as probes for the extrahepatic UGT isoforms. PMID:16399346

  16. A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase—extensive moonlighting in mitochondrial tRNA biogenesis

    PubMed Central

    Vilardo, Elisa; Nachbagauer, Christa; Buzet, Aurélie; Taschner, Andreas; Holzmann, Johann; Rossmanith, Walter

    2012-01-01

    Transfer RNAs (tRNAs) reach their mature functional form through several steps of processing and modification. Some nucleotide modifications affect the proper folding of tRNAs, and they are crucial in case of the non-canonically structured animal mitochondrial tRNAs, as exemplified by the apparently ubiquitous methylation of purines at position 9. Here, we show that a subcomplex of human mitochondrial RNase P, the endonuclease removing tRNA 5′ extensions, is the methyltransferase responsible for m1G9 and m1A9 formation. The ability of the mitochondrial tRNA:m1R9 methyltransferase to modify both purines is uncommon among nucleic acid modification enzymes. In contrast to all the related methyltransferases, the human mitochondrial enzyme, moreover, requires a short-chain dehydrogenase as a partner protein. Human mitochondrial RNase P, thus, constitutes a multifunctional complex, whose subunits moonlight in cascade: a fatty and amino acid degradation enzyme in tRNA methylation and the methyltransferase, in turn, in tRNA 5′ end processing. PMID:23042678

  17. [Chronic osteitis and arthritis of palmoplantar pustulosis. A familial form of B-27 negative spondylarthropathy].

    PubMed

    Kurc, D; De Saint-Père, R; Madoule, P; Laoussadi, S; Caquet, R

    1987-01-01

    A 35-year old woman presented with pustulosis palmaris et plantaris evolving in acute episodes parallel to those of a rheumatic disease consisting of bilateral sacro-iliac arthritis, manubriosternal fusion and sterno-clavicular arthritis. Her brother had spondylitis compatible with the diagnosis of pustular osteo-arthritis though without pustulosis. He presented with bilateral sacro-iliac arthritis, manubriosternal fusion, sterno-clavicular arthritis and an ossified fragment detached from the antero-inferior angle of C6. The two patients had the same HLA phenotype: A1, A9, B5, B41, CW4, DR2, DR4, absence of B27. In a specimen from the sacro-iliac joint the authors found active bone remodelling and inflammatory osteitis with fibrosis and infiltrates rich in mononucleate cells. An electron microscopic study--to the authors' knowledge, the first to be performed in such cases--demonstrated intracytoplasmic filamentous inclusions in two macrophages of the synovial fringe. Only one other case of the familial form has been published so far. Like the rheumatism of acne conglobata, the spondylitis of pustulosis palmaris et plantaris is one of the causes of sterno-costo-clavicular hyperostosis. PMID:3563168

  18. SiC lightweight telescopes for advanced space applications. I - Mirror technology

    NASA Technical Reports Server (NTRS)

    Anapol, Michael I.; Hadfield, Peter

    1992-01-01

    A SiC based telescope is an extremely attractive emerging technology which offers the lightweight and stiffness features of beryllium, the optical performance of glass to diffraction limited visible resolution, superior optical/thermal stability to cryogenic temperatures, and the cost advantages of an aluminum telescope. SSG has developed various SiC mirrors with and without a silicon coating and tested these mirrors over temperature ranges from +50 C to -250 C. Our test results show less than 0.2 waves P-V in visible wavefront change and no hysteresis over this wide temperature range. Several SSG mirrors are representative of very lightweight SiC/Si mirrors including (1) a 9 cm diameter, high aspect ratio mirror weighing less than 30 grams and (2) a 23 cm diameter eggcrated mirror weighing less than 400 grams. SSG has also designed and analyzed a 0.6 meter SiC based, on axis, three mirror reimaging telescope in which the primary mirror weighs less than 6 kg and a 0.5 meter GOES-like scan mirror. SSG has also diamond turned several general aspheric SiC/Si mirrors with excellent cryo optical performance.

  19. Synthesis, structure, photoluminescence and antitumour activity of zinc complex based on 2-(2-(1H-benzo-[d]imidazol-2-yl)benzyl)-1H-benzo-[d]imidazole

    NASA Astrophysics Data System (ADS)

    Che, Zhijian; Wang, Shaoxiang; Liu, Shenggui; Li, Guobi; Wu, Qiting; Lin, Chunyu; Kong, Linglang; Wang, Sheng

    2015-01-01

    A new complex [Zn(bbb)Cl2]·DMF, where bbb is 2-(2-(1H-benzo[d]imidazol-2-yl)benzyl)-1H-benzo[d]imidazole, was synthesized and characterized by element analysis, 1H NMR and X-ray single crystal structure analyses. For complex: crystal system, triclinic, space group, P-1, a = 9.4661(13), b = 10.3534(14), c = 13.0025(18) Å, α = 73.477(2), β = 80.743(2), γ = 88.658(2)°, V = 1205.5(3) Å3, Z = 2. In this complex, the Zn2+ distorted tetrahedron geometry is coordinated by two nitrogen atoms from 2-(2-(1H-benzo[d]imidazol-2-yl)benzyl)-1H-benzo[d]imidazole and two Cl-. The complex emits yellow green luminescence with the maximal emission peak at 550 nm in DMF solution. The complex exhibits inhibition on the growth of Eca109 cancer cell with IC50 value of 8.9 ± 1.1 μM, which was lower than that of cisplatin (14.3 ± 1.4 μM). This complex has potential application in treatment of esophageal cancer.

  20. Benzo(a)pyrene and 7,12-dimethylbenz(a)anthrecene differentially affect bone marrow cells of the lymphoid and myeloid lineages

    SciTech Connect

    Galvan, Noe; Page, Todd J.; Czuprynski, Charles J.; Jefcoate, Colin R. . E-mail: jefcoate@facstaff.wisc.edu

    2006-06-01

    Polycyclic aromatic hydrocarbons (PAHs) are common environmental contaminants that are carcinogenic and immunosuppressive. Benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) are two prototypic PAHs known to impair the cell-mediated and humoral immune responses. We have previously shown that, in C57BL/6J mice, total bone marrow (BM) cellularity decreased two-fold following intraperitoneal DMBA treatment but not BP treatment. Here, we have used flow cytometry to demonstrate that BP and DMBA differentially alter the lymphoid and myeloid lineages. Following DMBA treatment, the pro/pre B-lymphocytes (B220{sup lo}/IgM{sup -}) and the immature B-lymphocytes (B220{sup lo}/IgM{sup +}) significantly decreased, while the mature B-lymphocytes (B220{sup hi}/IgM{sup +}) remained unaffected. In contrast, BP treatment decreased the pro/pre B-lymphocytes, and did not affect the immature B-lymphocytes or mature B-lymphocytes. The Gr-1{sup +} cells of the myeloid lineage were depleted 50% following DMBA treatment and only minimally depleted following BP treatment. Interestingly, the monocytes (7/4{sup +}1A8{sup lo}) and neutrophils (7/4{sup +}1A8{sup hi}) within this Gr-1{sup +} population were differentially affected by these PAHs. Monocytes and neutrophils were depleted following DMBA treatment whereas neutrophils decreased and monocytes increased following BP treatment. Although TNF{alpha} and CYP1B1 are implicated as essential mediators of hypocellularity, the similar induction of TNF{alpha} mRNA and CYP1B1 mRNA in the BM by BP and DMBA suggests that they are not limiting factors in mediating the different effects of these PAHs. Given that similar amounts of BP and DMBA reach the BM when administered intraperitoneally, their differential effects on the lymphoid and myeloid lineages probably stem from differences in reactive metabolites such as PAH quinones and PAH-dihydrodiol-epoxides.

  1. Y-chromosomal variation in sub-Saharan Africa: insights into the history of Niger-Congo groups.

    PubMed

    de Filippo, Cesare; Barbieri, Chiara; Whitten, Mark; Mpoloka, Sununguko Wata; Gunnarsdóttir, Ellen Drofn; Bostoen, Koen; Nyambe, Terry; Beyer, Klaus; Schreiber, Henning; de Knijff, Peter; Luiselli, Donata; Stoneking, Mark; Pakendorf, Brigitte

    2011-03-01

    Technological and cultural innovations as well as climate changes are thought to have influenced the diffusion of major language phyla in sub-Saharan Africa. The most widespread and the richest in diversity is the Niger-Congo phylum, thought to have originated in West Africa ∼ 10,000 years ago (ya). The expansion of Bantu languages (a family within the Niger-Congo phylum) ∼ 5,000 ya represents a major event in the past demography of the continent. Many previous studies on Y chromosomal variation in Africa associated the Bantu expansion with haplogroup E1b1a (and sometimes its sublineage E1b1a7). However, the distribution of these two lineages extends far beyond the area occupied nowadays by Bantu-speaking people, raising questions on the actual genetic structure behind this expansion. To address these issues, we directly genotyped 31 biallelic markers and 12 microsatellites on the Y chromosome in 1,195 individuals of African ancestry focusing on areas that were previously poorly characterized (Botswana, Burkina Faso, Democratic Republic of Congo, and Zambia). With the inclusion of published data, we analyzed 2,736 individuals from 26 groups representing all linguistic phyla and covering a large portion of sub-Saharan Africa. Within the Niger-Congo phylum, we ascertain for the first time differences in haplogroup composition between Bantu and non-Bantu groups via two markers (U174 and U175) on the background of haplogroup E1b1a (and E1b1a7), which were directly genotyped in our samples and for which genotypes were inferred from published data using linear discriminant analysis on short tandem repeat (STR) haplotypes. No reduction in STR diversity levels was found across the Bantu groups, suggesting the absence of serial founder effects. In addition, the homogeneity of haplogroup composition and pattern of haplotype sharing between Western and Eastern Bantu groups suggests that their expansion throughout sub-Saharan Africa reflects a rapid spread followed by

  2. Design of co-crystals/salts of some Nitrogenous bases and some derivatives of thiophene carboxylic acids through a combination of hydrogen and halogen bonds

    PubMed Central

    2014-01-01

    Background The utility of N-heterocyclic bases to obtain molecular complexes with carboxylic acids is well studied. Depending on the solid state interaction between the N-heterocyclic base and a carboxylic acid a variety of neutral or ionic synthons are observed. Meanwhile, pyridines and pyrimidines have been frequently chosen in the area of crystal engineering for their multipurpose functionality. HT (hetero trimers) and LHT (linear heterotetramers) are the well known synthons that are formed in the presence of pyrimidines and carboxylic acids. Results Fourteen crystals involving various substituted thiophene carboxylic acid derivatives and nitrogenous bases were prepared and characterized by using single crystal X-ray diffraction. The 14 crystals can further be divided into two groups [1a-7a], [8b-14b] based on the nature of the nitrogenous base. Carboxylic acid to pyridine proton transfer has occurred in 3 compounds of each group. In addition to the commonly occurring hydrogen bond based pyridine/carboxylic acid and pyrimidine/carboxylic acid synthons which is the reason for assembly of primary motifs, various other interactions like Cl…Cl, Cl…O, C–H…Cl, C-H…S add additional support in organizing these supermolecules into extended architectures. It is also interesting to note that in all the compounds π-π stacking occurs between the pyrimidine-pyrimidine or pyridine-pyridine or acid-acid moieties rather than acid-pyrimidine/pyridine. Conclusions In all the compounds (1a-14b) either neutral O–H…Npyridyl/pyrimidine or charge-assisted Npyridinium-H…Ocarboxylate hydrogen bonds are present. The HT (hetero trimers) and LHT (linear heterotetramers) are dominant in the crystal structures of the adducts containing N-heterocyclic bases with two proton acceptors (1a-7a). Similar type supramolecular ladders are observed in 5TPC44BIPY (8b), TPC44BIPY (9b), TPC44TMBP (11b). Among the seven compounds [8b-14b] the extended ligands are linear in all except for

  3. Molecular evolution of coding and non-coding sequences of the growth hormone receptor (GHR) gene in the family Bovidae.

    PubMed

    Maj, Andrzej; Zwierzchowski, Lech

    2006-01-01

    The GHR gene exon 1A and exon 4 with fragments of its flanking introns were sequenced in twelve Bovidae species and the obtained sequences were aligned and analysed by the ClustalW method. In coding exon 4 only three interspecies differences were found, one of which had an effect on the amino-acid sequence--leucine 152 proline. The average mutation frequency in non-coding exon 1A was 10.5 per 100 bp, and was 4.6-fold higher than that in coding exon 4 (2.3 per 100 bp). The mutation frequency in intron sequences was similar to that in non-coding exon 1A (8.9 vs 10.5/100 bp). For non-coding exon 1A, the mutation levels were lower within than between the subfamilies Bovinae and Caprinae. Exon 4 was 100% identical within the genera Ovis, Capra, Bison, and Bos and 97.7% identical for Ovis moschatus, Ammotragus lervia and Bovinae species. The identity level of non-coding exon 1A of the GHR gene was 93.8% between species belonging to Bovinae and Caprinae. The average mutation rate was 0.2222/100 bp/MY and 0.0513/100 bp/MY for the Bovidae GHR gene exons 1A and 4, respectively. Thus, the GHR gene is well conserved in the Bovidae family. Also, in this study some novel intraspecies polymorphisms were found for cattle and sheep. PMID:17044257

  4. Full Genomic Characterization of a Novel Genotype Combination, G4P[14], of a Human Rotavirus Strain from Barbados

    PubMed Central

    Tam, Ka Ian; Roy, Sunando; Esona, Mathew D.; Jones, Starlene; Sobers, Stephanie; Morris-Glasgow, Victoria; Rey-Benito, Gloria; Gentsch, Jon R.; Bowen, Michael D.

    2015-01-01

    Since 2004, the Pan American Health Organization (PAHO) has carried out rotavirus surveillance in Latin America and the Caribbean. Here we report the characterization of human rotavirus with the novel G-P combination of G4P[14], detected through PAHO surveillance in Barbados. Full genome sequencing of strain RVA/Human-wt/BRB/CDC1133/2012/G4P[14] revealed that its genotype is G4-P[14]-I1-R1-C1-M1-A8-N1-T1-E1-H1. The possession of a Genogroup 1 (Wa-like) backbone distinguishes this strain from other P[14] rotavirus strains. Phylogenetic analyses suggested that this strain was likely generated by genetic reassortment between human, porcine and possibly other animal rotavirus strains and identified 7 lineages within the P[14] genotype. The results of this study reinforce the potential role of interspecies transmission in generating human rotavirus diversity through reassortment. Continued surveillance is important to determine if rotavirus vaccines will protect against strains that express the P[14] rotavirus genotype. PMID:25251674

  5. Whole genomic analysis of a porcine-like human G5P[6] rotavirus strain isolated from a child with diarrhoea and encephalopathy in Japan.

    PubMed

    Komoto, Satoshi; Maeno, Yoshimasa; Tomita, Mayuko; Matsuoka, Tsuyoshi; Ohfu, Masaharu; Yodoshi, Toshifumi; Akeda, Hideki; Taniguchi, Koki

    2013-07-01

    An unusual rotavirus strain, Ryukyu-1120, with G5P[6] genotypes (RVA/Human-wt/JPN/Ryukyu-1120/2011/G5P[6]) was identified in a stool specimen from a hospitalized child aged 4 years who showed diarrhoea and encephalopathy. In this study, we sequenced and characterized the complete genome of strain Ryukyu-1120. On whole genomic analysis, this strain was found to have a unique genotype constellation: G5-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1. The VP6 and NSP1 genotypes I5 and A8 are those commonly found in porcine strains. Furthermore, phylogenetic analysis indicated that each of the 11 genes of strain Ryukyu-1120 appeared to be of porcine origin. Thus, strain Ryukyu-1120 was found to have a porcine rotavirus genetic backbone and is likely to be of porcine origin. To our knowledge, this is the first report of whole-genome-based characterization of the emerging G5P[6] strains in Asian countries. Our observations will provide important insights into the origin of G5P[6] strains and the dynamic interactions between human and porcine rotavirus strains. PMID:23515025

  6. Serum protein polymorphism in Bali (Indonesia).

    PubMed

    Constans, J; Gouaillard, C; Breguet, G

    1986-01-01

    Serum samples from Bali, obtained in three different ethnic groups and in one isolated village were tested by isoelectric focusing electrophoresis for Gc, Pi, Tf and Hp subtyping. In addition to the three common alleles Gc1F, Gc1S and Gc2, two variants Gc1A1 and Gc1A8 were observed. In the Pi system, five alleles were present: PiM1, PiM2, PiM3, PiM4 and PiX. The Tf variability was exceptional with the presence of eight alleles: TfB1, TfC1, TfC2, TfC3, TfC4, TfC8, TfD1 and TfDchi. For Hp, there were two common alleles Hp1S and Hp1FS and two rare ones: Hp1F and Hp2SS. As expected, the genetic polymorphism is reduced in the isolated community. The anthropological significance of these genetic data is discussed. PMID:3493727

  7. Compartment-specific remodeling of splenic micro-architecture during experimental visceral leishmaniasis.

    PubMed

    Yurdakul, Pinar; Dalton, Jane; Beattie, Lynette; Brown, Najmeeyah; Erguven, Sibel; Maroof, Asher; Kaye, Paul M

    2011-07-01

    Progressive splenomegaly is a hallmark of visceral leishmaniasis in humans, canids, and rodents. In experimental murine visceral leishmaniasis, splenomegaly is accompanied by pronounced changes in microarchitecture, including expansion of the red pulp vascular system, neovascularization of the white pulp, and remodeling of the stromal cell populations that define the B-cell and T-cell compartments. Here, we show that Ly6C/G(+) (Gr-1(+)) cells, including neutrophils and inflammatory monocytes, accumulate in the splenic red pulp during infection. Cell depletion using monoclonal antibody against either Ly6C/G(+) (Gr-1; RB6) or Ly6G(+) (1A8) cells increased parasite burden. In contrast, depletion of Ly6C/G(+) cells, but not Ly6G(+) cells, halted the progressive remodeling of Meca-32(+) and CD31(+) red pulp vasculature. Strikingly, neither treatment affected white pulp neovascularization or the remodeling of the fibroblastic reticular cell and follicular dendritic cell networks. These findings demonstrate a previously unrecognized compartment-dependent selectivity to the process of splenic vascular remodeling during experimental murine visceral leishmaniasis, attributable to Ly6C(+) inflammatory monocytes. PMID:21703391

  8. Amphiphilic ferrocenylated alkylpyridinium: the formation of micelles and hydrogels and their disaggregation induced by an external stimulus.

    PubMed

    Suzaki, Yuji; Endo, Hirotaka; Kojima, Takahiro; Osakada, Kohtaro

    2013-12-01

    Ferrocene-containing amphiphiles [py-N-(CH2)nOCH2Fc]Cl (n = 6 (1a), 8 (1b), 10 (1c); py = C5H5N, Fc = Fe(C5H4)(C5H5)) were synthesized. The absorption spectra of 1a-1c in the presence of a small amount of dye (Nile red and pyrene) in aqueous media suggested the formation of micelles which encapsulated the dye molecules. Two critical micelle concentrations were observed at 1.1 mM and 2.3 mM at 20 °C. Compounds 1a and 1c showed a single CMC for each, while the formation of two kinds of micelles, the spherical and rod-like ones, depended on the concentrations. The addition of an oxidant, NaOCl, to the aqueous solution of the micelles of 1b turned ferrocene to ferrocenium and caused the disaggregation of the micelles. The addition of α-cyclodextrin (α-CD) to 2b caused the disaggregation of the micelle and the formation of water-soluble [2]- and [3]pseudorotaxane [{py-N-(CH2)8OCH2Fc}(α-CD)m]Cl (1b(α-CD)m) (m = 1, 2), while mixing 1c and α-CD in water formed the rotaxane gel. The addition of NaOCl to the hydrogel of 1c and α-CD changed the gel to sol. PMID:24141739

  9. Solution behavior and crystallization of cytochrome bc₁ in the presence of amphipols.

    PubMed

    Charvolin, Delphine; Picard, Martin; Huang, Li-Shar; Berry, Edward A; Popot, Jean-Luc

    2014-10-01

    Detergents classically are used to keep membrane proteins soluble in aqueous solutions, but they tend to destabilize them. This problem can be largely alleviated thanks to the use of amphipols (APols), small amphipathic polymers designed to substitute for detergents. APols adsorb at the surface of the transmembrane region of membrane proteins, keeping them water-soluble while stabilizing them bio-chemically. Membrane protein/APol complexes have proven, however, difficult to crystallize. In this study, the composition and solution properties of complexes formed between mitochondrial cytochrome bc1 and A8-35, the most extensively used APol to date, have been studied by means of size exclusion chromatography, sucrose gradient sedimentation, and small-angle neutron scattering. Stable, monodisperse preparations of bc1/A8-35 complexes can be obtained, which, depending on the medium, undergo either repulsive or attractive interactions. Under crystallization conditions, diffracting three-dimensional crystals of A8-35-stabilized cytochrome bc1 formed, but only in the concomitant presence of APol and detergent. PMID:24942818

  10. Deep into the roots of the Libyan Tuareg: a genetic survey of their paternal heritage.

    PubMed

    Ottoni, Claudio; Larmuseau, Maarten H D; Vanderheyden, Nancy; Martínez-Labarga, Cristina; Primativo, Giuseppina; Biondi, Gianfranco; Decorte, Ronny; Rickards, Olga

    2011-05-01

    Recent genetic studies of the Tuareg have begun to uncover the origin of this semi-nomadic northwest African people and their relationship with African populations. For centuries they were caravan traders plying the trade routes between the Mediterranean coast and south-Saharan Africa. Their origin most likely coincides with the fall of the Garamantes who inhabited the Fezzan (Libya) between the 1st millennium BC and the 5th century AD. In this study we report novel data on the Y-chromosome variation in the Libyan Tuareg from Al Awaynat and Tahala, two villages in Fezzan, whose maternal genetic pool was previously characterized. High-resolution investigation of 37 Y-chromosome STR loci and analysis of 35 bi-allelic markers in 47 individuals revealed a predominant northwest African component (E-M81, haplogroup E1b1b1b) which likely originated in the second half of the Holocene in the same ancestral population that contributed to the maternal pool of the Libyan Tuareg. A significant paternal contribution from south-Saharan Africa (E-U175, haplogroup E1b1a8) was also detected, which may likely be due to recent secondary introduction, possibly through slavery practices or fusion between different tribal groups. The difference in haplogroup composition between the villages of Al Awaynat and Tahala suggests that founder effects and drift played a significant role in shaping the genetic pool of the Libyan Tuareg. PMID:21312181

  11. IN VITRO GLUCURONIDATION OF APREPITANT: A MODERATE INHIBITOR OF UGT2B7

    PubMed Central

    House, Larry; Ramirez, Jacqueline; Seminerio, Michael; Mirkov, Snezana; Ratain, Mark J.

    2016-01-01

    Aprepitant, an oral antiemetic, commonly used in the prevention of chemotherapy-induced nausea and vomiting, is primarily metabolized by CYP3A4. Aprepitant glucuronidation has yet to be evaluated in humans. The contribution of human UDP-glucuronosyltransferase (UGT) isoforms to the metabolism of aprepitant was investigated by performing kinetic studies, inhibition studies, and correlation analyses. In addition, aprepitant was evaluated as an inhibitor of UGTs.Glucuronidation of aprepitant was catalyzed by UGT1A4 (82%), UGT1A3 (12%), and UGT1A8 (6%) and Kms were 161.6 ± 15.6 µM, 69.4 ± 1.9 µM, and 197.1 ± 28.2 µM, respectively. Aprepitant glucuronidation was significantly correlated with both UGT1A4 substrates anastrazole and imipramine (rs = 0.77, P < 0.0001 for both substrates; n = 44), and with the UGT1A3 substrate thyroxine (rs = 0.58, P < 0.0001; n = 44).We found aprepitant to be a moderate inhibitor of UGT2B7 with a Ki of ~10 µM for 4-MU, morphine, and zidovudine. Our results suggest aprepitant can alter clearance of drugs primarily eliminated by UGT2B7. Given the likelihood for first-pass metabolism by intestinal UGT2B7, this is of particular concern for oral aprepitant co-administered with oral substrates of UGT2B7, such as zidovudine and morphine. PMID:26053558

  12. Neutrophils have a protective role during early stages of Leishmania amazonensis infection in BALB/c mice.

    PubMed

    Sousa, L M A; Carneiro, M B H; Resende, M E; Martins, L S; Dos Santos, L M; Vaz, L G; Mello, P S; Mosser, D M; Oliveira, M A P; Vieira, L Q

    2014-01-01

    Neutrophils are involved in the early stages of immune responses to pathogens. Here, we investigated the role of neutrophils during the establishment of Leishmania amazonensis infection in BALB/c and C57BL/6 mice. First, we showed an accumulation of neutrophils between 6 and 24 h post-infection, followed by a reduction in neutrophil numbers after 72 h. Next, we depleted neutrophils prior to infection using RB6-8C5 or 1A8 mAb. Neutrophil depletion led to faster lesion development, increased parasite numbers and higher arginase activity during the first week of infection in BALB/c mice, but not in C57BL/6 mice. Increased susceptibility was accompanied by augmented levels of anti-L. amazonensis IgG and increased production of IL-10 and IL-17. Because IL-10 is a mediator of susceptibility to Leishmania infection, we blocked IL-10 signalling in neutrophil-depleted mice using anti-IL-10R. Interestingly, inhibition of IL-10 signalling abrogated the increase in parasite loads observed in neutrophil-depleted mice, suggesting that parasite proliferation is at least partially mediated by IL-10. Additionally, we tested the effect of IL-17 in inflammatory macrophages and observed that IL-17 increased arginase activity and favoured parasite growth. Taken together, our data indicate that neutrophils control parasite numbers and limit lesion development during the first week of infection in BALB/c mice. PMID:24102495

  13. A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

    PubMed Central

    Milton, Jacqueline N.; Sebastiani, Paola; Solovieff, Nadia; Hartley, Stephen W.; Bhatnagar, Pallav; Arking, Dan E.; Dworkis, Daniel A.; Casella, James F.; Barron-Casella, Emily; Bean, Christopher J.; Hooper, W. Craig; DeBaun, Michael R.; Garrett, Melanie E.; Soldano, Karen; Telen, Marilyn J.; Ashley-Koch, Allison; Gladwin, Mark T.; Baldwin, Clinton T.; Steinberg, Martin H.; Klings, Elizabeth S.

    2012-01-01

    Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5×10−8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10−25). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15×10−4). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities. PMID:22558097

  14. Synthesis, structural characterization and in vitro biological screening of some homoleptic copper(II) complexes with substituted guanidines.

    PubMed

    Murtaza, Ghulam; Rauf, Muhammad Khawar; Badshah, Amin; Ebihara, Masahiro; Said, Muhammad; Gielen, Marcel; de Vos, Dick; Dilshad, Erum; Mirza, Bushra

    2012-02-01

    A series of homoleptic copper(II) complexes (1a-8a) with N,N',N″-trisubstituted guanidines, [Cu(II){PhCONHC(NHR)NPh}(2)] (where R = phenyl (1a), n-butyl (2a), sec-butyl (3a), cyclohexyl (4a), 1-naphthyl (5a), 2,4-dichlorophenyl (6a), 3,4-dichlorophenyl (7a), and 3,5-dichlorophenyl (8a)) have been synthesized and characterized by elemental analyses, FT-IR, UV-visible, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction analysis. The X-ray crystal structures revealed that the complexes 2a and 4a are mononuclear in the solid state and that the geometry around the copper atom is nearly square planar. In both the cases, N,N',N″-trisubstituted guanidine ligands have been coordinated to the Cu(II) through the oxygen and nitrogen atoms. The synthesized guanidines and their complexes were initially screened for their anti-microbial activities, and Brine Shrimps Lethality assay. The complexes were also screened for in vitro cytotoxicity activity in human cell lines carcinomas A498, EVSAT, H226, IGROV, M19, MCF-7 and WIDR. The results show a moderate level of cytotoxicity against these seven human cancer cell lines as compared with standard chemotherapeutic drugs. PMID:22177420

  15. Neutrophil Dependence of Vascular Remodeling after Mycoplasma Infection of Mouse Airways

    PubMed Central

    Baluk, Peter; Phillips, Keeley; Yao, Li-Chin; Adams, Alicia; Nitschké, Maximilian; McDonald, Donald M.

    2015-01-01

    Vascular remodeling is a feature of sustained inflammation in which capillaries enlarge and acquire the phenotype of venules specialized for plasma leakage and leukocyte recruitment. We sought to determine whether neutrophils are required for vascular remodeling in the respiratory tract by using Mycoplasma pulmonis infection as a model of sustained inflammation in mice. The time course of vascular remodeling coincided with the influx of neutrophils during the first few days after infection and peaked at day 5. Depletion of neutrophils with antibody RB6-8C5 or 1A8 reduced neutrophil influx and vascular remodeling after infection by about 90%. Similarly, vascular remodeling after infection was suppressed in Cxcr2−/− mice, in which neutrophils adhered to the endothelium of venules but did not extravasate into the tissue. Expression of the venular adhesion molecule P-selectin increased in endothelial cells from day 1 to day 3 after infection, as did expression of the Cxcr2-receptor ligands Cxcl1 and Cxcl2. Tumor necrosis factor α (TNFα) expression increased more than sixfold in the trachea of wild-type and Cxcr2−/− mice, but intratracheal administration of TNFα did not induce vascular remodeling similar to that seen in infection. We conclude that neutrophil influx is required for remodeling of capillaries into venules in the airways of mice with Mycoplasma infection and that TNFα signaling is necessary but not sufficient for vascular remodeling. PMID:24726646

  16. Synthesis, structure and electrochemical behavior of a 3D crystalline copper(II) metal-organic framework

    NASA Astrophysics Data System (ADS)

    Bai, Hong-Ye; Fan, Wei-Qiang; Liu, Chun-Bo; Shi, Wei-Dong; Yan, Yong-Sheng

    2014-05-01

    Using an flexible amide-type tripodal ligand N,N‧,N″-tris(3-pyridyl)-1,3,5-benzenetricarboxamide (L) and 1,4-benzenedicarboxylic acid (H2bdc), a three-dimensional copper(II) metal-organic framework (MOF) formulated as [Cu(bdc)(L)]n has been hydrothermally synthesized and structurally characterized by IR, elemental, X-ray single-crystal diffraction and thermal analysis. The complex crystallizes in the triclinic, space group P - 1, a = 8.891(2) Å, b = 11.760(2) Å, c = 15.348(3) Å, α = 96.73(3)°, β = 105.96(3)°, γ = 106.47(3)°, V = 1446.2(5) Å3, Mr = 666.10, Dc = 1.530 g/cm3, Z = 2, F(000) = 682, GOOF = 1.0560, μ(MoKα) = 0.817 mm-1, R = 0.0366 and wR = 0.0885. The structural analyses reveal that the title compound consists of one Cu(II) atom, two halves of bdc, and one L ligand. Each Cu(II) atom is linked by two bdc ligands and three L ligands to form a three-dimensional network. In addition, the electrochemical behavior of title compound has been studied. CCDC No. 990526.

  17. The synthesis and structure of a chiral 1D aluminophosphate chain compound: d-Co(en) 3[AlP 2O 8]·6.5H 2O

    NASA Astrophysics Data System (ADS)

    Chen, Peng; Li, Jiyang; Yu, Jihong; Wang, Yu; Pan, Qinhe; Xu, Ruren

    2005-06-01

    A new chiral one-dimensional (1D) aluminophosphate chain compound [ d-Co(en) 3][AlP 2O 8]·6.5H 2O (designated AlPO-CJ22) has been hydrothermally synthesized by using the optically pure d-Co(en) 3I 3 complex as the template. Single-crystal structural analysis reveals that its structure is built up from alternating connection of AlO 4 and PO 2(=O 2) tetrahedra to form corner-shared Al 2P 2 four-membered ring (4-MR) chains. The d-Co(en) 33+ complex cations extended along the 2 1 screw axis interact with the inorganic chains through hydrogen-bonds of N⋯O atoms in a helical fashion. Optical rotation measurement shows that AlPO-CJ22 is chiral as with d-Co(en) 33+ complex cations. Crystal data: orthorhombic, I2 12 12 1, a=8.5573(8) Å, b=22.613(2) Å, c=22.605(2) Å, Z=8, R1=0.067, wR2=0.1291, and Flack parameter: -0.02(3). CCDC number: 254179.

  18. Rotavirus vaccine: a cost effective control measure for India.

    PubMed

    Kumar, Arun; Goel, Manish K; Jain, Ram Bilas; Khanna, Pardeep; Vibha, Vibha

    2012-04-01

    Globally, rotavirus diarrhea results in 453,000 deaths in children younger than 5 y—37% of deaths attributable to diarrhea and 5% of all deaths in children younger than 5 y. India alone accounts for 22% (~100,000 deaths) of all deaths attributable to rotavirus infection. Two oral rotavirus vaccines are available: Rotarix, a monovalent P1A[8] G1 vaccine (GlaxoSmithKline), and RotaTeq, a pentavalent bovine-human reassortant vaccine (Merck). Rotarix is administered in a 2-dose schedule with the first and second doses of DTP (DTP1, DTP2). RotaTeq requires a 3-dose schedule with DTP1, DTP2 and DTP3 with an interval of 4–10 weeks between doses. The first dose of either vaccine should be administered to infants aged 6–15 weeks irrespective of the history of previous rotavirus infection, and the maximum age for administering the last dose of either vaccine should be 32 weeks. Although India would require funding from international health organizations/GAVI until new indigenous rotavirus vaccine candidates are developed at a cheaper price, introduction of vaccination into the national immunization program would be a cost-effective step toward control of the rotavirus diarrhea-related morbidity and mortality in India. PMID:23071989

  19. Interaction between oblongifolin C and UDP-glucuronosyltransferase isoforms in human liver and intestine microsomes.

    PubMed

    Gao, Cui; Shi, Rong; Wang, Tianming; Tan, Hongsheng; Xu, Hongxi; Ma, Yueming

    2015-01-01

    1. Oblongifolin C (OC) is a potential natural anticancer candidate, and its metabolic profile has not yet been established. 2. One major OC glucuronidation metabolite (OCG) has been identified in a pool of human liver microsomes (HLMs). Chemical inhibition experiments suggested that OCG was mainly formed by UGT1A. A screen of recombinant UDP-glucuronosyltransferase isoforms (UGTs) indicated that UGT1A1 primarily mediates OC conjugation, with minor contributions from UGT1A3 and UGT1A8. Enzyme kinetic studies showed that UGT1A1 was the main UGT isoform involved in OCG in HLMs. 3. Further investigation suggested that OC is a broad inhibitor of UGTs. Additionally, OC competitively inhibited UGT1A6 with a Ki value of 3.49 ± 0.57 μM, whereas non-competitively inhibited UGT1A10 with a Ki value of 2.12 ± 0.18 μM. 4. Understanding the interaction between OC and UGTs will greatly contribute to future investigations regarding the inter-individual differences in OC metabolism in clinical trials and potential drug-drug interactions. PMID:25714435

  20. (Dithiocarbamato)iron(II) complexes: Photochemical chelation and ligand exchange, comparison with electron-transfer processes, and X-ray crystal structures of Fe(. eta. sup 5 -C sub 5 Me sub 5 )(. eta. sup 1 -SC(S)NMe sub 2 )(CO) sub 2 and Fe(. eta. sup 5 -C sub 5 Me sub 5 )(. eta. sup 2 -S sub 2 CNMe sub 2 )(PPh sub 3 )

    SciTech Connect

    Desbois, M.H.; Astruc, D. ); Nunn, C.M.; Cowley, A.H. )

    1990-03-01

    The X-ray crystal structure of FeCp{sup *}({eta}{sup 1}-dtc)(CO){sub 2} (1, Cp{sup *} = {eta}{sup 5}-C{sub 5}Me{sub 5}, dtc = S{sub 2}CNMe{sub 2}) confirms that the dithiocarbamate ligand is bound to iron in a monodentate mode. The photochemical chelation of 1 is carried out in dichloromethane using visible light and quantitatively gives the chelate FeCp{sup *}({eta}{sup 2}-dtc)(CO) (2) and CO. This reaction is the best route to 2 and compares with the electron-transfer chain (ETC) processes 1 {yields} 2 catalyzed by either oxidizing or reducing agents. The photolytic reaction, which can be carried out by monochromatic (330 nm) irradiation and monitored by visible spectroscopy, gives to isosbestic points at 394 and 432 nm. Both complexes 1 and 3 crystallize in a triclinic system. 1: a = 8.582 (2) {angstrom}, b = 9.046 (4) {angstrom}, c = 12.377 (7) {angstrom}, {alpha} = 97.05 (4){degree}, {beta} = 96.84 (3){degree}, {gamma} = 111.99 (3){degree}, space group P{bar 1}, Z = 2. 3: a = 11.142 (4) {angstrom}, b = 14.958 (4) {angstrom}, c = 10.382 (4) {angstrom}, {alpha} = 98.22 (2){degree}, {beta} = 115.22 (3){degree}, {gamma} 102.62 (3){degree}, space group P{bar 1}, Z = 2.

  1. Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development

    PubMed Central

    Maciag, Dorota; Coppinger, David; Paul, Ian A.

    2006-01-01

    Neonatal (postnatal days 8-21) exposure of rats to the selective serotonin reuptake inhibitor (SSRI), citalopram, results in persistent changes in behavior including decreased sexual activity in adult animals. We hypothesized that this effect was a consequence of abnormal stimulation of serotonergic receptors 5- HT1A or/and 5-HT1B as a result of increased synaptic availability of serotonin during a critical period of development. We examined whether neonatal exposure to a 5-HT1A (8OH-DPAT) and/or a 5-HT1B (CGS 12066B) receptor agonist can mimic the effect of neonatal exposure to citalopram on adult sexual behavior. Results showed that neonatal treatment with 5-HT1B receptor agonist robustly impaired sexual behavior similar to the effect of citalopram whereas exposure to 5-HT1A receptor agonist only moderately influenced male sexual activity in adult animals. These data support the hypothesis that stimulation of serotonin autoreceptors during development contributes to the adult sexual deficit in rats neonatally exposed to citalopram. PMID:17101120

  2. Crystallographic, magnetic and dielectric studies of the potential multiferroic cryolite (NH 4) 3FeF 6

    NASA Astrophysics Data System (ADS)

    Goff, Richard J.; Tang, Chiu C.; Parker, Julia E.; Morrison, Finlay D.; Lightfoot, Philip

    2011-05-01

    The cryolite phase (NH 4) 3FeF 6 has been studied using variable temperature X-ray powder diffraction, together with dielectric and magnetic measurements, in order to resolve its potential multiferroic properties. The X-ray data reveal a direct transition from cubic to triclinic symmetry between 270 and 250 K, consistent with earlier reports of a ferroelectric TC of 264 K. The crystal structure of the low temperature phase has been modelled approximately in a pseudo-tetragonal, triclinic space group F1, a = 8.98258(9) Å, b = 8.99631(9) Å, c = 9.27961(9) Å, α = 90.039(1)°, β = 90.451(1)° and γ = 90.339(1)° (at 100 K) but weak superlattice reflections remain unindexed, suggesting the true unit cell to be larger. Electrical measurements indicted an increase in capacitance above 260 K, however this was accompanied by an increase in dielectric loss and so is inconclusive evidence of a ferroelectric-paraelectric phase transition. Polarisation-field loops were not possible due to overriding leakage. Magnetic susceptibility data show paramagnetic behaviour with no indication of long-range order above 2 K, and only weak antiferromagnetic interactions ( θ ˜ -7 K). This therefore clearly demonstrates the material is not multiferroic.

  3. Non-thermal Dupree diffusivity and shielding effects on atomic collisions in Lorentzian turbulent plasmas

    NASA Astrophysics Data System (ADS)

    Lee, Myoung-Jae; Jung, Young-Dae

    2016-05-01

    The influence of non-thermal Dupree turbulence and the plasma shielding on the electron-ion collision is investigated in Lorentzian turbulent plasmas. The second-order eikonal analysis and the effective interaction potential including the Lorentzian far-field term are employed to obtain the eikonal scattering phase shift and the eikonal collision cross section as functions of the diffusion coefficient, impact parameter, collision energy, Debye length and spectral index of the astrophysical Lorentzian plasma. It is shown that the non-thermal effect suppresses the eikonal scattering phase shift. However, it enhances the eikonal collision cross section in astrophysical non-thermal turbulent plasmas. The effect of non-thermal turbulence on the eikonal atomic collision cross section is weakened with increasing collision energy. The variation of the atomic cross section due to the non-thermal Dupree turbulence is also discussed. This research was supported by Nuclear Fusion Research Program through NRF funded by the Ministry of Science, ICT & Future Planning (Grant No. 2015M1A7A1A01002786).

  4. Activities of xenobiotic metabolizing enzymes in rat placenta and liver in vitro.

    PubMed

    Fabian, Eric; Wang, Xinyi; Engel, Franziska; Li, Hequn; Landsiedel, Robert; van Ravenzwaay, Bennard

    2016-06-01

    In order to assess whether the placental metabolism of xenobiotic compounds should be taken into consideration for physiologically-based toxicokinetic (PBTK) modelling, the activities of seven phase I and phase II enzymes have been quantified in the 18-day placenta of untreated Wistar rats. To determine their relative contribution, these activities were compared to those of untreated adult male rat liver, using commonly accepted assays. The enzymes comprised cytochrome P450 (CYP), flavin-containing monooxygenase (FMO), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), esterase, UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). In contrast to liver, no activities were measurable for 7-ethylresorufin-O-dealkylase (CYP1A), 7-pentylresorufin-O-dealkylase (CYP2B), 7-benzylresorufin-O-dealkylase (CYP2B, 2C and 3 A), UGT1, UGT2 and GST in placenta, indicating that the placental activity of these enzymes was well below their hepatic activity. Low activities in placenta were determined for FMO (4%), and esterase (8%), whereas the activity of placental ADH and ALDH accounted for 35% and 40% of the hepatic activities, respectively. In support of the negligible placental CYP activity, testosterone and six model azole fungicides, which were readily metabolized by rat hepatic microsomes, failed to exhibit any metabolic turnover with rat placental microsomes. Hence, with the possible exception of ADH and ALDH, the activities of xenobiotic-metabolizing enzymes in rat placenta are too low to warrant consideration in PBTK modelling. PMID:26944803

  5. Psilocybin-induced stimulus control in the rat

    PubMed Central

    Winter, J.C.; Rice, K.C.; Amorosi, D.J.; Rabin, R.A.

    2007-01-01

    Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of psilocybin was observed following treatment with the 5-HT2A receptor antagonist, M100907. In contrast, no significant antagonism was observed following treatment with the 5-HT1A/7 receptor antagonist, WAY-100635, or the DA D2 antagonist, remoxipride. Psilocybin generalized fully to DOM, LSD, psilocin, and, in the presence of WAY-100635, DMT while partial generalization was seen to 2C-T-7 and mescaline. LSD and MDMA partially generalized to psilocybin and these effects were completely blocked by M-100907; no generalization of PCP to psilocybin was seen. The present data suggest that psilocybin induces a compound stimulus in which activity at the 5-HT2A receptor plays a prominent but incomplete role. In addition, psilocybin differs from closely related hallucinogens such as 5-MeO-DMT in that agonism at 5-HT1A receptors appears to play no role in psilocybin-induced stimulus control. PMID:17688928

  6. Crystal structure of the major peanut allergen Ara h 1.

    PubMed

    Cabanos, Cerrone; Urabe, Hiroyuki; Tandang-Silvas, Mary Rose; Utsumi, Shigeru; Mikami, Bunzo; Maruyama, Nobuyuki

    2011-10-01

    Ara h 1, a 7S globulin, is one of the three major peanut allergens. We previously reported the crystallization of the core region of recombinant Ara h 1. Here, we present the crystal structure of the Ara h 1 core at a resolution of 2.43 Å. We also assayed the Ara h 1 core thermal stability and compared its final structure against other 7S globulins. The Ara h 1 core has a thermal denaturation temperature of 88.3°C and a structure that is very similar to other 7S globulins. Previously identified linear IgE epitopes were also mapped on the three-dimensional structure. Most linear epitopes were found in the extended loop domains and the coils between the N- and C-terminal modules, while others were found in the less accessible β-sheets of the C-terminal core β-barrel domain of each monomer. Most of these epitopes become either slightly or significantly buried upon trimer formation, implying that allergen digestion in the gut is required for these epitopes to be accessible to immunoglobulins. Our findings also suggest that both intact and partially degraded allergens should be employed in future diagnostic and immunotherapeutic strategies. PMID:21903274

  7. Nonthermal and positron effects on the dust acoustic surface wave in a semi-bounded multi-component Lorentzian dusty plasma

    NASA Astrophysics Data System (ADS)

    Lee, Myoung-Jae; Jung, Young-Dae

    2015-09-01

    Nonthermal and positron effects on the dust acoustic surface waves propagating at the interface between a multi-component Lorentzian dusty plasma and a vacuum are investigated. The dispersion relation is kinetically derived by employing the specular reflection boundary condition and the dielectric permittivity for dusty plasma containing positrons. We found that there exist two modes of the dust acoustic surface wave; high- and low-frequency modes. We observe that both H- and L-modes are enhanced by the increase of the pair annihilation rate. However, the effects of positron density are duplex depending on the ratio of annihilated positrons. The effects of nonthermal plasmas are also investigated on the H- and L-modes of dust acoustic surface waves. We found that the nonthermal plasmas suppress the frequencies both H- and L-modes. This research was supported by Nuclear Fusion Research Program through NRF funded by the Ministry of Science, ICT & Future Planning (Grant No. 2015M1A7A1A01002786).

  8. Psilocybin-induced stimulus control in the rat.

    PubMed

    Winter, J C; Rice, K C; Amorosi, D J; Rabin, R A

    2007-10-01

    Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of psilocybin was observed following treatment with the 5-HT(2A) receptor antagonist, M100907. In contrast, no significant antagonism was observed following treatment with the 5-HT(1A/7) receptor antagonist, WAY-100635, or the DA D(2) antagonist, remoxipride. Psilocybin generalized fully to DOM, LSD, psilocin, and, in the presence of WAY-100635, DMT while partial generalization was seen to 2C-T-7 and mescaline. LSD and MDMA partially generalized to psilocybin and these effects were completely blocked by M-100907; no generalization of PCP to psilocybin was seen. The present data suggest that psilocybin induces a compound stimulus in which activity at the 5-HT(2A) receptor plays a prominent but incomplete role. In addition, psilocybin differs from closely related hallucinogens such as 5-MeO-DMT in that agonism at 5-HT(1A) receptors appears to play no role in psilocybin-induced stimulus control. PMID:17688928

  9. New insights into nonradiative heating in late A star chromospheres

    NASA Technical Reports Server (NTRS)

    Walter, Frederick M.; Matthews, Lynn D.; Linsky, Jeffrey L.

    1995-01-01

    Using new and archival spectra from the Goddard High Resolution Spectrograph, we have searched for evidence of chromospheric and transition region emission in six stars of mid to late A spectral type. Two of the stars, alpha Aq1 (A7 IV-V) and alpha Cep (A7 IV-V), show emission in the C II 1335 A doublet, confirming the presence of hot plasma with temperatures comparable to that of the solar transition region. Using radiative equilibrium photospheric models, we estimate the net surface fluxes in the CII emission line to be 9.4 x 10(exp 4) ergs/sq cm/s for alpha Aq1 and 6.5 x 10(exp 4)ergs/sq cm/s for alpha Cep. These are comparable to fluxes observed in stars as hot as approximately 8000 K (B-V = 0.22). We find no evidence for the blueshifted emission reported by Simon et al. (1994). We estimate the basal flux level to be about 30% of that seen in early F stars, and that the bulk of the emission is not basal in origin. We conclude that the basal flux level drops rapidly for B-V approximately less than 0.3, but that magnetic activity may persist to B-v as small as 0.22.

  10. Effect of dietary eugenol on xenobiotic metabolism and mediation of UDP-glucuronosyltransferase and cytochrome P450 1A1 expression in rat liver.

    PubMed

    Iwano, Hidetomo; Ujita, Wakako; Nishikawa, Miyu; Ishii, Satomi; Inoue, Hiroki; Yokota, Hiroshi

    2014-03-01

    Xenobiotic-metabolizing enzymes (XMEs) play an important role in the elimination and detoxification of xenobiotics and drugs. A variety of natural dietary agents are known to protect against cancer by inducing XME. To elucidate the molecular mechanism of XME induction, we examined the effect of dietary eugenol (4-allyl-1-hydroxy-2-methoxybenzene) on xenobiotic metabolism. In this study, rats were administered dietary eugenol for 4 weeks to investigate the various effects of UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) expression. In rats administered dietary eugenol, expression levels of hepatic CYP1A 1 were reduced to 40% than of the controls, while expression of hepatic UGT1A6, UGT1A7 and UGT2B1 increased to 2-3 times than observed in the controls. Hepatic protein levels of UGT1A6 and 2B1 were also elevated in the eugenol-treated rats. These results suggest that the natural compound eugenol improves the xenobiotic-metabolizing systems that suppress and induce the expression of CYP1A1 and UGT, respectively. PMID:24144396

  11. Genetic data from Y chromosome STR and SNP loci in Ukrainian population.

    PubMed

    Mielnik-Sikorska, Marta; Daca, Patrycja; Woźniak, Marcin; Malyarchuk, Boris A; Bednarek, Jarosław; Dobosz, Tadeusz; Grzybowski, Tomasz

    2013-01-01

    We have tested a sample of 154 unrelated males from Lviv region (Ukraine) for 11 Y-chromosomal single nucleotide polymorphisms (SNPs) and 17 Y-chromosomal STR loci (DYS19, DYS385a, DYS385b, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, YGATA_H4.1). Haplotype and haplogroup diversity values were calculated for the population under study. Genetic distances (R(ST)) to 9 other Slavic populations were calculated based on 12 Y-STR loci. Haplotype frequencies and MDS plots were constructed based on genetic distances. Haplogroup frequency patterns revealed in Ukraine are similar to those characteristic of other European populations. However, it also allowed for identification a specific genetic component in Ukrainian sample which seems to originate from areas dwelled by Western Slavs, i.e. subhaplogroup R1a1a7, at frequency of 13.65%. Analysis of R(ST) distances and AMOVA revealed high level of heterogeneity between Slavic populations inhabiting the south and north part of Europe, determined geographically rather than by linguistic factors. It has also been found a closer similarity (in the values of R(ST)) between Ukrainian and Slovak populations than between Ukrainians and other Slavic population samples. PMID:22673612

  12. [Two siblings with eyelid myoclonia with absences].

    PubMed

    Yagi, S; Matsuzawa, J; Hongou, K; Yamatani, M; Miyawaki, T; Konishi, T

    2001-11-01

    We report two siblings with eyelid myoclonia with absences. Patient 1, a 7-year-old boy, visited us because of eyelid blinking resembling a tic. He had experienced the movements since 2 years old. The diagnosis of a simple motor tic was initially made, however, the episodes worsened gradually. Patient 2, a younger brother of patient 1, was a 5-year-old boy. His eyelid blinking also began at age of 2 years. Additionally, the mother's aunt and her cousin had a history of grand mal on awakening, and the patient's cousin has febrile seizures. Their clinical features were as follows; (i) eyelid myoclonia, described as rapid, rhythmic eyelid fluttering with upward jerking of the eyes and head, lasting for 1-2 seconds; (ii) it occurred frequently each day; (iii) when it lasted for more than 2-3 seconds, it was associated with absences; (iv) both hyperventilation and photic stimulation on 18 f/c induced clinical seizures; and (v) ictal EEG revealed 3-4 c/s generalized irregular spike-waves with a duration of 1-3 seconds. Based on these characteristics, a diagnosis of eyelid myoclonia with absences was made. The present cases are the first sibling cases reported in Japan and, according to their family history, a genetic predisposition should be considered. PMID:11725520

  13. Molecular structure, photophysical and thermal properties of samarium (III) complexes

    NASA Astrophysics Data System (ADS)

    Kumar, Rajeev; Singh, Udai P.

    2008-03-01

    Some 8-coordinated samarium (III) complexes ( 1- 4) having bipy (2,2'-bipyridine), terpy (2,2':6',2″-terpyridine), phen (1,10-phenanthroline) and tp [hydrotris (pyrazol-1-yl) borate] as supporting ligands have been synthesized and structurally characterized by different techniques including X-ray crystallography. The X-ray studies demonstrated that the complexes 1, 2 and 4 crystallized in triclinic space group P1¯ with cell dimensions a = 8.5640(2) Å, b = 8.8696(2) Å, c = 15.8608(4) Å for 1; a = 7.2113(9) Å, b = 11.0737(14) Å, c = 13.6289(18) Å for 2; a = 12.440(3) Å, b = 12.874(3) Å, c = 17.822(4) Å for 4, whereas the complex 3 crystallized in the monoclinic space group P2 1/ c with cell dimensions a = 9.472(3) Å, b = 17.092(5) Å, c = 14.516(5) Å. The IR study suggested that the azide is coordinated in 1, 3-bridging mode in complex 4. The photophysical properties of above complexes have been studied with ultraviolet absorption and emission spectral studies. Thermogravimetric analyses suggested that all these complexes undergo the complete decomposition to form the thermally stable samarium oxide (Sm 2O 3).

  14. De Novo-Synthesized Retinoic Acid in Ovarian Antral Follicles Enhances FSH-Mediated Ovarian Follicular Cell Differentiation and Female Fertility.

    PubMed

    Kawai, Tomoko; Yanaka, Noriyuki; Richards, JoAnne S; Shimada, Masayuki

    2016-05-01

    Retinoic acid (RA) is the active form of vitamin A and is synthesized from retinol by two key enzymes, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). As the physiological precursor of RA, retinol impacts female reproductive functions and fertility. The expression of Adh1 and Adh5 as well as Aldh1a1 and Aldh1a7 are significantly increased in the ovaries of mice treated with equine chorionic gonadotropin/FSH. The RA receptor is expressed and localized in granulosa cells and is activated by endogenous RA as indicated by LacZ expression in granulosa cells of RA-responsive transgene-LacZ transgenic mice (RA reporter mice). Coinjection of the ADH inhibitor, 4-methylpyrazole, with equine chorionic gonadotropin significantly decreases the number and developmental competence of oocytes ovulated in response to human chorionic gonadotropin/LH as compared with controls. Injections of RA completely reverse the effects of the inhibitor of ovulation and oocyte development. When mice were fed a retinol-free, vitamin A-deficient diet that significantly reduced the serum levels of retinol, the expression of the LH receptor (Lhcgr) was significantly lower in the ovaries of the vitamin A-deficient mice, and injections of human chorionic gonadotropin failed to induce genes controlling ovulation. These results indicate that ovarian de novo biosynthesis of RA is required for the follicular expression of Lhcgr in granulosa cells and their ability to respond to the ovulatory LH surge. PMID:27022678

  15. Vessel wall enhancement in the diagnosis and management of primary angiitis of the central nervous system in children.

    PubMed

    Ohno, Koyo; Saito, Yoshiaki; Kurata, Hirofumi; Saiki, Yusuke; Ohtahara, Hiroko; Yoshioka, Hiroki; Yamashita, Eijiro; Fujii, Shinya; Maegaki, Yoshihiro

    2016-08-01

    We describe two cases of primary angiitis of the central nervous system in children (cPACNS) diagnosed by vessel wall contrast enhancement on magnetic resonance imaging (MRI). Both patients developed acute cerebral infarction after fever and malaise. In patient 1, a 7-month-old boy, MRI revealed extensive cerebral infarction in the right middle cerebral artery (MCA) area and stenosis at the M1 portion of the right MCA. Oral glucocorticoid therapy was initiated. Vessel wall enhancement was ameliorated 3months after onset, and stenosis was mostly restored. Patient 2, a 5-year-old boy, suffered from cerebral infarction in the left MCA area, and stenosis was identified in the left internal carotid artery, left MCA, and left posterior cerebral artery. Although vessel wall enhancement was reduced after glucocorticoid therapy, vessel wall enhancement of left MCA re-emerged, accompanied by increased erythrocyte sedimentation rate (ESR) and, decreased cerebral blood flow (CBF) in the affected hemisphere. Intravenous methylprednisolone therapy followed by oral glucocorticoid and mycophenolate mofetil resulted in resolution of these findings. Vessel wall enhancement is a promising finding in the diagnosis of cPACNS. Disease flares occur rarely in medium-to-large vessel cPACNS during dose tapering. Vessel wall enhancement, ESR, and CBF may be useful for the assessment of the activity of angiitis. PMID:26852378

  16. Gene expression profile of duodenal epithelial cells in response to chronic metabolic acidosis.

    PubMed

    Wongdee, Kannikar; Teerapornpuntakit, Jarinthorn; Riengrojpitak, Suda; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2009-01-01

    Chronic metabolic acidosis (CMA) affects ion transport, permeability, and metabolism of the intestinal absorptive cells. Most effects of CMA on the intestine are long-term adaptations at genomic level. To identify the CMA-regulated genes, the Illumina's microarray featuring high-performance BeadArray technology was performed on RNA samples from the rat duodenal epithelial cells exposed to long-standing acidemia. After 21 days of CMA, we found 423 transcripts upregulated and 261 transcripts downregulated. Gene ontology analysis suggested effects of CMA on cellular processes, such as cell adhesion, proliferation, fuel metabolism, and biotransformation. Interestingly, 27 upregulated transcripts (e.g., Aqp1, Cacnb1, Atp1a2, Kcnab2, and Slc2a1) and 13 downregulated transcripts (e.g., Slc17a7, Slc9a4, and Slc30a3) are involved in the absorption of water, ions, and nutrients. Some upregulated genes, such as Slc38a5 and Slc1a7 encoding glutamine transporters, may be parts of the total body adaptation to alleviate negative nitrogen balance. Therefore, the present results provided a novel genome-wide information for further investigations of the mechanism of CMA effect on the intestine. PMID:18979233

  17. Methylmercury content of eggs in yellow perch related to maternal exposure in four Wisconsin lakes

    USGS Publications Warehouse

    Hammerschmidt, Chad R.; Wiener, James G.; Frazier, Brdaley E.; Rada, Ronald G.

    1999-01-01

    We examined the influence of maternal mercury and selected lacustrine variables on the mercury content of eggs from yellow perch (Perca flavescens). Total mercury, methylmercury, and inorganic mercury were determined in eggs and carcasses (less eggs) from three seepage lakes with a pH range of 6.1a??7.0 and a fourth lake in which pH was experimentally increased from 5.5 to 6.8 by addition of alkaline groundwater. The concentration of total mercury in eggs was strongly correlated with that in the maternal carcass. Concentrations and burdens of mercury in eggs and carcasses were inversely correlated with lake water pH, acid-neutralizing capacity, calcium, and dissolved organic carbon. In eggs containing more than 30 ng/g dry weight (4.5 ng/g wet weight) of total mercury, methylmercury averaged 91% of total mercury and ranged from 85% to 96%. Mean burdens of total mercury in individual eggs varied greatly among lakes (range, 2.3a??63 pg), and the egg mass averaged 1.9% of the whole-body burden. We conclude that exposure of the developing yellow perch embryo to methylmercury is strongly affected by maternal bioaccumulation, which can vary substantially among and within lakes; however, the toxicological significance of the observed exposure of embryos to methylmercury is unclear.

  18. Lignans from the rhizomes of Iris tectorum.

    PubMed

    Zhang, Chun-Lei; Wang, Yan; Liu, Yan-Fei; Liang, Dong; Hao, Zhi-You; Luo, Huan; Chen, Ruo-Yun; Yu, De-Quan

    2016-01-01

    Chemical examination of the ethanol extract of rhizomes of Iris tectorum led to the isolation and characterization of three new lignans, (7R,7'R,8S,8'S)-5'-methoxy-neo-olivil (1a), (7S,7'S,8R,8'R) -5'-methoxy-neo-olivil (1b), (7S,7'R,8S,8'S)-neo-olivil (2a), (7R,7'S,8R,8'R)-neo-olivil (2b), (7R,7'R,8S,8'S,7''S,8''S)-threo-neo-olivil-4'-O-8-guaiacylglycerol ether (3), together with six known ones (4-9). Among them, compounds 1 and 2 were found to be racemic mixtures, respectively, which were verified by chiral HPLC analysis, compound 3 was a new sesquineolignan. The structures were elucidated on the basis of extensive spectroscopic analysis. To our knowledge, this is the first report of lignan constituents isolated from I. tectorum. All compounds were evaluated for their cytotoxicity against five human tumor cell lines and none of them displayed significant toxicity in tested cell lines at a concentration of 10 μM. PMID:26625840

  19. Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

    PubMed Central

    Peter, Inga; Hazarika, Suwagmani; Vasiadi, Magdalini; Greenblatt, David J.; Lee, William M.

    2014-01-01

    Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a single-time-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophen-metabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1–4.9; P = 0.034) compared with all other ALF patients. This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0–17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminophen-induced ALF. PMID:24104197

  20. Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding

    PubMed Central

    Begaye, Adrian; Trostel, Shana; Zhao, Zhiming; Taylor, Richard E; Schriemer, David C

    2011-01-01

    Peloruside A is a microtubule-stabilizing macrolide that binds to β-tubulin at a site distinct from the taxol site. The site was previously identified by H-D exchange mapping and molecular docking as a region close to the outer surface of the microtubule and confined in a cavity surrounded by a continuous loop of protein folded so as to center on Y340. We have isolated a series of peloruside A-resistant lines of the human ovarian carcinoma cell line A2780(1A9) to better characterize this binding site and the consequences of altering residues in it. Four resistant lines (Pel A-D) are described with single-base mutations in class I β-tubulin that result in the following substitutions: R306H, Y340S, N337D and A296S in various combinations. The mutations are localized to peptides previously identified by Hydrogen-Deuterium exchange mapping, and center on a cleft in which the drug side chain appears to dock. The Pel lines are 10–15-fold resistant to peloruside A and show cross resistance to laulimalide but not to any other microtubule stabilizers. They show no cross-sensitivity to any microtubule destabilizers, nor to two drugs with targets unrelated to microtubules. Peloruside A induces G2/M arrest in the Pel cell lines at concentrations 10–15 times that required in the parental line. The cells show notable changes in morphology compared with the parental line. PMID:21926482

  1. Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells

    PubMed Central

    Scharer, Christopher D; Laycock, Noelani; Osunkoya, Adeboye O; Logani, Sanjay; McDonald, John F; Benigno, Benedict B; Moreno, Carlos S

    2008-01-01

    Background A large percentage of patients with recurrent ovarian cancer develop resistance to the taxane class of chemotherapeutics. While mechanisms of resistance are being discovered, novel treatment options and a better understanding of disease resistance are sorely needed. The mitotic kinase Aurora-A directly regulates cellular processes targeted by the taxanes and is overexpressed in several malignancies, including ovarian cancer. Recent data has shown that overexpression of Aurora-A can confer resistance to the taxane paclitaxel. Methods We used expression profiling of ovarian tumor samples to determine the most significantly overexpressed genes. In this study we sought to determine if chemical inhibition of the Aurora kinase family using VE-465 could synergize with paclitaxel to induce apoptosis in paclitaxel-resistant and sensitive ovarian cancer cells. Results Aurora-A kinase and TPX2, an activator of Aurora-A, are two of the most significantly overexpressed genes in ovarian carcinomas. We show that inhibition of the Aurora kinases prevents phosphorylation of a mitotic marker and demonstrate a dose-dependent increase of apoptosis in treated ovarian cancer cells. We demonstrate at low doses that are specific to Aurora-A, VE-465 synergizes with paclitaxel to induce 4.5-fold greater apoptosis than paclitaxel alone in 1A9 cells. Higher doses are needed to induce apoptosis in paclitaxel-resistant PTX10 cells. Conclusion Our results show that VE-465 is a potent killer of taxane resistant ovarian cancer cells and can synergize with paclitaxel at low doses. These data suggest patients whose tumors exhibit high Aurora-A expression may benefit from a combination therapy of taxanes and Aurora-A inhibition. PMID:19077237

  2. Thorium and uranium porphyrins. Synthesis and crystal structure of bis(acetylacetonato)(2,3,7,8,12,13,17,18-octaethylporphyrinato)thorium(IV)

    SciTech Connect

    Dormond, A.; Belkalem, B.; Charpin, P.; Lance, M.; Vigner, D.; Folcher, G.; Guilard, R.

    1986-12-17

    The action of thorium tetrachloride or uranium tetrachloride with porphyrins affords the dichloro complexes (Por)MCl/sub 2/ (M = Th or U). The latter derivatives react with sodium acetylacetonate giving rise to bis(acetylacetonato) complexes (Por)M(acac)/sub 2/. The two series of complexes are characterized on the basis of mass spectral, IR, UV-visible, and NMR data. The crystal structure of the title compound has been determined by X-ray diffraction methods: (OEP)Th(acac)/sub 2/, C/sub 46/H/sub 58/N/sub 4/O/sub 4/Th; M/sub r/ = 963; triclinic, P anti 1; a = 9.493 (7), b = 21.185 (5), c = 24.331 (7) A; ..cap alpha.. = 104.18 (2), ..beta.. = 96.11 (4), ..gamma.. = 92.35 (4)/sup 0/; V = 4705 A/sup 3/; d/sub calcd/ = 1.359 g cm/sup -3/; Z = 4; T = 298 K. A total of 9019 intensities were measured on a CAD 4 Enraf-Nonius diffractometer in the omega-2 theta scan mode with monochromatized Mo K..cap alpha.. radiation (1.5 < theta < 20/sup 0/). The crystal structure was refined to a conventional R(F) = 0.047 for 5323 reflections having sigma (I)/I < 0.33. The thorium atom is octacoordinated by the four porphyrin nitrogen atoms and by the four oxygen atoms of the two acetylacetonato groups. 18 references, 2 figures, 8 tables.

  3. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms

    PubMed Central

    2013-01-01

    Synopsis Although it is widely appreciated that cats respond differently to certain drugs when compared with other companion animal species, the causes of these differences are poorly understood. This review critically evaluates published evidence for altered drug effects in cats, focusing on pharmacokinetic differences between cats, dogs and humans, and the molecular mechanisms underlying these differences. Pharmacokinetic studies indicate that acetaminophen, propofol, carprofen, and acetylsalicylic acid (aspirin) are cleared significantly more slowly in cats versus dogs and humans. All of these drugs are metabolized by conjugation. Cats lack the major phenol UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6 and UGT1A9, that glucuronidate acetaminophen and propofol. Deficient glucuronidation may also explain slower carprofen clearance, although there is no direct evidence for this. However, poor aspirin clearance in cats appears to be mainly a consequence of slower glycine conjugation. Cats are also deficient in several other conjugation enzymes, including N-acetyltransferase (NAT) 2 and thiopurine methyltransferase (TMPT). NAT2 deficiency may be the reason cats are more prone to developing methemoglobinemia rather than hepatotoxicity from acetaminophen. TMPT deficiency may predispose cats to azathioprine toxicity. No evidence was found for slower elimination of drugs cleared by oxidation or unchanged into urine or bile. Piroxicam, an oxidized drug, was cleared much more rapidly in cats than humans and dogs, although the mechanism for this difference is unclear. More work is needed to better understand drug metabolism and disposition differences in cats, thereby enabling more rational prescribing of existing medications, and the development of safer drugs for this species. PMID:23890237

  4. Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants

    PubMed Central

    Devineni, Damayanthi; Vaccaro, Nicole; Murphy, Joe; Curtin, Christopher; Mamidi, Rao N.V.S.; Weiner, Sveta; Wang, Shean-Sheng; Ariyawansa, Jay; Stieltjes, Hans; Wajs, Ewa; Di Prospero, Nicholas A.; Rothenberg, Paul

    2015-01-01

    Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. Methods: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4 – 12); study 2: canagliflozin 300 mg (days 1 – 17), probenecid 500 mg twice daily (days 15 – 17); and study 3: canagliflozin 300 mg (days 1 – 8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at pre-specified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2 – 8 (study 3). Results: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. Conclusion: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control. PMID:25407255

  5. Regulation of Hepatic Phase II Metabolism in Pregnant Mice

    PubMed Central

    Wen, Xia; Donepudi, Ajay C.; Thomas, Paul E.; Slitt, Angela L.; King, Roberta S.

    2013-01-01

    Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo- and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARα, and PXR and their target genes were downregulated, whereas ERα mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARα, PXR, and ERα signaling pathways may be candidate signaling pathways responsible for these changes. PMID:23055538

  6. Structural characterization and composition of Y-rich hainite from Sakharjok nepheline syenite pegmatite (Kola Peninsula, Russia)

    NASA Astrophysics Data System (ADS)

    Lyalina, L.; Zolotarev, A.; Selivanova, E.; Savchenko, Ye.; Zozulya, D.; Krivovichev, S.; Mikhailova, Yu.

    2015-08-01

    Y-rich hainite occurs in nepheline syenite pegmatite of the Sakharjok massif (Kola Peninsula, Russia). It forms euhedral prismatic crystals up to 2 mm in length as well as rims around an unidentified mineral phase (silicate of Ca, Y, Zr and Ti). The mineral is triclinic, space group P-1, a 9.6054(10), b 5.6928(6), c 7.3344(7) Å, α 89.903(2), β 101.082(2), γ 100.830(2)°, V 386.32(7) Å3, Z = 1. The calculated density is 3.39 g/cm3. Chemical composition of Sakharjok hainite is different from the previously published data by much higher Y and Nb contents up to 0.72 and 0.20 atoms per formula unit, respectively, by the two- to five-fold depletion in the LREEs and by the strong enrichment of the HREEs. From the single-crystal X-ray diffraction data, there is a significant amount of Y in the M1 site associated with the absence of Zr in it. Nb and Zr are concentrated in the M5 site substituting Ti. Combination of single-crystal X-ray diffraction data and electron microprobe data give the empirical formula (Ca1.04Y0.63REE0.24Mn0.02)∑1.93(Na0.92Ca0.77)∑1.69Ca2.00(Na0.65Ca0.10)∑0.75(Ti0.60Zr0.21Nb0.15Fe0.03)∑0.99((Si4.00Al0.02)∑4.02O14) (F2.61O1.39)∑4.00.

  7. The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure.

    PubMed

    Court, Michael H; Freytsis, Marina; Wang, Xueding; Peter, Inga; Guillemette, Chantal; Hazarika, Suwagmani; Duan, Su X; Greenblatt, David J; Lee, William M

    2013-05-01

    Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3'UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3'UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, χ(2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual's risk for acetaminophen-induced liver injury. PMID:23408116

  8. Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin.

    PubMed

    Zhang, Hui; Zhao, Zhenying; Wang, Tao; Wang, Yijia; Cui, Xiao; Zhang, Huijuan; Fang, Zhong-Ze

    2016-07-01

    Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, respectively. Based on the inhibition evaluation standard ([I]/Ki  < 0.1, low possibility; 0.1 < [I]/Ki  < 1, medium possibility; [I]/Ki  > 1, high possibility), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27145339

  9. Species difference in glucuronidation formation kinetics with a selective mTOR inhibitor.

    PubMed

    Berry, Loren M; Liu, Jingzhou; Colletti, Adria; Krolikowski, Paul; Zhao, Zhiyang; Teffera, Yohannes

    2014-04-01

    The mammalian target of rapamycin (mTOR) is a protein kinase that shows key involvement in age-related disease and promises to be a target for treatment of cancer. In the present study, the elimination of potent ATP-competitive mTOR inhibitor 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine (compound 1) is studied in bile duct-cannulated rats, and the metabolism of compound 1 in liver microsomes is compared across species. Compound 1 was shown to undergo extensive N-glucuronidation in bile duct-catheterized rats. N-glucuronides were detected on positions N1 (M2) and N2 (M1) of the pyrazole moiety as well as on the primary amine (M3). All three N-glucuronide metabolites were detected in liver microsomes of the rat, dog, and human, while primary amine glucuronidation was not detected in cynomolgus monkey. In addition, N1- and N2-glucuronidation showed strong species selectivity in vitro, with rat, dog, and human favoring N2-glucuronidation and monkey favoring N1-glucuronide formation. Formation of M1 in monkey liver microsomes also followed sigmoidal kinetics, singling out monkey as unique among the species with regard to compound 1 N-glucuronidation. In this respect, monkeys might not always be the best animal model for N-glucuronidation of uridine diphosphate glucuronosyltransferase (UGT) 1A9 or UGT1A1 substrates in humans. The impact of N-glucuronidation of compound 1 could be more pronounced in higher species such as monkey and human, leading to high clearance in these species. While compound 1 shows promise as a candidate for investigating the impact of pan-mTOR inhibition in vivo, opportunities may exist through medicinal chemistry efforts to reduce metabolic liability with the goal of improving systemic exposure. PMID:24423753

  10. Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin

    PubMed Central

    Lee, Jin-Ah; Ha, Sang Keun; Cho, EunJung; Choi, Inwook

    2015-01-01

    The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin’s anti-inflammatory activities in the body. PMID:26610561

  11. Prevalence and antimicrobial resistance of Shigella flexneri serotype 2 variant in China

    PubMed Central

    Cui, Xianyan; Wang, Jian; Yang, Chaojie; Liang, Beibei; Ma, Qiuxia; Yi, Shengjie; Li, Hao; Liu, Hongbo; Li, Peng; Wu, Zhihao; Xie, Jing; Jia, Leili; Hao, Rongzhang; Wang, Ligui; Hua, Yuejin; Qiu, Shaofu; Song, Hongbin

    2015-01-01

    Shigella flexneri serotype 2 variant (II:3,4,7,8) was isolated in 2008 and first reported in China in 2013. In the present study, epidemiological surveillance from 2003 to 2013 in China suggested that this serotype first appeared in Guangxi in 2003; it then emerged in Shanghai and Xinjiang in 2004 and in Henan in 2008. Of the 1813 S. flexneri isolates, 58 S. flexneri serotype 2 variant strains were identified. Serotype 2 variant has emerged as a prominent serotype in recent years, with 2a (32.6%), X variant (25.2%), 1a (9.4%), X (6.3%), 2b (5.4%), and 1b (3.6%). According to phenotypic and genotypic analysis, the serotype 2 variant originated from 2a to 2b. A higher antibiotic resistance rate was observed between 2009 and 2013 than that between 2003 and 2008. Among 22 cephalosporin-resistant isolates, blaTEM-1, blaOXA-1, blaCTX-3, blaCTX-14, and blaCTX-79 were detected. Among 22 fluoroquinolone-resistant isolates, a Ser80Ile mutation in parC was present in all of the isolates. Moreover, 21 isolates had three gyrA point mutations (Ser83Leu, His211Tyr, Asp87Asn, or Gly) and one isolate had two gyrA point mutations (Ser83Leu and His211Tyr). The prevalence of His211Tyr in the fluoroquinolone-resistant isolates is concerning, and the mutation was first reported in China. Besides, 22 isolates harbored the aac(6′)-Ib-cr gene, and two isolates harbored qnrS1. In view of the increased epidemic frequency and multidrug-resistant strain emergence, continuous surveillance will be needed to understand the actual disease burden and provide guidance for shigellosis. PMID:25999941

  12. An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver.

    PubMed

    Ito, Yusuke; Fukami, Tatsuki; Yokoi, Tsuyoshi; Nakajima, Miki

    2014-12-01

    Probenecid, a widely used uricosuric agent, is mainly metabolized to probenecid acyl glucuronide (PRAG), which is considered a causal substance of severe allergic or anaphylactoid reactions. PRAG can be hydrolyzed (deglucuronidated) to probenecid. The purpose of this study was to identify enzymes responsible for probenecid acyl glucuronidation and PRAG deglucuronidation in human livers and to examine the effect of deglucuronidation in PRAG formation. In human liver homogenates (HLHs), the intrinsic clearance (CLint) of PRAG deglucuronidation was much greater (497-fold) than that of probenecid acyl glucuronidation. Evaluation of PRAG formation by recombinant UDP-glucuronosyltransferase (UGT) isoforms and an inhibition study using HLHs as an enzyme source demonstrated that multiple UGT isoforms, including UGT1A1, UGT1A9, and UGT2B7, catalyzed probenecid acyl glucuronidation. We found that recombinant α/β hydrolase domain containing 10 (ABHD10) substantially catalyzed PRAG deglucuronidation activity, whereas carboxylesterases did not. Similar inhibitory patterns by chemicals between HLHs and recombinant ABHD10 supported the major contribution of ABHD10 to PRAG deglucuronidation in human liver. Interestingly, it was demonstrated that the CLint value of probenecid acyl glucuronidation in HLHs was increased by 1.7-fold in the presence of phenylmethylsulfonyl fluoride, which potently inhibited ABHD10 activity. In conclusion, we found that PRAG deglucuronidation catalyzed by ABHD10 suppressively regulates PRAG formation via multiple UGT enzymes in human liver. The balance of activities by these enzymes is important for the formation of PRAG, which may be associated with the adverse reactions observed after probenecid administration. PMID:25217485

  13. The synthesis, crystal chemistry and structures of Y-doped brannerite (U 1- xY xTi 2O 6) and thorutite (Th 1- xY xTi 2O 6- δ) phases

    NASA Astrophysics Data System (ADS)

    James, M.; Carter, M. L.; Watson, J. N.

    2003-09-01

    Yttrium-doped uranium brannerite (U 1- xY xTi 2O 6) and thorutite (Th 1- xY xTi 2O 6- δ) phases were synthesized in air at 1400°C. Powder X-ray diffraction revealed that these phases crystallized to form monoclinic ( C2/ m) structures. Crystal structures of U 0.54Y 0.46Ti 2O 6 ( 1) ( a=9.8008(2); b=3.7276(1); c=6.8745(1); β=118.38(1); V=220.97(1); Z=2; RP=7.3%; RB=4.6%) and Th 0.91Y 0.09Ti 2O 6- δ ( 2) ( a=9.8002(7); b=3.7510(3); c=6.9990(5); β=118.37(4); V=226.40(3); Z=2; RP=4.5%; RB=2.9%) were refined from powder neutron diffraction data. These two phases were isostructural, revealing planes of corner and edge-sharing TiO 6 octahedra separated by irregular eight-fold coordinate U/Y or Th/Y atoms. The oxygen sites within the structure of 1 were found to be fully occupied, confirming that the doping of lower valence Y atoms occurs in conjunction with the oxidation of U(IV) to U(V). Y doping of the thorutite phase 2 does not lead to oxidation but rather the formation of oxygen vacancies within the structure.

  14. DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment.

    PubMed

    Mikysková, Romana; Indrová, Marie; Vlková, Veronika; Bieblová, Jana; Símová, Jana; Paracková, Zuzana; Pajtasz-Piasecka, Elzbieta; Rossowska, Joanna; Reinis, Milan

    2014-01-01

    MDSCs represent one of the key players mediating immunosuppression. These cells accumulate in the TME, lymphoid organs, and blood during tumor growth. Their mobilization was also reported after CY therapy. DNMTi 5AC has been intensively studied as an antitumor agent. In this study, we examined, using two different murine tumor models, the modulatory effects of 5AC on TU-MDSCs and CY-MDSCs tumor growth and CY therapy. Indeed, the percentage of MDSCs in the TME and spleens of 5AC-treated mice bearing TRAMP-C2 or TC-1/A9 tumors was found decreased. The changes in the MDSC percentage were accompanied by a decrease in the Arg-1 gene expression, both in the TME and spleens. CY treatment of the tumors resulted in additional MDSC accumulation in the TME and spleens. This accumulation was subsequently inhibited by 5AC treatment. A combination of CY with 5AC led to the highest tumor growth inhibition. Furthermore, in vitro cultivation of spleen MDSCs in the presence of 5AC reduced the percentage of MDSCs. This reduction was associated with an increased percentage of CD11c(+) and CD86(+)/MHCII(+) cells. The observed modulatory effect on MDSCs correlated with a reduction of the Arg-1 gene expression, VEGF production, and loss of suppressive capacity. Similar, albeit weaker effects were observed when MDSCs from the spleens of tumor-bearing animals were cultivated with 5AC. Our findings indicate that beside the direct antitumor effect, 5AC can reduce the percentage of MDSCs accumulating in the TME and spleens during tumor growth and CY chemotherapy, which can be beneficial for the outcome of cancer therapy. PMID:24389335

  15. Metabolic Drug-Drug Interaction Potential of Macrolactin A and 7-O-Succinyl Macrolactin A Assessed by Evaluating Cytochrome P450 Inhibition and Induction and UDP-Glucuronosyltransferase Inhibition In Vitro

    PubMed Central

    Bae, Soo Hyeon; Kwon, Min Jo; Park, Jung Bae; Kim, Doyun; Kim, Dong-Hee; Kang, Jae-Seon; Kim, Chun-Gyu; Oh, Euichaul

    2014-01-01

    Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice. PMID:24890600

  16. Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5'-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes.

    PubMed

    Kwon, Soon-Sang; Kim, Ju-Hyun; Jeong, Hyeon-Uk; Cho, Yong Yeon; Oh, Sei-Ryang; Lee, Hye Suk

    2016-01-01

    Aschantin is a bioactive neolignan found in Magnolia flos with antiplasmodial, Ca(2+)-antagonistic, platelet activating factor-antagonistic, and chemopreventive activities. We investigated its inhibitory effects on the activities of eight major human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes of human liver microsomes to determine if mechanistic aschantin-enzyme interactions were evident. Aschantin potently inhibited CYP2C8-mediated amodiaquine N-de-ethylation, CYP2C9-mediated diclofenac 4'-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4'-hydroxylation, and CYP3A4-mediated midazolam 1'-hydroxylation, with Ki values of 10.2, 3.7, 5.8, and 12.6 µM, respectively. Aschantin at 100 µM negligibly inhibited CYP1A2-mediated phenacetin O-de-ethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated bupropion hydroxylation, and CYP2D6-mediated bufuralol 1'-hydroxylation. At 200 µM, it weakly inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A6-catalyzed N-acetylserotonin glucuronidation, and UGT1A9-catalyzed mycophenolic acid glucuronidation, with IC50 values of 131.7, 144.1, and 71.0 µM, respectively, but did not show inhibition against UGT1A3, UGT1A4, or UGT2B7 up to 200 µM. These in vitro results indicate that aschantin should be examined in terms of potential interactions with pharmacokinetic drugs in vivo. It exhibited potent mechanism-based inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4. PMID:27128896

  17. Biotransformation of the chemopreventive agent 2',4',4-trihydroxychalcone (isoliquiritigenin) by UDP-glucuronosyltransferases.

    PubMed

    Guo, Jian; Liu, Ang; Cao, Hongmei; Luo, Yan; Pezzuto, John M; van Breemen, Richard B

    2008-10-01

    2',4',4-trihydroxychalcone (isoliquiritigenin), a chalcone found in licorice root and shallots, exhibits antioxidant, estrogenic, and antitumor activities. To complement our previous studies concerning the phase 1 metabolism of isoliquiritigenin, the phase 2 transformation of isoliquiritigenin by human hepatocytes and pooled human liver microsomes (HLMs) was investigated using liquid chromatography/tandem mass spectrometry and UV absorbance. Five glucuronides were detected corresponding to monoglucuronides of isoliquiritigenin and liquiritigenin, but no sulfate conjugates were observed. The UDP-glucuronosyltransferases (UGTs) involved in the formation of the major glucuronide conjugates were identified using recombinant human UGTs in combination with liquid chromatography/mass spectrometry. UGT1A1 and UGT1A9 were the major enzymes responsible for the formation of the most abundant conjugate, isoliquiritigenin 4'-O-glucuronide (MG5), with Km values of 4.30+/-0.47 and 3.15+/-0.24 microM, respectively. UGT1A1 and UGT1A10 converted isoliquiritigenin to the next most abundant phase 2 metabolite, isoliquiritigenin 2'-O-glucuronide (MG4), with Km values of 2.98+/-0.8 and 25.8+/-1.3 microM, respectively. In addition, isoliquiritigenin glucuronides MG4 and MG5 were formed by pooled human intestine and kidney microsomes, respectively. Based on the in vitro determination of a 25.3-min half-life for isoliquiritigenin when incubated with HLMs, the intrinsic clearance of isoliquiritigenin was estimated to be 36.4 ml/min/kg. These studies indicate that isoliquiritigenin will be conjugated rapidly in the liver to form up to five monoglucuronides. PMID:18653743

  18. Metabolism and pharmacokinetics of 8-hydroxypiperidinylmethyl-baicalein (BA-j) as a novel selective CDK1 inhibitor in monkey.

    PubMed

    Guo, Hong-Min; Sun, Yu-Ming; Zhang, Shi-Xuan; Ju, Xiu-Lan; Xie, Ai-Yun; Li, Jing; Zou, Liang; Sun, Xiao-Dan; Li, Hai-Liang; Zheng, Yang

    2015-12-01

    Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. 8-Hydroxypiperidinemethyl-baicalein (BA-j) is a Mannich base derivative of baicalein (BA) isolated from Scutellaria baicalensis, as a novel selective CDK1 inhibitor. 12 metabolites of BA-j in the monkey urine were identified by LC-MS-MS and (1)H NMR. The major metabolic pathways of BA-j, by capturing oxygen free radicals ((.)O2(-)) and releasing peroxides (H2O2), are degraded into active intermediate metabolite dihydroflavonol, then into main metabolite M179 by Shiff reaction, second metabolite M264 by sulfation, trace amount of metabolite M559 by glucuronidation UGT1A9, and without metabolism by CYP3A4. The metabolic process of BA-j by regulating intracellular reactive oxygen species (ROS) was related with BA-j selectively inducing apoptosis in cancer cells. Pharmacokinetics of 10mg/kg oral BA-j in monkey by HPLC-UV was best fitted to a two-compartment open model, with t1/2(β) of 4.2h, Cmax 25.4μM at 2h, and Vd 12.6L, meaning the drug distributing widely in body fluids with no special selectivity to certain tissues, and being able to permeate through the blood-brain barrier. The protein binding rate of BA-j was 91.8%. BA-j has excellent druggability for oral administration or injection, and it may be developed into a novel anti-cancer drug as a selective CDK1 inhibitor. PMID:26474673

  19. Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug–Drug Interactions

    PubMed Central

    Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

    2016-01-01

    Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions. PMID:26927160

  20. Pharmacogenetic Biomarkers Predictive of the Pharmacokinetics and Pharmacodynamics of Immunosuppressive Drugs.

    PubMed

    Picard, Nicolas; Bergan, Stein; Marquet, Pierre; van Gelder, Teun; Wallemacq, Pierre; Hesselink, Dennis A; Haufroid, Vincent

    2016-04-01

    In association with therapeutic drug monitoring of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and within a limited analytical time frame, which make them compatible with the clinical decision process. However, despite some evidence of clear associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several immunosuppressive drugs, pre-emptive genotyping and selection of the optimal starting dose based on the genetic background of the patient is still rarely performed in clinical practice. The main reason is probably the lack of formal proof that clinical outcome really improves after genotype-based dosing. So far, the only clinical recommendation in relation to pharmacogenetic biomarkers should be a doubling of the starting tacrolimus dose in patients who are CYP3A5 expressers, and even in this case, some authors still do not recommend pre-emptive genotyping but only genotype-based adaptation if the CYP3A5 genotype is already known. However, with the rise of new technologies, as next generation sequencing, allowing to obtain pre-emptive genetic information, one must be aware that the question will no longer be whether to genotype or not but rather whether or not to use the information already there. There was therefore a need to update the information available in relation to pharmacogenetic biomarkers for calcineurin inhibitors, mycophenolic acid, and mammalian target of rapamycin inhibitors. PMID:26469711

  1. Measurements of hindlimb blood flow recorded using Doppler ultrasound during administration of vasoactive agents in halothane-anesthetized horses.

    PubMed

    Raisis, A L; Young, L E; Meire, H B; Taylor, P M; Blissitt, K J; Marlin, D; Lekeux, P

    2000-01-01

    The purpose of the study was to determine the ability of Doppler ultrasound to detect changes in femoral blood flow during pharmacologic manipulation of arterial blood pressure. Doppler ultrasonography was performed in the femoral vessels of six halothane-anesthetized horses before and during administration of phenylephrine HCI and sodium nitroprusside. The time-averaged mean velocity and volumetric flow were calculated. The contour of the velocity waveform was assessed, and the early diastolic deceleration slope (EDDS) and pulsatility index (PI) were calculated. Administration of phenylephrine HCI resulted in increased mean aortic blood pressure (MABP) by 40% (29.3-53.0%). This caused significant decrease in cardiac output (26.8 to 13.5 l/min), femoral arterial velocity (left artery 7.20 to 4.00 cm/s; right artery 5.01 to 3.39 cm/s) and volumetric flow (left artery 556 to 221 ml/min; right artery 397 to 193 ml/min) in the femoral vessels and significant increase in systemic vascular resistance (163 to 433 dyn-s/cm5), EDDS (1a: 285 to 468: ra: 250 to 481) and PI (1a: 9.38 to 20.4; ra 17.1 to 29.1). Administration of sodium nitroprusside resulted in a decreased MABP of 27.2% (22.5-33%). This increased cardiac output (20.8 to 32.4 L/min), however, no significant changes were observed in femoral blood flow. Despite obvious changes in the waveform contour, no significant change occurred in EDDS or PI. These results suggest that Doppler ultrasound may be useful for measuring femoral blood flow in anesthetized horses. However, waveform analysis appears to be limited when multiple changes occur in central and peripheral haemodynamics. PMID:10695883

  2. Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans.

    PubMed

    Bowers, Gary David; Culp, Amanda; Reese, Melinda J; Tabolt, Glenn; Moss, Lee; Piscitelli, Stephen; Huynh, Phuong; Wagner, David; Ford, Susan L; Gould, Elizabeth P; Pan, Rennan; Lou, Yu; Margolis, David A; Spreen, William R

    2016-01-01

    1.  Cabotegravir [(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide] is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing. 2. Metabolism, pharmacokinetics and excretion were investigated in healthy human subjects who received either a single oral dose (28.2 mg) of [(14)C]cabotegravir in a mass balance study, or LA formulations of unlabeled cabotegravir (200-800 mg), intramuscularly or subcutaneously, in a separate study. Metabolism, distribution and excretion of [(14)C]cabotegravir were also investigated in mice, rats and monkeys. 3. Recovery of radioactivity in humans represented a mean total of 85.3% of the dose, including 26.8% in the urine. The mean apparent terminal phase half-life was similar for both cabotegravir and radioactivity, 39 h compared to 41 h. 4. Following oral, intramuscular and subcutaneous administration, cabotegravir was the major component in plasma and the glucuronic acid conjugate (M1) represented the predominant component in urine. Cabotegravir was present in bile along with its major metabolite (M1). 5. The primary metabolite of [(14)C]cabotegravir in mouse, rat and monkey was the same as that in human. In vitro phenotyping experiments demonstrated that cabotegravir was metabolized by UDP-glucuronosyltransferase (UGT) 1A1 and UGT1A9. PMID:26134155

  3. Interaction of a rhizobial DNA-binding protein with the promoter region of a plant leghemoglobin gene

    SciTech Connect

    Welters, P.; Metz, B.; Felix, G.; Palme, K. ); Szczyglowski, K. ); Bruijn, F.J. de Michigan State Univ., East Lansing, MI )

    1993-08-01

    A nucleotide sequence was identified approximately 650 bp upstream of the Sesbania rostrata leghemoglobin gene Srglb3 start codon, which interacts specifically with a proteinaceous DNA-binding factor found in nodule extracts but not in extracts from leaves or root. The binding site for this factor was delimited using footprinting techniques. The DNA-binding activity of this factor was found to be heat stable, dependent on divalent cations, and derived from the (infecting) Azorhizobium caulinodans bacteria or bacteroids (A. caulinodans bacterial binding factor 1, AcBBF1). A 9- to 10-kD protein was isolated from a free-living culture of A. caulinodans that co-purifies with the DNA-binding activity (A. caulinodans bacterial binding protein 1, AcBBP1) and interacts specifically with its target (S. rostrata bacterial binding site 1, SrBBS1). The amino acid sequence of the N-terminal 27 residues of AcBBP1 was determined and was found to share significant similarity (46% identity; 68% similarity) with a domain of the herpes simplex virus major DNA-binding protein infected cell protein 8(ICP8). An insertion mutation in the SrBBS1 was found to result in a substantial reduction of the expression of a Srglb3-gus reporter gene fusion in nodules of transgenic Lotus corniculatus plants, suggesting a role for this element in Srglb3 promoter activity. Based on these results, the authors propose that (a) bacterial transacting factor(s) may play a role in infected cell-specific expression of the symbiotically induced plant lb genes. 70 refs., 11 figs.

  4. Metabolism-mediated drug interaction potential of HS-23, a new herbal drug for the treatment of sepsis in human hepatocytes and liver microsomes.

    PubMed

    Jeong, Hyeon-Uk; Lee, Ji Young; Kwon, Soon-Sang; Kim, Ju Hyun; Kim, Young-Mok; Hong, Sung-Woon; Yeon, Sung Hum; Lee, Sun-Mee; Cho, Yong-Yeon; Lee, Hye Suk

    2015-02-01

    HS-23, an extract of the dried flower buds of Lonicera japonica, is a new botanical drug currently being evaluated in a phase I clinical study in Korea for the treatment of sepsis. The in vitro induction and inhibition potentials of HS-23 on the drug-metabolizing enzymes using human hepatocytes and liver microsomes were assessed to evaluate herb-drug interaction according to botanical drug guideline and drug interaction guidance of FDA. HS-23 slightly inhibited CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activities in human liver microsomes with IC50 values of 80.6, 160.7, 169.5, 85.4, and 76.6 μg/mL, respectively. HS-23 showed negligible inhibition of CYP1A2, CYP2C8, CYP2D6, UGT1A1, UGT1A4, UGT1A9, and UGT2B7 activities in human liver microsomes. Based on these results, HS-23 may not inhibit the metabolism of CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4-catalyzed drugs in humans. HS-23 did not affect the mRNA expression of CYP1A2, CYP2B6, and CYP3A4 after 48 h treatment at three concentrations (0.5, 5, and 50 μg/mL) in three independent human hepatocytes, indicating that HS-23 has no effect on herb-drug interactions that up- or down-regulate CYP1A2, CYP2B6, and CYP3A4. These results indicate that the administration of HS-23 in human may not cause clinically relevant inhibition and induction of these cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and HS-23 may be promising therapeutic agent for treatment of sepsis. PMID:25052959

  5. Isolation and characterization of a new strain of Ehrlichia chaffeensis from a patient with nearly fatal monocytic ehrlichiosis.

    PubMed Central

    Dumler, J S; Chen, S M; Asanovich, K; Trigiani, E; Popov, V L; Walker, D H

    1995-01-01

    Ehrlichia chaffeensis is the causative agent of human monocytic ehrlichiosis, a disease that ranges in severity from asymptomatic infection to death. Only one isolate of E. chaffeensis has been made, the Arkansas strain, upon which all characterizations of the agent of human monocytic ehrlichiosis have been based. We report the isolation and characterization of a new strain of E. chaffeensis, the 91HE17 strain, which was cultivated from a patient with a nearly fatal illness. The new isolate grows best in culture with careful control of pH. The two isolates are nearly identical as determined by light and electron microscopy and have significant antigenic identity in fluorescent-antibody and immunoblot assays using polyclonal antisera and the E. chaffeensis-specific monoclonal antibody 1A9. Isolate 91HE17 had 99.9% nucleotide sequence identity with the Arkansas strain in the 16S rRNA gene. Parts of the Escherichia coli GroE operon homologs had identical restriction enzyme digestion patterns, and a 425-bp region of the GroEL gene had at least 99.8% sequence identity between the E. chaffeensis Arkansas and 91HE17 strains. Isolate 91HE17 lacked an epitope identified in E. chaffeensis Arkansas by the monoclonal antibody 6A1. This new E. chaffeensis isolate is very similar to the Arkansas strain and provides the opportunity to substantiate the existence of diversity among ehrlichiae which infect humans. Specific factors which differ among strains may then be compared to assess their potential contributions toward cellular pathogenicity and ultimately toward the development of disease in humans. PMID:7665632

  6. Vibrational analysis of amino acids and short peptides in hydrated media. 3. Successive KL repeats induce highly stable beta-strands capable of forming non-H-bonded aggregates.

    PubMed

    Guiffo-Soh, Guy; Hernandez, Belén; Coïc, Yves-Marie; Boukhalfa-Heniche, Fatima-Zohra; Fadda, Giulia; Ghomi, Mahmoud

    2008-01-31

    Circular dichroism (CD) and Raman scattering were applied to the aqueous solution of minimalist LK peptides constructed with successive KL repeats leading to the following generic primary sequence: (KL)nK. Three peptides of this family, a 3-mer (n=1), a 9-mer (n=4), and a 15-mer (n=7), are analyzed in this report. Raman spectra of the 3-mer (KLK, a random chain) and its labile-hydrogen deuterated species yield a set of interesting information for analyzing longer peptides of this series. Although the CD spectrum of the 9-mer (KLKLKLKLK) reveals a signal traditionally assigned to a random structure, the corresponding Raman spectrum allows finding a mixture of conformations in solution, adopting predominantly beta-type structures. This fact proves the utility of Raman spectroscopy to eliminate eventual ambiguity concerning conformational assignments in peptides based only on the use of CD technique. Finally, the 15-mer (KLKLKLKLKLKLKLK) gives rise to CD and Raman spectra clearly assignable to a beta-type structure. On the basis of all the observed results on the 15-mer, we can confirm that this peptide may exist as isolated beta-strands at low concentration (sub-micromolar), flat-oriented at the air/water interface, whereas at high concentrations (millimolar), non-H-bonded immersible aggregates might be formed. A hypothetical model for these beta-strand aggregates could be proposed as stabilized by an interior hydrophobic core and a hydrophilic external face, formed by leucine and lysine side chains, respectively. PMID:18177032

  7. Synthesis and characterization of two novel pyridine-containing framework gallium ethylenediphosphonates

    SciTech Connect

    Yuan Zhanhui; Clegg, William . E-mail: w.clegg@ncl.ac.uk; Attfield, Martin P. . E-mail: m.attfield@manchester.ac.uk

    2006-06-15

    Two novel gallium diphosphonates, (C{sub 5}H{sub 5}N)Ga{sub 3}F(O{sub 3}PC{sub 2}H{sub 4}PO{sub 3}){sub 2} (I) (triclinic, P-1, a=8.2880(12) A, b=11.7197(16) A, c=11.7601(17) A, {alpha}=71.589(3){sup o}, {beta}=70.577(3){sup o}, {gamma}=77.313(3){sup o}, V=1013.7(2) A{sup 3}, Z=2, R {sub 1}=0.0352, wR {sub 2}=0.0980) and (C{sub 5}H{sub 5}NH){sub 2}[Ga{sub 4}F{sub 2}(O{sub 3}PC{sub 2}H{sub 4}PO{sub 3}){sub 3}] (II) (triclinic, P-1, a=8.670(4) A, b=9.742(3) A, c=10.406(2) A, {alpha}=81.44(3){sup o}, {beta}=65.83(5){sup o}, {gamma}=67.16(3){sup o}, V=739.0(4) A{sup 3}, Z=2, R {sub 1}=0.0600, wR {sub 2}=0.1495) have been synthesised by solvothermal methods in the presence of pyridine and their structures determined using single-crystal X-ray diffraction data. Both compounds I and II are composed of various Ga-centered polyhedra and ethylenediphosphonate groups that link together to form framework materials with one- and two-dimensional channel systems, respectively. The two structures are formed in the presence of structure-directing pyridine molecules that are directly bound to some of the Ga atoms in I, and are protonated as pyridinium cations in II. Compounds I has a charge-neutral framework, while compound II has an anionic framework. Both materials provide rare examples of organically structure-directed framework metal diphosphonate materials. - Graphical abstract: (C{sub 5}H{sub 5}N)Ga{sub 3}F(O{sub 3}PC{sub 2}H{sub 4}PO{sub 3}){sub 2} (I) and (C{sub 5}H{sub 5}NH){sub 2}[Ga{sub 4}F{sub 2}(O{sub 3}PC{sub 2}H{sub 4}PO{sub 3}){sub 3}] (II) are novel gallium diphosphonate materials composed of Ga-centered polyhedra and ethylenediphosphonate groups that link together to form framework materials with one- and two-dimensional channel systems, respectively. The two structures are formed in the presence of structure-directing pyridine molecules or pyridinium cations and are examples of organically structure-directed framework metal diphosphonates.

  8. NMR investigation of the interaction of vanadate with carbasilatranes in aqueous solutions.

    PubMed

    Evgeniou, Evgenios M; Pergantis, Spyros A; Leontidis, Epameinondas; Keramidas, Anastasios D

    2005-10-17

    Reaction of vanadate with carbasilatranes [methoxy{N,N',N' '-2,2',3-[bis(1-methylethanolato)(propyl)]amino}silane (1), methoxy{N,N',N' '-2,2',3-[bis(1-ethanolethanolato)(propyl)]amino}silane (2), and {N,N',N' '-2,2',2-[bis(ethanolato)(glycolpropyl ether)]amino}silane (3)] in aqueous solution results in the formation of vanadosilicates and five-coordinated chelate vanadium(V) complexes as evidenced by 51V, 1H, and 13C NMR spectroscopy. Chiral carbasilatrane S,S-1 was characterized in the solid state by X-ray diffraction, revealing a trigonal bipyramidal geometry around the metal ion, with one unidentate methoxy group and one atrane nitrogen atom at the axial positions and one carbon and two atrane oxygen atoms at the equatorial plane of the bipyramid. Crystal data (Mo Kalpha; 100(2) K) are as follows: orthorhombic space group P2(1)2(1)2(1); a = 8.8751(6), b = 9.7031(7), c = 14.2263(12) A; Z = 4. The complexation of vanadium either with 1 or 2 is stereoselective yielding approximately 94% of the complex containing ligand in the S,R-configuration. The lower ability of the S,S- and R,R-diastereoisomers of 1 and 2 to ligate vanadate was attributed to stereochemical factors, dictating a square pyramidal geometry for the chelated complexes. A dynamic process between the vanadium chelate complexes and the respective carbasilatranes was evaluated by 2D {1H} EXSY NMR spectroscopy. These spectra show that the vanadate complexes with the open carbasilatranes exchange more slowly with the free ligand compared to the respective alcohol aminate complexes. PMID:16212377

  9. Neutrophil Extracellular Traps are Involved in the Innate Immune Response to Infection with Leptospira

    PubMed Central

    Scharrig, Emilia; Carestia, Agostina; Ferrer, María F.; Cédola, Maia; Pretre, Gabriela; Drut, Ricardo; Picardeau, Mathieu; Schattner, Mirta; Gómez, Ricardo M.

    2015-01-01

    NETosis is a process by which neutrophils extrude their DNA together with bactericidal proteins that trap and/or kill pathogens. In the present study, we evaluated the ability of Leptospira spp. to induce NETosis using human ex vivo and murine in vivo models. Microscopy and fluorometric studies showed that incubation of human neutrophils with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 (LIC) resulted in the release of DNA extracellular traps (NETs). The bacteria number, pathogenicity and viability were relevant factors for induction of NETs, but bacteria motility was not. Entrapment of LIC in the NETs resulted in LIC death; however, pathogenic but not saprophytic Leptospira sp. exerted nuclease activity and degraded DNA. Mice infected with LIC showed circulating NETs after 2 days post-infection (dpi). Depletion of neutrophils with mAb1A8 significantly reduced the amount of intravascular NETs in LIC-infected mice, increasing bacteremia at 3 dpi. Although there was a low bacterial burden, scarce neutrophils and an absence of inflammation in the early stages of infection in the kidney and liver, at the beginning of the leptospiruric phase, the bacterial burden was significantly higher in kidneys of neutrophil-depleted-mice compared to non-depleted and infected mice. Surprisingly, interstitial nephritis was of similar intensity in both groups of infected mice. Taken together, these data suggest that LIC triggers NETs, and that the intravascular formation of these DNA traps appears to be critical not only to prevent early leptospiral dissemination but also to preclude further bacterial burden. PMID:26161745

  10. Synthesis and structural characterization of rhenium(I) tricarbonyl complexes with the bidentate ligands o-(diphenylphosphino)benzaldehyde (P∩O) and o-[(diphenylphosphino)benzylidene]analine (P∩N)

    PubMed Central

    Chen, Xiaoyuan; Femia, Frank J.; Babich, John W.; Zubieta, Jon

    2010-01-01

    A series of rhenium(I) tricarbonyl complexes with bidentate P,O donor ligand o-(diphenylphosphino)benzaldehyde (P∩O) and its Schiff base P,N donor ligand o-[diphenylphosphino)benzylidene]analine (P∩N) have been synthesized and structurally characterized. All the complexes of the type [ReX(CO)3(LL)] (where LL = P∩O, P∩N) reveal a distorted octahedral structure with the three carbonyl ligands arranged in the facial fashion. Crystal data for 1, C22H15ClO4PRe·1/2C6H14: triclinic, P1, a=8.7430(4), b=9.5767(4), c=13.9449(6) Å, α=93.651(1), β=101.265(1), γ=93.048(1); V=1140.20(9) Å3, Z=2.2, C22H15BrO4Pre: monoclinic, C2/c, a=31.6800(16), b=8.8880(4), c=18.4517(9) Å, β=124.990(1); V=4256.4(4) Å3, Z=8. 3, C28H20ClNO3Pre: monoclinic, C2/c, a=22.675(4), b=8.803(2), c=28.218(5) Å, β=100.192(3); V=5543.5(16) Å3, Z=8.4, C28H20BrNO3Pre: monoclinic, C2/c, a=23.035(1), b=8.7561(4), c=28.269(1) Å, β=100.811(1); V=5600.4(5) Å3, Z=8. PMID:21603092

  11. Synthesis and structural characterization of rhenium(I) tricarbonyl complexes with the bidentate ligands o-(diphenylphosphino)benzaldehyde (P∩O) and o-[(diphenylphosphino)benzylidene]analine (P∩N).

    PubMed

    Chen, Xiaoyuan; Femia, Frank J; Babich, John W; Zubieta, Jon

    2001-04-27

    A series of rhenium(I) tricarbonyl complexes with bidentate P,O donor ligand o-(diphenylphosphino)benzaldehyde (P∩O) and its Schiff base P,N donor ligand o-[diphenylphosphino)benzylidene]analine (P∩N) have been synthesized and structurally characterized. All the complexes of the type [ReX(CO)(3)(LL)] (where LL = P∩O, P∩N) reveal a distorted octahedral structure with the three carbonyl ligands arranged in the facial fashion. Crystal data for 1, C(22)H(15)ClO(4)PRe·1/2C(6)H(14): triclinic, P1, a=8.7430(4), b=9.5767(4), c=13.9449(6) Å, α=93.651(1), β=101.265(1), γ=93.048(1); V=1140.20(9) Å(3), Z=2.2, C(22)H(15)BrO(4)Pre: monoclinic, C2/c, a=31.6800(16), b=8.8880(4), c=18.4517(9) Å, β=124.990(1); V=4256.4(4) Å(3), Z=8. 3, C(28)H(20)ClNO(3)Pre: monoclinic, C2/c, a=22.675(4), b=8.803(2), c=28.218(5) Å, β=100.192(3); V=5543.5(16) Å(3), Z=8.4, C(28)H(20)BrNO(3)Pre: monoclinic, C2/c, a=23.035(1), b=8.7561(4), c=28.269(1) Å, β=100.811(1); V=5600.4(5) Å(3), Z=8. PMID:21603092

  12. Activities of wogonin analogs and other flavones against Flavobacterium columnare.

    PubMed

    Tan, Cheng-Xia; Schrader, Kevin K; Khan, Ikhlas A; Rimando, Agnes M

    2015-02-01

    In our on-going pursuit to discover natural products and natural product-based compounds to control the bacterial species Flavobacterium columnare, which causes columnaris disease in channel catfish (Ictalurus punctatus), we synthesized flavone and chalcone analogs, and evaluated these compounds, along with flavonoids from natural sources, for their antibacterial activities against two isolates of F. columnare (ALM-00-173 and BioMed) using a rapid bioassay. The flavonoids chrysin (1a), 5,7-dihydroxy-4'-methoxyflavone (11), isorhamnetin (26), luteolin (27), and biochanin A (29), and chalcone derivative 8b showed strong antibacterial activities against F. columnare ALM-00-173 based on minimum inhibition concentration (MIC) results. Flavonoids 1a, 8, 11, 13 (5,4'-dihydroxy-7-methoxyflavone), 26, and 29 exhibited strong antibacterial activities against F. columnare BioMed based upon MIC results. The 24-h 50% inhibition concentration (IC50 ) results revealed that 27 and 29 were the most active compounds against F. columnare ALM-00-173 (IC50 of 7.5 and 8.5 mg/l, resp.), while 26 and 29 were the most toxic compound against F. columnare BioMed (IC50 of 9.2 and 3.5 mg/l, resp.). These IC50 results were lower than those obtained for wogonin against F. columnare ALM-00-173 and F. columnare BioMed (28.4 and 5.4 mg/l, resp.). However, based on MIC results, none of the compounds evaluated in this study were as active as wogonin (MIC 0.3 mg/l for each F. columnare isolate). Further modification of the wogonin structure to enhance antibacterial is of interest. PMID:25676507

  13. Synthesis, structure determination, and infrared spectroscopy of (NpO{sub 2}){sub 2}(SO{sub 4})(H{sub 2}O){sub 4}: Prevalence of cation-cation interactions and cationic nets in neptunyl sulfate compounds

    SciTech Connect

    Forbes, T.Z. Burns, P.C.

    2009-01-15

    The compound (NpO{sub 2}){sub 2}(SO{sub 4})(H{sub 2}O){sub 4} was synthesized by evaporation of a Np{sup 5+} sulfate solution. The crystal structure was determined using single crystal X-ray diffraction and refined to an R{sub 1}=0.0310. (NpO{sub 2}){sub 2}(SO{sub 4})(H{sub 2}O){sub 4} crystallizes in triclinic space group P-1, a=8.1102(7) A, b=8.7506(7) A, c=16.234(1) A, {alpha}=90.242(2){sup o}, {beta}=92.855(2){sup o}, {gamma}=113.067(2){sup o}, V=1058.3(2) A{sup 3}, and Z=2. The structure contains neptunyl pentagonal bipyramids that share vertices through cation-cation interactions to form a sheet or cationic net. The sheet is decorated on each side by vertex sharing with sulfate tetrahedra, and adjacent sheets are linked together through hydrogen bonding. A graphical representation of (NpO{sub 2}){sub 2}(SO{sub 4})(H{sub 2}O){sub 4} was constructed to facilitate the structural comparison to similar Np{sup 5+} compounds. The prevalence of the cationic nets in neptunyl sulfate compounds related to the overall stability of the structure is also discussed. - Graphical abstract: (NpO{sub 2}){sub 2}(SO{sub 4})(H{sub 2}O){sub 4} was synthesized by hydrothermal methods and its structure determined. A graphical representation of the compound was constructed to facilitate the structural comparison to similar Np{sup 5+} compounds and the prevalence of the cationic nets in neptunyl sulfate compounds related to the overall stability of the structure is discussed.

  14. Comparative embryogenesis of Mecoptera and Lepidoptera with special reference to the abdominal prolegs.

    PubMed

    Kou, Li-Xuan; Hua, Bao-Zhen

    2016-05-01

    The eruciform larvae of holometabolous insects are primarily characterized by bearing a varying number of abdominal prolegs in addition to three pairs of thoracic legs. However, whether the prolegs are evolutionarily homologous among different insect orders is still a disputable issue. We examined the embryonic features and histological structure of the prolegs of the scorpionfly Panorpa byersi Hua and Huang (Mecoptera: Panorpidae) and the Oriental armyworm Mythimna separata (Walker) (Lepidoptera: Noctuidae) to investigate whether the prolegs are homologous between these two holometabolous insect orders. In the scorpionfly, paired lateral process primordia arise on abdominal segments I-VIII (A1-A8) in line with the thoracic legs in early embryonic stages, but degenerate into triangular protuberances in later stages, and paired medial processes appear along the midventral line before dorsal closure and eventually develop into unjointed, cone-shaped prolegs. Histological observation showed that the lumina of the prolegs are not continuous with the hemocoel, differing distinctly from that of the basic appendicular plan of thoracic legs. These results suggest that the prolegs are likely secondary outgrowths in Mecoptera. In the armyworm, lateral process primordia appear on A1-A10 in alignment with the thoracic legs in the early embryonic stages, although only the rudiments on A3-A6 and A10 develop into segmented prolegs with the lumina continuous with the hemocoel and others degenerate eventually, suggesting that the prolegs are true segmental appendages serially homologous with the thoracic legs in Lepidoptera. Therefore, we conclude that the larval prolegs are likely not evolutionarily homologous between Mecoptera and Lepidoptera. J. Morphol. 277:585-593, 2016. © 2016 Wiley Periodicals, Inc. PMID:26891764

  15. Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma

    PubMed Central

    Lázcoz, Paula; Muñoz, Jorge; Nistal, Manuel; Pestaña, Ángel; Encío, Ignacio; Castresana, Javier S

    2006-01-01

    Background Epigenetic alterations and loss of heterozygosity are mechanisms of tumor suppressor gene inactivation. A new carcinogenic pathway, targeting the RAS effectors has recently been documented. RASSF1A, on 3p21.3, and NORE1A, on 1q32.1, are among the most important, representative RAS effectors. Methods We screened the 3p21 locus for the loss of heterozygosity and the hypermethylation status of RASSF1A, NORE1A and BLU (the latter located at 3p21.3) in 41 neuroblastic tumors. The statistical relationship of these data was correlated with CASP8 hypermethylation. The expression levels of these genes, in cell lines, were analyzed by RT-PCR. Results Loss of heterozygosity and microsatellite instability at 3p21 were detected in 14% of the analyzed tumors. Methylation was different for tumors and cell lines (tumors: 83% in RASSF1A, 3% in NORE1A, 8% in BLU and 60% in CASP8; cell lines: 100% in RASSF1A, 50% in NORE1A, 66% in BLU and 92% in CASP8). In cell lines, a correlation with lack of expression was evident for RASSF1A, but less clear for NORE1A, BLU and CASP8. We could only demonstrate a statistically significant association between hypermethylation of RASSF1A and hypermethylation of CASP8, while no association with MYCN amplification, 1p deletion, and/or aggressive histological pattern of the tumor was demonstrated. Conclusion 1) LOH at 3p21 appears in a small percentage of neuroblastomas, indicating that a candidate tumor suppressor gene of neuroblastic tumors is not located in this region. 2) Promoter hypermethylation of RASSF1A and CASP8 occurs at a high frequency in neuroblastomas. PMID:17064406

  16. Antibody-induced neutrophil depletion prior to the onset of pneumococcal meningitis influences long-term neurological complications in mice.

    PubMed

    Too, Lay Khoon; Mitchell, Andrew J; McGregor, Iain S; Hunt, Nicholas H

    2016-08-01

    During pneumococcal meningitis, clearance of bacteria by recruited neutrophils is crucial for host protection. However, these innate immune mechanisms are often insufficient and treatment with antibiotics is necessary to prevent death. Despite this antibiotic treatment, approximately half of all survivors suffer lifelong neurological problems. There is growing evidence indicating the harmful effects of neutrophils on CNS integrity. Therefore, the present study investigated the roles of neutrophils in the acute inflammatory response and the resulting long-term neuropsychological effects in murine pneumococcal meningitis. Long-term behavioural and cognitive functions in mice were measured using an automated IntelliCage system. Neutrophil depletion with antibody 1A8 as adjunctive therapy was shown to remarkably impair survival in meningitic C57BL/6J mice despite antibiotic (ceftriaxone) treatment. This was accompanied by increased bacterial load in the cerebrospinal fluid (CSF) and an increase in IL-1β, but decrease in TNF, within the CSF at 20h after bacterial inoculation. In the longer term, the surviving neutrophil-depleted post-meningitic (PM) mice displayed reduced diurnal hypolocomotion compared to PM mice treated with an isotype antibody. However, they showed nocturnal hyperactivity, and greater learning impairment in a patrolling task that is believed to depend upon an intact hippocampus. The data thus demonstrate two important mechanisms: 1. Neutrophil extravasation into the CNS during pneumococcal meningitis influences the pro-inflammatory response and is central to control of the bacterial load, an increase in which may lead to death. 2. Neutrophil-mediated changes in the acute inflammatory response modulate the neuropsychological sequelae in mice that survive pneumococcal meningitis. PMID:26965652

  17. Phase 1 Study of ABT-751 in Combination With CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients With Advanced Colorectal Cancer.

    PubMed

    Rudek, Michelle A; Dasari, Arvind; Laheru, Daniel; He, Ping; Jin, Runyan; Walker, Rosalind; Taylor, Gretchen E; Jimeno, Antonio; Donehower, Ross C; Hidalgo, Manuel; Messersmith, Wells A; Purcell, W Thomas

    2016-08-01

    ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A nonrandomized phase 1 dose-escalation study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT-751 daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751 daily and capecitabine twice daily for 14 days plus irinotecan on day 1 intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1 after the first 2 dose levels. Because of intolerance to the regimen, a reduced dose of ABT-751 was also explored with reduced-dose and full-dose CAPIRI with bevacizumab. ABT-751 and irinotecan pharmacokinetics, ABT-751 glucuronidation, and protein binding were explored. Twenty-four patients were treated over 5 dose levels. The maximum tolerated dose was ABT-751 125 mg combined with full-dose CAPIRI and bevacizumab 7.5 mg/kg on day 1. DLTs were hypokalemia, elevated liver tests, and febrile neutropenia. ABT-751 is metabolized by UGT1A8 and to a lesser extent UGT1A4 and UGT1A1. Irinotecan and APC exposure were increased, SN-38 exposure was similar, and SN-38 glucuronide exposure was decreased. Clinically relevant alterations in ABT-751 and irinotecan pharmacokinetics were not observed. Despite modest efficacy, the combination of ABT-751, CAPIRI, and bevacizumab will not be studied further in colorectal cancer. PMID:26632033

  18. Neutrophils Select Hypervirulent CovRS Mutants of M1T1 Group A Streptococcus during Subcutaneous Infection of Mice

    PubMed Central

    Li, Jinquan; Liu, Guanghui; Feng, Wenchao; Zhou, Yang; Liu, Mengyao; Wiley, James A.

    2014-01-01

    Pathogen mutants arise during infections. Mechanisms of selection for pathogen variants are poorly understood. We tested whether neutrophils select mutations in the two-component regulatory system CovRS of group A Streptococcus (GAS) during infection using the lack of production of the protease SpeB (SpeB activity negative [SpeBA−]) as a marker. Depletion of neutrophils by antibodies RB6-8C5 and 1A8 reduced the percentage of SpeBA− variants (SpeBA−%) recovered from mice infected with GAS strain MGAS2221 by >76%. Neutrophil recruitment and SpeBA−% among recovered GAS were reduced by 95% and 92%, respectively, in subcutaneous MGAS2221 infection of CXCR2−/− mice compared with control mice. In air sac infection with MGAS2221, levels of neutrophils and macrophages in lavage fluid were reduced by 49% and increased by 287%, respectively, in CXCR2−/− mice compared with control mice, implying that macrophages play an insignificant role in the reduction of selection for SpeBA− variants in CXCR2−/− mice. One randomly chosen SpeBA− mutant outcompeted MGAS2221 in normal mice but was outcompeted by MGAS2221 in neutropenic mice and had enhancements in expression of virulence factors, innate immune evasion, skin invasion, and virulence. This and nine other SpeBA− variants from a mouse all had nonsynonymous covRS mutations that resulted in the SpeBA− phenotype and enhanced expression of the CovRS-controlled secreted streptococcal esterase (SsE). Our findings are consistent with a model that neutrophils select spontaneous covRS mutations that maximize the potential of GAS to evade neutrophil responses, resulting in variants with enhanced survival and virulence. To our knowledge, this is the first report of the critical contribution of neutrophils to the selection of pathogen variants. PMID:24452689

  19. Vacuum-Ultraviolet photoionization studies of the microhydrationof DNA bases (Guanine, Cytosine, Adenine and Thymine)

    SciTech Connect

    Belau, L.; Wilson, K.R.; Leone, S.R.; Musahid, Ahmed

    2007-01-22

    In this work, we report on a photoionization study of the microhydration of the four DNA bases. Gas-phase clusters of water with DNA bases [guanine (G), cytosine (C), adenine (A), and thymine (T)] are generated via thermal vaporization of the bases and expansion of the resultant vapor in a continuous supersonic jet expansion of water seeded in Ar. The resulting clusters are investigated by single-photon ionization with tunable vacuum-ultraviolet synchrotron radiation and mass analyzed using reflectron mass spectrometry. Photoionization efficiency (PIE) curves are recorded for the DNA bases and the following water (W) clusters: G, GW{sub n} (n = 1-3); C, CW{sub n} (n = 1-3); A, AW{sub n} (n = 1,2); and T, TW{sub n} (n = 1-3). Appearance energies (AE) are derived from the onset of these PIE curves (all energies in eV): G (8.1 {+-} 0.1), GW (8.0 {+-} 0.1), GW{sub 2} (8.0 {+-} 0.1), and GW{sub 3} (8.0); C (8.65 {+-} 0.05), CW (8.45 {+-} 0.05), CW{sub 2} (8.4 {+-} 0.1), and CW{sub 3} (8.3 {+-} 0.1); A (8.30 {+-} 0.05), AW (8.20 {+-} 0.05), and AW{sub 2} (8.1 {+-} 0.1); T (8.90 {+-} 0.05); and TW (8.75 {+-} 0.05), TW{sub 2} (8.6 {+-} 0.1), and TW{sub 3} (8.6 {+-} 0.1). The AEs of the DNA bases decrease slightly with the addition of water molecules (up to three) but do not converge to values found for photoinduced electron removal from DNA bases in solution.

  20. Expression and Characterization of a Potent Long-Acting GLP-1 Receptor Agonist, GLP-1-IgG2σ-Fc

    PubMed Central

    Yang, Yi; Chen, Fang; Wan, Deyou; Liu, Yunhui; Yang, Li; Feng, Hongru; Cui, Xinling; Gao, Xin; Song, Haifeng

    2016-01-01

    Human GLP-1 (glucagon-like peptide-1) can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2σ-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G) to a human IgG2σ constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2σ-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2σ-Fc in cynomolgus monkeys was approximately 57.1 ± 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2σ-Fc (1 mg/kg) reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2σ-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2σ-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1-IgG2σ-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes. PMID:27232339

  1. Synthesis, crystal structure, and properties of Mg(x)B50C8 or Mg(x)(B12)4(CBC)2(C2)2 (x = 2.4-4).

    PubMed

    Adasch, Volker; Schroeder, Melanie; Kotzott, Dominik; Ludwig, Thilo; Vojteer, Natascha; Hillebrecht, Harald

    2010-10-01

    Single crystals of a new magnesium boride carbide Mg(x)B(50)C(8) (x = 2.4-4) were synthesized from the elements in a metallic melt using tantalum ampules. Crystals were characterized by single crystal X-ray diffraction and electron microprobe analysis. The variation of the Mg content results from different reaction conditions. The composition Mg(∼3)B(50)C(8) is by far the most favored. It fulfills the electron counting rules of Wade and Longuet-Higgins and thus explains the light-green to yellow transparent color. The structure of Mg(∼3)B(50)C(8) (C2/m, Z = 1, a = 8.9384(12) Å, b = 5.6514(9) Å, c = 9.6021(13) Å, β = 105.86(1)°) consists of B(12) icosahedra. The icosahedra are interconnected by four exohedral B-B bonds to layers. The layers are connected to a three-dimensional covalent network by C(2) and CBC units and further exohedral B-B bonds. The Mg sites are partially occupied. Different site occupation factors cause the various compositions and colors (Mg(2.4)B(50)C(8), brown; Mg(4)B(50)C(8), black). The vibrational spectra show the modes of B(12) icosahedra and C(2) and CBC units as well. Measurements of the microhardness according to Vickers and Knoop revealed remarkably high values of H(V) = 3286 (32.0 GPa) and H(K) = 3165 (31.5 GPa), which exceed the values of B(4)C. Optical spectra reveal a band gap of 2.7 eV for Mg(∼3)B(50)C(8), in agreement to the observed color. This justifies an ionic description, and the formula can be written as (Mg(2+))(3)(B(12)(2-))(4)(CBC(+))(2)(C(2))(2). PMID:20839790

  2. Acid-, water- and high-temperature-stable ruthenium complexes for the total catalytic deoxygenation of glycerol to propane.

    PubMed

    Taher, Deeb; Thibault, Michelle E; Di Mondo, Domenico; Jennings, Michael; Schlaf, Marcel

    2009-10-01

    The ruthenium aqua complexes [Ru(H(2)O)(2)(bipy)(2)](OTf)(2), [cis-Ru(6,6'-Cl(2)-bipy)(2)(OH(2))(2)](OTf)(2), [Ru(H(2)O)(2)(phen)(2)](OTf)(2), [Ru(H(2)O)(3)(2,2':6',2''-terpy)](OTf)(2) and [Ru(H(2)O)(3)(Phterpy)](OTf)(2) (bipy = 2,2'-bipyridine; OTf(-) = triflate; phen = phenanthroline; terpy = terpyridine; Phterpy = 4'-phenyl-2,2':6',2''-terpyridine) are water- and acid-stable catalysts for the hydrogenation of aldehydes and ketones in sulfolane solution. In the presence of HOS(O)(2)CF(3) (triflic acid) as a dehydration co-catalyst they directly convert 1,2-hexanediol to n-hexanol and hexane. The terpyridine complexes are stable and active as catalysts at temperatures > or = 250 degrees C and in either aqueous sulfolane solution or pure water convert glycerol into n-propanol and ultimately propane as the final reaction product in up to quantitative yield. For the terpy complexes the active catalyst is postulated to be a carbonyl species [(4'-R-2,2':6',2''-terpy)Ru(CO)(H(2)O)(2)](OTf)(2) (R = H, Ph) formed by the decarbonylation of aldehydes (hexanal for 1,2-hexanediol and 3-hydroxypropanal for glycerol) generated in the reaction mixture through acid-catalyzed dehydration. The structure of the dimeric complex [{(4'-phenyl-2,2':6',2''-terpy)Ru(CO)}(2)(mu-OCH(3))(2)](OTf)(2) has been determined by single crystal X-ray crystallography (Space group P1 (a = 8.2532(17); b = 12.858(3); c = 14.363(3) A; alpha = 64.38(3); beta = 77.26(3); gamma = 87.12(3) degrees, R = 4.36 %). PMID:19693757

  3. Myeloid-derived suppressor cells (MDSCs) contribute to S. aureus orthopedic biofilm infection

    PubMed Central

    Heim, Cortney E.; Vidlak, Debbie; Scherr, Tyler D.; Kozel, Jessica A.; Holzapfel, Melissa; Muirhead, David E.; Kielian, Tammy

    2014-01-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature monocytes and granulocytes that are potent inhibitors of T cell activation. A role for MDSCs in bacterial infections has only recently emerged and nothing is known about MDSC function in the context of Staphylococcus aureus (S. aureus) infection. Since S. aureus biofilms are capable of subverting immune-mediated clearance, we examined whether MDSCs could play a role in this process. CD11b+Gr-1+ MDSCs represented the main cellular infiltrate during S. aureus orthopedic biofilm infection, accounting for over 75% of the CD45+ population. Biofilm-associated MDSCs inhibited T cell proliferation and cytokine production, which correlated with a paucity of T cell infiltrates at the infection site. Analysis of FACS-purified MDSCs recovered from S. aureus biofilms revealed increased Arg-1, iNOS, and IL-10 expression, key mediators of MDSC suppressive activity. Targeted depletion of MDSCs and neutrophils using the mAb 1A8 (anti-Ly6G) improved bacterial clearance by enhancing the intrinsic pro-inflammatory attributes of infiltrating monocytes and macrophages. Furthermore, the ability of monocytes/macrophages to promote biofilm clearance in the absence of MDSC action was revealed with RB6-C85 (anti-Gr-1 or anti-Ly6G/Ly6C) administration, which resulted in significantly increased S. aureus burdens both locally and in the periphery, since effector Ly-6C monocytes and by extension, mature macrophages, were also depleted. Collectively, these results are the first to demonstrate that MDSCs are key contributors to the chronicity of S. aureus biofilm infection, as their immunosuppressive function prevents monocyte/macrophage proinflammatory activity, which facilitates biofilm persistence. PMID:24646737

  4. A Combretastatin-Mediated Decrease in Neutrophil Concentration in Peripheral Blood and the Impact on the Anti-Tumor Activity of This Drug in Two Different Murine Tumor Models

    PubMed Central

    Bohn, Anja Bille; Wittenborn, Thomas; Brems-Eskildsen, Anne Sofie; Laurberg, Tinne; Bertelsen, Lotte Bonde; Nielsen, Thomas; Stødkilde-Jørgensen, Hans; Møller, Bjarne Kuno; Horsman, Michael R.

    2014-01-01

    The vascular disrupting agent combretastatin A-4 disodium phosphate (CA4P) induces fluctuations in peripheral blood neutrophil concentration. Because neutrophils have the potential to induce both vascular damage and angiogenesis we analyzed neutrophil involvement in the anti-tumoral effects of CA4P in C3H mammary carcinomas in CDF1 mice and in SCCVII squamous cell carcinomas in C3H/HeN mice. Flow cytometry analyses of peripheral blood before and up to 144 h after CA4P administration (25 and 250 mg/kg) revealed a decrease 1 h after treatment, followed by an early (3–6 h) and a late (>72 h) increase in the granulocyte concentration. We suggest that the early increase (3–6 h) in granulocyte concentration was caused by the initial decrease at 1 h and found that the late increase was associated with tumor size, and hence independent of CA4P. No alterations in neutrophil infiltration into the C3H tumor after CA4P treatment (25 and 250 mg/kg) were found. Correspondingly, neutrophil depletion in vivo, using an anti-neutrophil antibody, followed by CA4P treatment (25 mg/kg) did not increase the necrotic fraction in C3H tumors significantly. However, by increasing the CA4P dose to 250 mg/kg we found a significant increase of 359% in necrotic fraction when compared to neutrophil-depleted mice; in mice with no neutrophil depletion CA4P induced an 89% change indicating that the presence of neutrophils reduced the effect of CA4P. In contrast, neither CA4P nor 1A8 affected the necrotic fraction in the SCCVII tumors significantly. Hence, we suggest that the initial decrease in granulocyte concentration was caused by non-tumor-specific recruitment of neutrophils and that neutrophils may attenuate CA4P-mediated anti-tumor effect in some tumor models. PMID:25299269

  5. Neutrophils select hypervirulent CovRS mutants of M1T1 group A Streptococcus during subcutaneous infection of mice.

    PubMed

    Li, Jinquan; Liu, Guanghui; Feng, Wenchao; Zhou, Yang; Liu, Mengyao; Wiley, James A; Lei, Benfang

    2014-04-01

    Pathogen mutants arise during infections. Mechanisms of selection for pathogen variants are poorly understood. We tested whether neutrophils select mutations in the two-component regulatory system CovRS of group A Streptococcus (GAS) during infection using the lack of production of the protease SpeB (SpeB activity negative [SpeB(A-)]) as a marker. Depletion of neutrophils by antibodies RB6-8C5 and 1A8 reduced the percentage of SpeB(A-) variants (SpeB(A-)%) recovered from mice infected with GAS strain MGAS2221 by >76%. Neutrophil recruitment and SpeB(A-)% among recovered GAS were reduced by 95% and 92%, respectively, in subcutaneous MGAS2221 infection of CXCR2(-/-) mice compared with control mice. In air sac infection with MGAS2221, levels of neutrophils and macrophages in lavage fluid were reduced by 49% and increased by 287%, respectively, in CXCR2(-/-) mice compared with control mice, implying that macrophages play an insignificant role in the reduction of selection for SpeB(A-) variants in CXCR2(-/-) mice. One randomly chosen SpeB(A-) mutant outcompeted MGAS2221 in normal mice but was outcompeted by MGAS2221 in neutropenic mice and had enhancements in expression of virulence factors, innate immune evasion, skin invasion, and virulence. This and nine other SpeB(A-) variants from a mouse all had nonsynonymous covRS mutations that resulted in the SpeB(A-) phenotype and enhanced expression of the CovRS-controlled secreted streptococcal esterase (SsE). Our findings are consistent with a model that neutrophils select spontaneous covRS mutations that maximize the potential of GAS to evade neutrophil responses, resulting in variants with enhanced survival and virulence. To our knowledge, this is the first report of the critical contribution of neutrophils to the selection of pathogen variants. PMID:24452689

  6. Expression and Characterization of a Potent Long-Acting GLP-1 Receptor Agonist, GLP-1-IgG2σ-Fc.

    PubMed

    Yang, Yi; Chen, Fang; Wan, Deyou; Liu, Yunhui; Yang, Li; Feng, Hongru; Cui, Xinling; Gao, Xin; Song, Haifeng

    2016-01-01

    Human GLP-1 (glucagon-like peptide-1) can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2σ-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G) to a human IgG2σ constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2σ-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2σ-Fc in cynomolgus monkeys was approximately 57.1 ± 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2σ-Fc (1 mg/kg) reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2σ-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2σ-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1-IgG2σ-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes. PMID:27232339

  7. High-temperature, high-pressure hydrothermal synthesis, characterization, and structural relationships of layered uranyl arsenates.

    PubMed

    Liu, Hsin-Kuan; Ramachandran, Eswaran; Chen, Yi-Hsin; Chang, Wen-Jung; Lii, Kwang-Hwa

    2014-09-01

    Five new uranyl arsenates, Na14[(UO2)5(AsO4)8]·2H2O (1), K6[(UO2)5O5(AsO4)2] (2a), K4[(UO2)3O2(AsO4)2] (2b), Rb4[(UO2)3O2(AsO4)2] (3), and Cs6[(UO2)5O2(AsO4)4] (4), were synthesized by high-temperature, high-pressure hydrothermal reactions at about 560 °C and 1440 bar and were characterized by single-crystal X-ray diffraction, thermogravimetric analysis, and photoluminescence spectroscopy. Crystal data for compound 1: triclinic, P1, a = 7.0005(3) Å, b = 12.1324(4) Å, c = 13.7428(5) Å, α = 64.175(2)°, β = 89.092(2)°, γ = 85.548(2)°, V = 1047.26(7) Å(3), Z = 1, R1 = 0.0185; compound 2a: monoclinic, P2₁/c, a = 6.8615(3) Å, b = 24.702(1) Å, c = 7.1269(3) Å, β = 98.749(2)°, V = 1193.89(9) Å(3), Z = 2, R1 = 0.0225; compound 2b: monoclinic, P2₁/c, a = 6.7852(3) Å, b = 17.3640(8) Å, c = 7.1151(3) Å, β = 98.801(3)°, V = 828.42(6) Å(3), Z = 2, R1 = 0.0269; compound 3: monoclinic, P2₁/m, a = 6.9783(3) Å, b = 17.4513(8) Å, c = 7.0867(3) Å, β = 90.808(3)°, V = 862.94(7) Å(3), Z = 2, R1 = 0.0269; compound 4: triclinic, P1, a = 7.7628(3) Å, b = 9.3324(4) Å, c = 11.9336(4) Å, α = 75.611(2)°, β = 73.136(2)°, γ = 86.329(2)°, V = 801.37(5) Å(3), Z = 1, R1 = 0.0336. The five compounds have layer structures consisting of uranyl square, pentagonal, and hexagonal bipyramids as well as AsO4 tetrahedra. Compound 1 contains chains of discrete uranyl square and pentagonal bipyramids, 2a contains three-polyhedron-wide ribbons of edge- and corner-sharing uranyl square and pentagonal bipyramids, 2b and 3 contain dimers of edge-shairing pentagonal bipyramids that share edges with hexagonal bipyramids to form chains, and 4 contains one-polyhedron-wide zigzag chains of edge-sharing uranyl polyhedra. The double sheet structure of 1 is new, but the chain topology has been observed in an organically templated uranyl sulfate. Compound 2b is a new geometrical isomer of the phosphuranylite group. The sheet anion topologies of 2a and 4 can be obtained by

  8. Orickite and coyoteite, two new sulfide minerals from Coyote Peak, Humboldt County, California.

    USGS Publications Warehouse

    Erd, Richard C.; Czamanske, G.K.

    1983-01-01

    Minute quantities of orickite and coyoteite occur with rare alkali iron sulphides in a mafic alkalic diatreme near Orick, Humboldt County. Orickite, NaxKyCu0.95Fe1.06zH2O (x,y < 0.03, z < 0.5), is hexagonal, a 3.695, c 6.16 A, D 4.212 g/cm3, Z = 4. The strongest XRD reflections are 3.08(100), 3.20(90), 2.84(60), 1.73(55), 1.583(30) A. The mineral is brass yellow, opaque, weakly pleochroic, but strongly anisotropic (greyish brown to greyish blue) in reflected light. Orickite is compositionally near to Fe-rich chalcopyrite, but it may be related to synthetic chalcogenides with a distorted wurtzite-(2H) structure. Coyoteite, NaFe3S5.2H2O, is triclinic, P1 or P1, a 7.409(8), b 9.881(6), c 6.441(3) A, alpha 100o25(3)', beta 104o37(5)', gamma 81o29(5)', D 2.879 g/cm3, Z = 2; strongest XRD reflections are 5.12(100), 7.13(90), 3.028(80), 3.080(70), 9.6(60), 5.60(60) A. Coyoteite is black, opaque, weakly pleochroic (pale brownish grey) and strongly anisotropic (grey to dull golden orange) in reflected light. It is unstable under normal atmospheric conditions. -J.A.Z.

  9. Genetic Map of Triticale Integrating Microsatellite, DArT and SNP Markers.

    PubMed

    Tyrka, Mirosław; Tyrka, Dorota; Wędzony, Maria

    2015-01-01

    Triticale (×Triticosecale Wittm) is an economically important crop for fodder and biomass production. To facilitate the identification of markers for agronomically important traits and for genetic and genomic characteristics of this species, a new high-density genetic linkage map of triticale was constructed using doubled haploid (DH) population derived from a cross between cultivars 'Hewo' and 'Magnat'. The map consists of 1615 bin markers, that represent 50 simple sequence repeat (SSR), 842 diversity array technology (DArT), and 16888 DArTseq markers mapped onto 20 linkage groups assigned to the A, B, and R genomes of triticale. No markers specific to chromosome 7R were found, instead mosaic linkage group composed of 1880 highly distorted markers (116 bins) from 10 wheat chromosomes was identified. The genetic map covers 4907 cM with a mean distance between two bins of 3.0 cM. Comparative analysis in respect to published maps of wheat, rye and triticale revealed possible deletions in chromosomes 4B, 5A, and 6A, as well as inversion in chromosome 7B. The number of bin markers in each chromosome varied from 24 in chromosome 3R to 147 in chromosome 6R. The length of individual chromosomes ranged between 50.7 cM for chromosome 2R and 386.2 cM for chromosome 7B. A total of 512 (31.7%) bin markers showed significant (P < 0.05) segregation distortion across all chromosomes. The number of 8 the segregation distorted regions (SDRs) were identified on 1A, 7A, 1B, 2B, 7B (2 SDRs), 5R and 6R chromosomes. The high-density genetic map of triticale will facilitate fine mapping of quantitative trait loci, the identification of candidate genes and map-based cloning. PMID:26717308

  10. P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression

    PubMed Central

    Zhang, E-b; Yin, D-d; Sun, M; Kong, R; Liu, X-h; You, L-h; Han, L; Xia, R; Wang, K-m; Yang, J-s; De, W; Shu, Y-q; Wang, Z-x

    2014-01-01

    Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy. PMID:24853421

  11. Crustal velocities near Coalinga, California, modeled from a combined earthquake/explosion refraction profile

    USGS Publications Warehouse

    Macgregor-Scott, N.; Walter, A.

    1988-01-01

    Crustal velocity structure for the region near Coalinga, California, has been derived from both earthquake and explosion seismic phase data recorded along a NW-SE seismic-refraction profile on the western flank of the Great Valley east of the Diablo Range. Comparison of the two data sets reveals P-wave phases in common which can be correlated with changes in the velocity structure below the earthquake hypocenters. In addition, the earthquake records reveal secondary phases at station ranges of less than 20 km that could be the result of S- to P-wave conversions at velocity interfaces above the earthquake hypocenters. Two-dimensional ray-trace modeling of the P-wave travel times resulted in a P-wave velocity model for the western flank of the Great Valley comprised of: 1) a 7- to 9-km thick section of sedimentary strata with velocities similar to those found elsewhere in the Great Valley (1.6 to 5.2 km s-1); 2) a middle crust extending to about 14 km depth with velocities comparable to those reported for the Franciscan assemblage in the Diablo Range (5.6 to 5.9 km s-1); and 3) a 13- to 14-km thick lower crust with velocities similar to those reported beneath the Diablo Range and the Great Valley (6.5 to 7.30 km s-1). This lower crust may have been derived from subducted oceanic crust that was thickened by accretionary underplating or crustal shortening. -Authors

  12. Genetic Map of Triticale Integrating Microsatellite, DArT and SNP Markers

    PubMed Central

    Tyrka, Mirosław; Tyrka, Dorota; Wędzony, Maria

    2015-01-01

    Triticale (×Triticosecale Wittm) is an economically important crop for fodder and biomass production. To facilitate the identification of markers for agronomically important traits and for genetic and genomic characteristics of this species, a new high-density genetic linkage map of triticale was constructed using doubled haploid (DH) population derived from a cross between cultivars ‘Hewo’ and ‘Magnat’. The map consists of 1615 bin markers, that represent 50 simple sequence repeat (SSR), 842 diversity array technology (DArT), and 16888 DArTseq markers mapped onto 20 linkage groups assigned to the A, B, and R genomes of triticale. No markers specific to chromosome 7R were found, instead mosaic linkage group composed of 1880 highly distorted markers (116 bins) from 10 wheat chromosomes was identified. The genetic map covers 4907 cM with a mean distance between two bins of 3.0 cM. Comparative analysis in respect to published maps of wheat, rye and triticale revealed possible deletions in chromosomes 4B, 5A, and 6A, as well as inversion in chromosome 7B. The number of bin markers in each chromosome varied from 24 in chromosome 3R to 147 in chromosome 6R. The length of individual chromosomes ranged between 50.7 cM for chromosome 2R and 386.2 cM for chromosome 7B. A total of 512 (31.7%) bin markers showed significant (P < 0.05) segregation distortion across all chromosomes. The number of 8 the segregation distorted regions (SDRs) were identified on 1A, 7A, 1B, 2B, 7B (2 SDRs), 5R and 6R chromosomes. The high-density genetic map of triticale will facilitate fine mapping of quantitative trait loci, the identification of candidate genes and map-based cloning. PMID:26717308

  13. Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity

    PubMed Central

    Shelton, Jonathan; Yun, Sujin; Losee Olson, Susan; Turek, Fred; Bonaventure, Pascal; Dvorak, Curt; Lovenberg, Timothy; Dugovic, Christine

    2015-01-01

    Recent reports have illustrated a reciprocal relationship between circadian rhythm disruption and mood disorders. The 5-HT7 receptor may provide a crucial link between the two sides of this equation since the receptor plays a critical role in sleep, depression, and circadian rhythm regulation. To further define the role of the 5-HT7 receptor as a potential pharmacotherapy to correct circadian rhythm disruptions, the current study utilized the selective 5-HT7 antagonist JNJ-18038683 (10 mg/kg) in three different circadian paradigms. While JNJ-18038683 was ineffective at phase shifting the onset of wheel running activity in mice when administered at different circadian time (CT) points across the circadian cycle, pretreatment with JNJ-18038683 blocked non-photic phase advance (CT6) induced by the 5-HT1A/7 receptor agonist 8-OH-DPAT (3 mg/kg). Since light induced phase shifts in mammals are partially mediated via the modulation of the serotonergic system, we determined if JNJ-18038683 altered phase shifts induced by a light pulse at times known to phase delay (CT15) or advance (CT22) wheel running activity in free running mice. Light exposure resulted in a robust shift in the onset of activity in vehicle treated animals at both times tested. Administration of JNJ-18038683 significantly attenuated the light induced phase delay and completely blocked the phase advance. The current study demonstrates that pharmacological blockade of the 5-HT7 receptor by JNJ-18038683 blunts both non-photic and photic phase shifts of circadian wheel running activity in mice. These findings highlight the importance of the 5-HT7 receptor in modulating circadian rhythms. Due to the opposite modulating effects of light resetting between diurnal and nocturnal species, pharmacotherapy targeting the 5-HT7 receptor in conjunction with bright light therapy may prove therapeutically beneficial by correcting the desynchronization of internal rhythms observed in depressed individuals. PMID:25642174

  14. Organic pollutant characterization and toxicity testing of settling particulate matter by nanoinjection in sea trout (Salmo trutta) eggs

    SciTech Connect

    Ishaq, R.; Aakerman, G.; Naef, C.; Balk, L.; Bandh, C.; Broman, D.

    1999-03-01

    A nanoinjection technique was used to expose sea trout (Salmo trutta) eggs to a toluene extract of settling particulate matter (SPM) and fractions thereof from the urban waters of Stockholm, Sweden. Total extract (unfractionated), fractions collected using fractionation on an open Florisil{reg_sign} column (F1-F4), high-performance liquid chromatography (HPLC) aminopropylsilica/2-(1-pyrenyl)ethyldimethylsiluted silica column (A1-A7 and A2/P1-P3), and recombined fractions of Florisil (F-Rec) and HPLC (A-Rec) were injected into fertilized sea trout eggs. Toxicity was evaluated on the basis of deformities at hatching and in larval stages and on the basis of larvae mortality. Chemical analysis, using gas chromatography-mass spectrometry, was performed on all HPLC fractions and indicated that major components of fractions A2/P1 and A3 through A7 were polycyclic aromatic hydrocarbons (PAHs) or their alkylated derivatives. Fraction A2/P2 contained non-ortho-chlorinated biphenyls, polychlorinated dibenzo-p-dioxins and dibenzofurans, and some Cl-substituted PAHs. Deformities at hatching were observed mainly in the larvae exposed to fraction A-Rec. F2 showed the highest effect on larvae mortality, and both F-Rec and A-Rec showed antagonistic mechanisms. The frequency of deformities in larvae was highest in fractions A2/P2, F4, and A-Rec. Fractions A2/P1 and F1, which partly contained similar substances, showed similar effects on deformity at hatching and larvae mortality; however, F1 showed no effect on larvae abnormality compared with A2/P1. This could have been due to antagonistic mechanisms acting in F1.

  15. Relationship between pulmonary function and indoor air pollution from coal combustion among adult residents in an inner-city area of southwest China

    PubMed Central

    Jie, Y.; Houjin, H.; Xun, M.; Kebin, L.; Xuesong, Y.; Jie, X.

    2014-01-01

    Few studies evaluate the amount of particulate matter less than 2.5 mm in diameter (PM2.5) in relation to a change in lung function among adults in a population. The aim of this study was to assess the association of coal as a domestic energy source to pulmonary function in an adult population in inner-city areas of Zunyi city in China where coal use is common. In a cross-sectional study of 104 households, pulmonary function measurements were assessed and compared in 110 coal users and 121 non-coal users (≥18 years old) who were all nonsmokers. Several sociodemographic factors were assessed by questionnaire, and ventilatory function measurements including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), the FEV1/FVC ratio, and peak expiratory flow rate (PEFR) were compared between the 2 groups. The amount of PM2.5 was also measured in all residences. There was a significant increase in the relative concentration of PM2.5 in the indoor kitchens and living rooms of the coal-exposed group compared to the non-coal-exposed group. In multivariate analysis, current exposure to coal smoke was associated with a 31.7% decrease in FVC, a 42.0% decrease in FEV1, a 7.46% decrease in the FEV1/FVC ratio, and a 23.1% decrease in PEFR in adult residents. The slope of lung function decrease for Chinese adults is approximately a 2-L decrease in FVC, a 3-L decrease in FEV1, and an 8 L/s decrease in PEFR per count per minute of PM2.5 exposure. These results demonstrate the harmful effects of indoor air pollution from coal smoke on the lung function of adult residents and emphasize the need for public health efforts to decrease exposure to coal smoke. PMID:25296361

  16. Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains.

    PubMed

    Sagvolden, T; Pettersen, M B; Larsen, M C

    1993-12-01

    Childhood hyperkinesis or attention-deficit hyperactivity disorder (ADHD) is a behavior disorder of which the main symptoms are attention problems and hyperactivity. The main objective of the present study was to investigate whether the spontaneously hypertensive rat (SHR) strain is a useful animal model of ADHD. Five different rat strains were tested: SHR, Wistar-Kyoto (WKY), Wistar, Sprague-Dawley (SPRD), and PVG (hooded) rats. The protocol consisted of three different test procedures: 1) A 7.5-min free-exploration open-field test (home cage accessible), where the SHR was less active than Wistar and SPRD but more active than WKY; SHR showed longer latencies to leave the home cage than both Wistar and SPRD rats, spending less time in the field, ambulating and rearing less than Wistar and SPRD but more than WKY. Within session, the SHR tended to be more active at the end of the session than at the start, while the opposite tended to be the case in the other groups. 2) A 7.5-min forced exploration open-field test (home cage not accessible), where the results showed that the SHR is less active than both the Wistar and Sprague-Dawley strains, but more active than PVG and WKY. 3) A two-component multiple schedule of reinforcement with a fixed interval 2 min signalled by houselight on and a 5-min extinction signalled by houselight off. Lever pressing by SHR was markedly different from that of the other four strains, which were quite Except early in the interval, SHR pressed the lever more than any of the other groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8295939

  17. Skp1, a component of E3 ubiquitin ligase, is necessary for growth, sporulation, development and pathogenicity in rice blast fungus (Magnaporthe oryzae).

    PubMed

    Prakash, Chandra; Manjrekar, Johannes; Chattoo, Bharat B

    2016-08-01

    Ubiqitination is an important process in eukaryotic cells involving E3 ubiquitin ligase, which co-ordinates with cell cycle proteins and controls various cell functions. Skp1 (S-phase kinase-associated protein 1) is a core component of the SCF (Skp1-Cullin 1-F-box) E3 ubiquitin ligase complex necessary for protein degradation by the 26S proteasomal pathway. The rice blast fungus Magnaporthe oryzae has a single MoSKP1(MGG_04978) required for viability. Skp1 has multiple functions; however, its roles in growth, sporulation and appressorial development are not understood. MoSKP1 complements Skp1 function in the fission yeast temperature-sensitive mutant skp1 A7, restoring the normal length of yeast cells at restrictive temperature. The MoSkp1 protein in M. oryzae is present in spores and germ tubes, and is abundantly expressed in appressoria. Various RNA interference (RNAi) and antisense transformants of MoSKP1 in B157 show reduced sporulation, defective spore morphology, lesser septation and diffuse nuclei. Further, they show elongated germ tubes and are unable to form appressoria. Transformants arrested in G1/S stage during initial spore germination show a similar phenotype to wild-type spores treated with hydroxyurea (HU). Reduced MoSkp1 transcript and protein levels in knockdown transformants result in atypical germ tube development. MoSkp1 interacts with the putative F-box protein (MGG_06351) revealing the ability to form protein complexes. Our investigation of the role of MoSKP1 suggests that a decrease in MoSkp1 manifests in decreased total protein ubiquitination and, consequently, defective cell cycle and appressorial development. Thus, MoSKP1 plays important roles in growth, sporulation, appressorial development and pathogenicity of M. oryzae. PMID:26575697

  18. Mapping, Complementation, and Targets of the Cysteine Protease Actinidin in Kiwifruit1[C][W][OA

    PubMed Central

    Nieuwenhuizen, Niels J.; Maddumage, Ratnasiri; Tsang, Gianna K.; Fraser, Lena G.; Cooney, Janine M.; De Silva, H. Nihal; Green, Sol; Richardson, Kim A.; Atkinson, Ross G.

    2012-01-01

    Cysteine proteases (CPs) accumulate to high concentration in many fruit, where they are believed to play a role in fungal and insect defense. The fruit of Actinidia species (kiwifruit) exhibit a range of CP activities (e.g. the Actinidia chinensis variety YellowA shows less than 2% of the activity of Actinidia deliciosa variety Hayward). A major quantitative trait locus for CP activity was mapped to linkage group 16 in a segregating population of A. chinensis. This quantitative trait locus colocated with the gene encoding actinidin, the major acidic CP in ripe Hayward fruit encoded by the ACT1A-1 allele. Sequence analysis indicated that the ACT1A locus in the segregating A. chinensis population contained one functional allele (A-2) and three nonfunctional alleles (a-3, a-4, and a-5) each containing a unique frameshift mutation. YellowA kiwifruit contained two further alleles: a-6, which was nonfunctional because of a large insertion, and a-7, which produced an inactive enzyme. Site-directed mutagenesis of the act1a-7 protein revealed a residue that restored CP activity. Expression of the functional ACT1A-1 cDNA in transgenic plants complemented the natural YellowA mutations and partially restored CP activity in fruit. Two consequences of the increase in CP activity were enhanced degradation of gelatin-based jellies in vitro and an increase in the processing of a class IV chitinase in planta. These results provide new insight into key residues required for CP activity and the in vivo protein targets of actinidin. PMID:22039217

  19. On-sky low order non-common path correction of the GPI calibration unit

    NASA Astrophysics Data System (ADS)

    Hartung, Markus; Macintosh, Bruce; Langlois, Paul; Sadakuni, Naru; Gavel, Don; Wallace, J. K.; Palmer, Dave; Poyneer, Lisa; Savransky, Dmitry; Thomas, Sandrine; Dillon, Daren; Dunn, Jennifer; Hibon, Pascale; Rantakyrö, Fredrik; Goodsell, Stephen

    2014-08-01

    The Gemini Planet Imager (GPI) entered on-sky commissioning phase, and had its First Light at the Gemini South telescope in November 2013. Meanwhile, the fast loops for atmospheric correction of the Extreme Adaptive Optics (XAO) system have been closed on many dozen stars at different magnitudes (I=4-8), elevation angles and a variety of seeing conditions, and a stable loop performance was achieved from the beginning. Ultimate contrast performance requires a very low residual wavefront error (design goal 60 nm RMS), and optimization of the planet finding instrument on different ends has just begun to deepen and widen its dark hole region. Laboratory raw contrast benchmarks are in the order of 10-6 or smaller. In the telescope environment and in standard operations new challenges are faced (changing gravity, temperature, vibrations) that are tackled by a variety of techniques such as Kalman filtering, open-loop models to keep alignment to within 5 mas, speckle nulling, and a calibration unit (CAL). The CAL unit was especially designed by the Jet Propulsion Laboratory to control slowly varying wavefront errors at the focal plane of the apodized Lyot coronagraph by the means of two wavefront sensors: 1) a 7x7 low order Shack-Hartmann SH wavefront sensor (LOWFS), and 2) a special Mach-Zehnder interferometer for mid-order spatial frequencies (HOWFS) - atypical in that the beam is split in the focal plane via a pinhole but recombined in the pupil plane with a beamsplitter. The original design goal aimed for sensing and correcting on a level of a few nm which is extremely challenging in a telescope environment. This paper focuses on non-common path low order wavefront correction as achieved through the CAL unit on sky. We will present the obtained results as well as explain challenges that we are facing.

  20. Paternal lineages signal distinct genetic contributions from British Loyalists and continental Africans among different Bahamian islands.

    PubMed

    Simms, Tanya M; Martinez, Emanuel; Herrera, Kristian J; Wright, Marisil R; Perez, Omar A; Hernandez, Michelle; Ramirez, Evelyn C; McCartney, Quinn; Herrera, Rene J

    2011-12-01

    Over the past 500 years, the Bahamas has been influenced by a wide array of settlers, some of whom have left marked genetic imprints throughout the archipelago. To assess the extent of each group's genetic contributions, high-resolution Y-chromosome analyses were performed, for the first time, to delineate the patriarchal ancestry of six islands in the Northwest (Abaco and Grand Bahama) and Central (Eleuthera, Exuma, Long Island, and New Providence) Bahamas and their genetic relationships with previously published reference populations. Our results reveal genetic signals emanating primarily from African and European sources, with the predominantly sub-Saharan African and Western European haplogroups E1b1a-M2 and R1b1b1-M269, respectively, accounting for greater than 75% of all Bahamian patrilineages. Surprisingly, we observe notable discrepancies among the six Bahamian populations in their distribution of these lineages, with E1b1a-M2 predominating Y-chromosomes in the collections from Abaco, Exuma, Eleuthera, Grand Bahama, and New Providence, whereas R1b1b1-M269 is found at elevated levels in the Long Island population. Substantial Y-STR haplotype variation within sub-haplogroups E1b1a7a-U174 and E1b1ba8-U175 (greater than any continental African collection) is also noted, possibly indicating genetic influences from a variety of West and Central African groups. Furthermore, differential European genetic contributions in each island (with the exception of Exuma) reflect settlement patterns of the British Loyalists subsequent to the American Revolution. PMID:21989964

  1. Uridine Diphosphate-Glucuronosyltransferase (UGT) Xenobiotic Metabolizing Activity and Genetic Evolution in Pinniped Species.

    PubMed

    Kakehi, Mayu; Ikenaka, Yoshinori; Nakayama, Shouta M M; Kawai, Yusuke K; Watanabe, Kensuke P; Mizukawa, Hazuki; Nomiyama, Kei; Tanabe, Shinsuke; Ishizuka, Mayumi

    2015-10-01

    There are various interspecies differences in xenobiotic-metabolizing enzymes. It is known that cats show slow glucuronidation of drugs such as acetaminophen and strong side effects due to the UGT1A6 pseudogene. Recently, the UGT1A6 pseudogene was found in the Northern elephant seal and Otariidae was suggested to be UGT1A6-deficient. From the results of measurements of uridine diphosphate-glucuronosyltransferase (UGT) activity using liver microsomes, the Steller sea lion, Northern fur seal, and Caspian seal showed UGT activity toward 1-hydroxypyrene and acetaminophen as low as in cats, which was significantly lower than in rat and dog. Furthermore, UGT1A6 pseudogenes were found in Steller sea lion and Northern fur seal, and all Otariidae species were suggested to have the UGT1A6 pseudogene. The UGT1 family genes appear to have undergone birth-and-death evolution based on a phylogenetic and synteny analysis of the UGT1 family in mammals including Carnivora. UGT1A2-1A5 and UGT1A7-1A10 are paralogous genes to UGT1A1 and UGTA6, respectively, and their numbers were lower in cat, ferret and Pacific walrus than in human, rat, and dog. Felidae and Pinnipedia, which are less exposed to natural xenobiotics such as plant-derived toxins due to their carnivorous diet, have experienced fewer gene duplications of xenobiotic-metabolizing UGT genes, and even possess UGT1A6 pseudogenes. Artificial environmental pollutants and drugs conjugated by UGT are increasing dramatically, and their elimination to the environment can be of great consequence to cat and Pinnipedia species, whose low xenobiotic glucuronidation capacity makes them highly sensitive to these compounds. PMID:26179383

  2. Solvent free synthesis, crystal studies, docking studies and antibacterial properties of some novel fluorinated pyridazinone derivatives

    NASA Astrophysics Data System (ADS)

    Sowmya, H. B. V.; Suresha Kumara, T. H.; Nagendrappa, G.; Jasinski, Jerry P.; Millikan, Sean P.; Jose, Gilish; R, Dileep; Sujan Ganapathy, P. S.

    2013-12-01

    The solvent free synthesis of six 6-(3,5-difluorophenyl)-4,5-dihydropyridazin-3(2H)-one derivatives was carried out by microwave irradiation of a pulverized mixture of 4-(3,5-difluorophenyl)-4-oxobutanoic acid and substituted hydrazine hydrochloride in presence of catalytic amount of acetic acid at 150 °C/75 W for 5 min. Single crystals of two derivatives, C16H12N2OF2 [3a] and C16H11N2OF3 [3f] were formed allowing for structural analysis. [C16H12N2OF2]: orthorhombic, Pbcn; a = 17.1583(5) Å, b = 11.3751(3) Å, c = 13.7704(4) Å, V = 2687.67(13) Å3, Z = 8, 173(2) K, μ(Cu Kα) = 0.920 mm-1, Dcalc = 1.415 g/mm3, 16553 reflections, 2651 unique (Rint = 0.0298); R1 = 0.0394 (I > 2σ(I)) and wR2 = 0.1118 (all data). [C16H11N2OF3]: triclinic, P-1, a = 7.4837(4) Å, b = 13.3707(10) Å, c = 13.7194(9) Å, α = 76.622(6)°, β = 88.771(5)°, γ = 81.453(5)°, V = 1320.60(16) Å3, Z = 4, 173(2) K, μ(Cu Kα) = 1.087 mm-1, Dcalc = 1.530 g/mm3, 8522 reflections, 5092 unique (Rint = 0.0277); R1 = 0.0441 (I > 2σ(I)) and wR2 = 0.1289 (all data). Preliminary antibacterial properties and docking studies are described for all the six derivatives.

  3. Liat1, an arginyltransferase-binding protein whose evolution among primates involved changes in the numbers of its 10-residue repeats.

    PubMed

    Brower, Christopher S; Rosen, Connor E; Jones, Richard H; Wadas, Brandon C; Piatkov, Konstantin I; Varshavsky, Alexander

    2014-11-18

    The arginyltransferase Ate1 is a component of the N-end rule pathway, which recognizes proteins containing N-terminal degradation signals called N-degrons, polyubiquitylates these proteins, and thereby causes their degradation by the proteasome. At least six isoforms of mouse Ate1 are produced through alternative splicing of Ate1 pre-mRNA. We identified a previously uncharacterized mouse protein, termed Liat1 (ligand of Ate1), that interacts with Ate1 but does not appear to be its arginylation substrate. Liat1 has a higher affinity for the isoforms Ate1(1A7A) and Ate1(1B7A). Liat1 stimulated the in vitro N-terminal arginylation of a model substrate by Ate1. All examined vertebrate and some invertebrate genomes encode proteins sequelogous (similar in sequence) to mouse Liat1. Sequelogs of Liat1 share a highly conserved ∼30-residue region that is shown here to be required for the binding of Liat1 to Ate1. We also identified non-Ate1 proteins that interact with Liat1. In contrast to Liat1 genes of nonprimate mammals, Liat1 genes of primates are subtelomeric, a location that tends to confer evolutionary instability on a gene. Remarkably, Liat1 proteins of some primates, from macaques to humans, contain tandem repeats of a 10-residue sequence, whereas Liat1 proteins of other mammals contain a single copy of this motif. Quantities of these repeats are, in general, different in Liat1 of different primates. For example, there are 1, 4, 13, 13, 17, and 17 repeats in the gibbon, gorilla, orangutan, bonobo, neanderthal, and human Liat1, respectively, suggesting that repeat number changes in this previously uncharacterized protein may contribute to evolution of primates. PMID:25369936

  4. Comparison of the in vitro metabolism of psoralidin among different species and characterization of its inhibitory effect against UDP- glucuronosyltransferase (UGT) or cytochrome p450 (CYP450) enzymes.

    PubMed

    Shi, Xianbao; Zhang, Gang; Mackie, Brianna; Yang, Shuman; Wang, Jian; Shan, Lina

    2016-09-01

    Psoralidin has shown a variety of biological and pharmacological activities such as anti-tumor anti-oxidant, anti-bacterial, anti-depressant and anti-inflammatory activities. Herein, we reported the metabolism of psoralidin among different species and its inhibitory effect against UGTs and CYP450s. Liquid chromatography was used to investigate the inhibitory activity of psoralidin against ten different UGTs and eight distinct CYP450 isoforms. In addition, we characterized the CYP450 isoforms involved in the psoralidin metabolism on the basis of chemical inhibition studies and screening assays with recombinant human cytochrome P450s. In vitro metabolic profiles and metabolites of psoralidin from varying liver microsomes obtained from human (HLMs), monkey (MLMs), rat (RLMs), dog (DLMs), minipig (PLMs) and rabbit (RAMs) were determined by LC-MS/MS. In vivo pharmacokinetic profiles were investigated by injecting psoralidin (2mg/kg) into the tail vein of Wistar rats. Molecular modeling studies were carried out in order to assess the binding profile and recognition motif between psoralidin and the enzymes. Psoralidin showed potent and noncompetitive inhibition against UGT1A1, UGT1A7, CYP1A2 and CYP2C8 with IC50 values of 6.12, 0.38, 1.81, 0.28μM, respectively. The metabolism of psoraldin exhibited significant differences among humans, monkeys, dogs, minipigs, rabbits and rats; however, monkeys showed the highest similarity to humans. Furthermore, eleven metabolites were observed among these species and their structures were characterized by LC-MS/MS. CYP2C19 played a key role in the metabolism of psorslidin in human liver microsomes. These findings could be used to advance the understanding of psoralidin. PMID:27428458

  5. Effect of Ambient Temperature on the Thermoregulatory and Locomotor Stimulant Effects of 4-Methylmethcathinone in Wistar and Sprague-Dawley Rats

    PubMed Central

    Wright, M. Jerry; Angrish, Deepshikha; Aarde, Shawn M.; Barlow, Deborah J.; Buczynski, Matthew W.; Creehan, Kevin M.; Vandewater, Sophia A.; Parsons, Loren H.; Houseknecht, Karen L.; Dickerson, Tobin J.; Taffe, Michael A.

    2012-01-01

    The drug 4-methylmethcathinone (4-MMC; aka, mephedrone, MMCAT, “plant food”, “bath salts”) is a recent addition to the list of popular recreational psychomotor-stimulant compounds. Relatively little information about this drug is available in the scientific literature, but popular media reports have driven recent drug control actions in the UK and several US States. Online user reports of subjective similarity to 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) prompted the current investigation of the thermoregulatory and locomotor effects of 4-MMC. Male Wistar and Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1–10 mg/kg ) using an implantable radiotelemetry system under conditions of low (23°C) and high (27°C) ambient temperature. A reliable reduction of body temperature was produced by 4-MMC in Wistar rats at 23°C or 27°C with only minimal effect in Sprague-Dawley rats. Increased locomotor activity was observed after 4-MMC administration in both strains with significantly more activity produced in the Sprague-Dawley strain. The 10 mg/kg s.c. dose evoked greater increase in extracellular serotonin, compared with dopamine, in the nucleus accumbens. Follow-up studies confirmed that the degree of locomotor stimulation produced by 10 mg/kg 4-MMC was nearly identical to that produced by 1 mg/kg d-methamphetamine in each strain. Furthermore, hypothermia produced by the serotonin 1A/7 receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) was similar in each strain. These results show that the cathinone analog 4-MMC exhibits thermoregulatory and locomotor properties that are distinct from those established for methamphetamine or MDMA in prior work, despite recent evidence of neuropharmacological similarity with MDMA. PMID:22952999

  6. Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents.

    PubMed

    Wu, Lin-tao; Jiang, Zhi; Shen, Jia-jia; Yi, Hong; Zhan, Yue-chen; Sha, Ming-quan; Wang, Zhen; Xue, Si-tu; Li, Zhuo-rong

    2016-05-23

    A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06-3.64 μM and 0.04-9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96-174.50 μM) and were close to that of Paclitaxel (IC50: 0.026-1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents. PMID:27017265

  7. Encoding the core electrons with graph concepts.

    PubMed

    Pogliani, Lionello

    2004-01-01

    The core electron problem of atoms in chemical graph studies has always been considered as a minor problem. Usually, chemical graphs had to encode just a small set of second row atoms, i.e., C, N, O, and F, thus, graph and, in some cases, pseudograph concepts were enough to "graph" encode the molecules at hand. Molecular connectivity theory, together with its side-branch the electrotopological state, introduced two "ad hoc" algorithms for the core electrons of higher-row atoms based, mainly, on quantum concepts alike. Recently, complete graphs, and, especially, odd complete graphs have been introduced to encode the core electrons of higher-row atoms. By the aid of these types of graphs a double-valued algorithm has been proposed for the valence delta, deltav, of any type of atoms of the periodic table with a principal quantum number n > or =2. The new algorithm is centered on an invariant suggested by the hand-shaking theorem, and the values it gives rise to parallel in some way the values derived by the aid of the two old "quantum" algorithms. A thorough comparative analysis of the newly proposed algorithms has been undertaken for atoms of the group 1A-7A of the periodic table. This comparative study includes the electronegativity, the size of the atoms, the first ionization energy, and the electron affinity. The given algorithm has also been tested with sequential complete graphs, while the even complete graphs give rise to conceptual difficulties. QSAR/QSPR studies do not show a clear-cut preference for any of the two values the algorithm gives rise to, even if recent results seem to prefer one of the two values. PMID:14741009

  8. Human Aldehyde Dehydrogenase Genes: Alternatively-Spliced Transcriptional Variants and Their Suggested Nomenclature

    PubMed Central

    Black, William J.; Stagos, Dimitrios; Marchitti, Satori A.; Nebert, Daniel W.; Tipton, Keith F.; Bairoch, Amos; Vasiliou, Vasilis

    2011-01-01

    OBJECTIVE The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)+-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g. Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimer’s disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes. METHODS Data-mining methods were used to retrieve all human ALDH sequences. Alternatively-spliced transcriptional variants were determined based upon: a) criteria for sequence integrity and genomic alignment; b) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and c) if available, empirical evidence of variants from the literature. RESULTS AND CONCLUSION Alternatively-spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. In order to avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein. In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily. PMID:19823103

  9. Site-specific effects of gastrin-releasing peptide in the suprachiasmatic nucleus

    PubMed Central

    Kallingal, George J.; Mintz, Eric M.

    2013-01-01

    The effects of gastrin-releasing peptide (GRP) on the circadian clock in the suprachiasmatic nucleus (SCN) are dependent on the activation of N-methyl-d-aspartate (NMDA) receptors in the SCN. In this study, the interaction between GRP, glutamate and serotonin in the regulation of circadian phase in Syrian hamsters was evaluated. Microinjection of GRP into the third ventricle induced c-fos and p-ERK expression throughout the SCN. Coadministration of an NMDA antagonist or 8-hydroxy-2-di-n-propylamino-tetralin [a serotonin (5-HT)1A,7 agonist, DPAT] with GRP limited c-fos expression in the SCN to a region dorsal to GRP cell bodies. Similar to the effects of NMDA antagonists, DPAT attenuated GRP-induced phase shifts in the early night, suggesting that the actions of serotonin on the photic phase shifting mechanism occur downstream from retinorecipient cells. c-fos and p-ERK immunoreactivity in the supraoptic (SON) and paraventricular hypothalamic nuclei also increased following ventricular microinjection of GRP. Because of this finding, a second set of experiments was designed to test a potential role for the SON in the regulation of clock function. Syrian hamsters were given microinjections of GRP into the peri-SON during the early night. GRP-induced c-fos activity in the SCN was similar to that following ventricular administration of GRP. GRP or bicuculline (a γ-aminobutyric acidA antagonist) administered near the SON during the early night elicited phase delays of circadian activity rhythms. These data suggest that GRP-induced phase-resetting is dependent on levels of glutamatergic and serotonergic neurotransmission in the SCN and implicate activity in the SON as a potential regulator of photic signaling in the SCN. PMID:24528136

  10. Precise measurement of parity nonconservation in atomic thallium

    SciTech Connect

    Hunter, L.R.

    1981-05-01

    Observation of parity non-conservation in the 6P/sub 1/2/ - 7P/sub 1/2/ transition in /sub 81/Tl/sup 203/ /sup 205/ is reported. The transition is nominally forbidden M1 with amplitude M. Due to the violation of parity in the electron-nucleon interaction, the transition acquires an additional (parity nonconserving) amplitude e/sub p/. In the presence of an electric field, incident 293 nm circularly polarized light results in a polarization of the 7P/sub 1/2/ state through interference of the Stark amplitude with M and E/sub p/. This polarization is observed by selective excitation of the 7P/sub 1/2/ - (8S/sub 1/2) transition with circularly polarized 2.18 ..mu..m light and observation of the subsequent fluorescence at 323 nm. By utilizing this technique and carefully determining possible systematic contributions through auxiliary measurements, the circular dichroism delta = 2Im(E/sub p/)/ M is observed: delta/sub exp/ = (2.8 + 1.0 - .9) x 10/sup -3/. In addition, measurements of A(6D/sub 3/2/ - 7P/sub 1/2/) = (5.97 +- .78) x 10/sup 5/ s/sup -1/, A(7P/sub 1/2/ - 7S/sub 1/2/) = (1.71 +- .07) x 10/sup 7/ s/sup -1/ and A(7P/sub 3/2/ - 7S/sub 1/2/) = (2.37 +- .09) s/sup -1/ are reported. These values are employed in a semiempirical determination of delta based on the Weinberg-Salam Model. The result of this calculation for sin/sup 2/THETA/sub 2/ = .23 is delta/sub Theo/ = 1.7 +- .8) x 10/sup -3/.

  11. Clinical Pharmacokinetic, Pharmacodynamic, and Drug-Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor.

    PubMed

    Devineni, Damayanthi; Polidori, David

    2015-10-01

    The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose

  12. Luminescent organoplatinum(II) complexes with functionalized cyclometalated C^N^C ligands: structures, photophysical properties, and material applications.

    PubMed

    Kui, Steven C F; Hung, Faan-Fung; Lai, Shiu-Lun; Yuen, Mai-Yan; Kwok, Chi-Chung; Low, Kam-Hung; Chui, Stephen Sin-Yin; Che, Chi-Ming

    2012-01-01

    A series of [(R'-C^N^C-R'')Pt(L)] complexes with doubly deprotonated cyclometalated R'-C^N^C-R'' ligands (R'-C^N^C-R''=2,6-diphenylpyridine derivatives) functionalized with carbazole, fluorene, or thiophene unit(s) have been synthesized and their photophysical properties studied. The X-ray crystal structures reveal extensive intermolecular π···π and C-H···π interactions between the cyclometalated C^N^C ligands. Compared to previously reported cyclometalated platinum(II) complexes [(C^N^C)Pt(L)], which are non-emissive in solution at room temperature, the carbazole-, fluorene- and thiophene-functionalized [(R'-C^N^C-R'')Pt(L)] (L=DMSO 1-9, C≡N-Ar, 1a-9a) complexes are emissive in solution at room temperature with λ(max) at 564-619 nm and Φ=0.02-0.26. The emissions of the [(R'-C^N^C-R'')Pt(L)] complexes are attributed to electronic excited states with mixed (3)MLCT and (3)IL character. The carbazole/fluorene/thiophene unit(s) allow the tuning of the electronic properties of the [(R'-C^N^C-R'')Pt] moiety, with the emission maxima in a range of 564-619 nm. These are the first examples of organoplatinum(II) complexes bearing doubly deprotonated cyclometalated C^N^C ligands that are emissive in solution at room temperature. In non-degassed DMSO, the emission intensities of 6a-9a are enhanced upon exposure to ambient light. This phenomenon is caused by reacting photogenerated (1)O(2) with a DMSO molecule to form dimethyl sulfone, leading to the removal of dissolved oxygen in solution. Self-assembled nanowires and nanorods are obtained from precipitation of 3a in THF/H(2)O and 8a in DMSO/Et(2)O, respectively. The [(R'-C^N^C-R'')Pt(L)] complexes are soluble in common organic solvents with a high thermal stability (>300 °C), rendering them as phosphorescent dopants for organic light-emitting diode (OLEDs) applications. Red OLEDs with CIE coordinates of (0.65±0.01, 0.35±0.01) were fabricated from 7a or 8a. A maximum external efficiency (η(Ext)) of 12.6% was

  13. Synthesis, structural characterization, superoxide dismutase and antimicrobial activities studies of copper (II) complexes with 2-(E)-(2-(2-aminoethylamino) methyl)-4-bromophenol and (19E, 27E)-N1, N2-bis (phenyl (pyridine-2-yl)-methylene)-ethane-1, 2-diamine as ligands

    NASA Astrophysics Data System (ADS)

    Choudhary, Mukesh; Patel, R. N.; Rawat, S. P.

    2014-07-01

    Three new copper (II) complexes, [Cu(L)(H2O)]ClO4 (1), [Cu(L1)(ClO4)]+ (2) and [Cu(L1)]2+ (3), where HL = 2-(E)-(2-(2-aminoethylamino)methyl)-4-bromophenol, L1 =(19E, 27E)-N1,N2-bis(phenyl(pyridine-2-yl)-methylene)-ethane-1, 2-diamine, have been synthesized and characterized by using various physic-chemical and spectroscopic methods. The solid-state structures of 1 and 2 were determined by single crystal X-ray crystallography. Infrared spectra, ligand field spectra and magnetic susceptibility measurements agree with the observed crystal structures. The molecular structure of copper complexes showed that the ligands occupies the basal plane of square pyramidal geometry with the H2O of 1 or the ClO4 of 2 occupying the remaining apical position. Complexes 1 and 2 crystallize in the monoclinic system of the space group P21/c, a = 10.5948(6)Å, b = 19.6164(11)Å, c = 8.6517(5)Å, α = 90°, β = 108.213(2)°, γ = 90° and Z = 4 for 1, a = 9.5019(3)Å, b = 11.3 801(3)Å, c = 25.3168(14)Å, α = 90°, β = 100.583(4)°, γ = 90°, and Z = 4 for 2. The synthesized Schiff base (HL/L1) was behaves as tetradentate ON3/N4 ligands with donor groups suitable placed for forming 2 or 3 five membered chelate rings. Copper (II) complexes display X-band EPR spectra in 100% DMSO at 77 K giving g|| > g⊥ > 2.0023 indicating dx2-y2 ground state. The half-wave potential values for Cu (II)/Cu (I) redox couple obtained in the reaction of the copper (II) complexes with molecular oxygen and superoxide radical (O2-) electronegated in DMSO are in agreement with the SOD-like activity of the copper (II) complexes. In vitro antimicrobial activities of the complexes against the two bacteria (Escherichia coli, Salmonella typhi) and the two fungi (Penicillium, Aspergillus sp.) have been investigated comparing with the Schiff base ligands.

  14. Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha.

    PubMed

    Lu, Hong; Gonzalez, Frank J; Klaassen, Curtis

    2010-12-01

    Hepatocyte nuclear factor 4 alpha (HNF4a) is a liver-enriched master regulator of liver function. HNF4a is important in regulating hepatic expression of certain cytochrome P450s. The purpose of this study was to use mice lacking HNF4a expression in liver (HNF4a-HNull) to elucidate the role of HNF4a in regulating hepatic expression of phase II enzymes and transporters in mice. Compared with male wild-type mice, HNF4a-HNull male mouse livers had (1) markedly lower messenger RNAs (mRNAs) encoding the uptake transporters sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide (Oatp) 1a1, Oatp2b1, organic anion transporter 2, sodium phosphate cotransporter type 1, sulfate anion transporter 1, sodium-dependent vitamin C transporter 1, the phase II enzymes Uridine 5'-diphospho (UDP)-glucuronosyltransferase (Ugt) 2a3, Ugt2b1, Ugt3a1, Ugt3a2, sulfotransferase (Sult) 1a1, Sult1b1, Sult5a1, the efflux transporters multidrug resistance-associated protein (Mrp) 6, and multidrug and toxin extrusion 1; (2) moderately lower mRNAs encoding Oatp1b2, organic cation transporter (Oct) 1, Ugt1a5, Ugt1a9, glutathione S-transferase (Gst) m4, Gstm6, and breast cancer resistance protein; but (3) higher mRNAs encoding Oatp1a4, Octn2, Ugt1a1, Sult1e1, Sult2a2, Gsta4, Gstm1-m3, multidrug resistance protein (Mdr) 1a, Mrp3, and Mrp4. Hepatic signaling of nuclear factor E2-related factor 2 and pregnane X receptor appear to be activated in HNF4a-HNull mice. In conclusion, HNF4a deficiency markedly alters hepatic mRNA expression of a large number of phase II enzymes and transporters, probably because of the loss of HNF4a, which is a transactivator and a determinant of gender-specific expression and/or adaptive activation of signaling pathways important in hepatic regulation of these phase II enzymes and transporters. PMID:20935164

  15. Novel Resveratrol-Based Substrates for Human Hepatic, Renal, and Intestinal UDP-Glucuronosyltransferases

    PubMed Central

    2015-01-01

    Trans-Resveratrol (tRes) has been shown to have powerful antioxidant, anti-inflammatory, anticarcinogenic, and antiaging properties; however, its use as a therapeutic agent is limited by its rapid metabolism into its conjugated forms by UDP-glucuronosyltransferases (UGTs). The aim of the current study was to test the hypothesis that the limited bioavailability of tRes can be improved by modifying its structure to create analogs which would be glucuronidated at a lower rate than tRes itself. In this work, three synthetic stilbenoids, (E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid (NI-12a), (E)-2,4-dimethoxy-6-(4-methoxystyryl)benzaldehyde oxime (NI-ST-05), and (E)-4-(3,5-dimethoxystyryl)-2,6-dinitrophenol (DNR-1), have been designed based on the structure of tRes and synthesized in our laboratory. UGTs recognize and glucuronidate tRes at each of the 3 hydroxyl groups attached to its aromatic rings. Therefore, each of the above compounds was designed with the majority of the hydroxyl groups blocked by methylation and the addition of other novel functional groups as part of a drug optimization program. The activities of recombinant human UGTs from the 1A and 2B families were examined for their capacity to metabolize these compounds. Glucuronide formation was identified using HPLC and verified by β-glucuronidase hydrolysis and LC–MS/MS analysis. NI-12a was glucuronidated at both the −COOH and −OH functions, NI-ST-05 formed a novel N–O-glucuronide, and no product was observed for DNR-1. NI-12a is primarily metabolized by the hepatic and renal enzyme UGT1A9, whereas NI-ST-05 is primarily metabolized by an extrahepatic enzyme, UGT1A10, with apparent Km values of 240 and 6.2 μM, respectively. The involvement of hepatic and intestinal UGTs in the metabolism of both compounds was further confirmed using a panel of human liver and intestinal microsomes, and high individual variation in activity was demonstrated between donors. In summary

  16. Novel 3D bismuth-based coordination polymers: Synthesis, structure, and second harmonic generation properties

    SciTech Connect

    Wibowo, Arief C.; Smith, Mark D.; Yeon, Jeongho; Halasyamani, P. Shiv; Loye, Hans-Conrad zur

    2012-11-15

    Two new 3D bismuth containing coordination polymers are reported along with their single crystal structures and SHG properties. Compound 1: Bi{sub 2}O{sub 2}(pydc) (pydc=pyridine-2, 5-dicarboxylate), crystallizes in the monoclinic, polar space group, P2{sub 1} (a=9.6479(9) A, b=4.2349(4) A, c=11.9615(11) A, {beta}=109.587(1) Degree-Sign ), which contains Bi{sub 2}O{sub 2} chains that are connected into a 3D structure via the pydc ligands. Compound 2: Bi{sub 4}Na{sub 4}(1R3S-cam){sub 8}(EtOH){sub 3.1}(H{sub 2}O){sub 3.4} (1R3S cam=1R3S-camphoric acid) crystallizes in the monoclinic, polar space group, P2{sub 1} (a=19.0855(7) A, b=13.7706(5) A, c=19.2429(7) A, {beta}=90.701(1) Degree-Sign ) and is a true 3D coordination polymer. These are two example of SHG compounds prepared using unsymmetric ligands (compound 1) or chiral ligands (compound 2), together with metals that often exhibit stereochemically-active lone pairs, such as Bi{sup 3+}, a synthetic approach that resulted in polar, non-centrosymmetric, 3D metal-organic coordination polymer. - Graphical Abstract: Structures of two new, polar, 3D Bismuth(III)-based coordination polymers: Bi{sub 2}O{sub 2}(pydc) (compound 1), and Bi{sub 4}Na{sub 4}(1R3S-cam){sub 8}(EtOH){sub 3.1}(H{sub 2}O){sub 3.4} (compound 2). Highlights: Black-Right-Pointing-Pointer New, polar, 3D Bismuth(III)-based coordination polymers. Black-Right-Pointing-Pointer First polar bismuth-based coordination polymers synthesized via a 'hybrid' strategy. Black-Right-Pointing-Pointer Combination of stereochemically-active lone pairs and unsymmetrical or chiral ligands. Black-Right-Pointing-Pointer Synthesis of class C-SHG materials based on Kurtz-Perry categories.

  17. In Vitro Inhibition of Human UDP-Glucuronosyl-Transferase (UGT) Isoforms by Astaxanthin, β-Cryptoxanthin, Canthaxanthin, Lutein, and Zeaxanthin: Prediction of in Vivo Dietary Supplement-Drug Interactions.

    PubMed

    Zheng, Yu Fen; Min, Jee Sun; Kim, Doyun; Park, Jung Bae; Choi, Sung-Wook; Lee, Eun Seong; Na, Kun; Bae, Soo Kyung

    2016-01-01

    Despite the widespread use of the five major xanthophylls astaxanthin, β-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin as dietary supplements, there have been no studies regarding their inhibitory effects on hepatic UDP-glucuronosyltransferases (UGTs). Here, we evaluated the inhibitory potential of these xanthophylls on the seven major human hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) in vitro by LC-MS/MS using specific marker reactions in human liver microsomes (except UGT2B15) or recombinant supersomes (UGT2B15). We also predicted potential dietary supplement-drug interactions for β-cryptoxanthin via UGT1A1 inhibition. We demonstrated that astaxanthin and zeaxanthin showed no apparent inhibition, while the remaining xanthophylls showed only weak inhibitory effects on the seven UGTs. β-Cryptoxanthin mildly inhibited UGT1A1, UGT1A3, and UGT1A4, with IC50 values of 18.8 ± 2.07, 28.3 ± 4.40 and 34.9 ± 5.98 μM, respectively. Canthaxanthin weakly inhibited UGT1A1 and UGT1A3, with IC50 values of 38.5 ± 4.65 and 41.2 ± 3.14 μM, respectively; and lutein inhibited UGT1A1 and UGT1A4, with IC50 values of 45.5 ± 4.01 and 28.7 ± 3.79 μM, respectively. Among the tested xanthophyll-UGT pairs, β-cryptoxanthin showed the strongest competitive inhibition of UGT1A1 (Ki, 12.2 ± 0.985 μM). In addition, we predicted the risk of UGT1A1 inhibition in vivo using the reported maximum plasma concentration after oral administration of β-cryptoxanthin in humans. Our data suggests that these xanthophylls are unlikely to cause dietary supplement-drug interactions mediated by inhibition of the hepatic UGTs. These findings provide useful information for the safe clinical use of the tested xanthophylls. PMID:27529203

  18. Introducing the “TCDD-Inducible AhR-Nrf2 Gene Battery”

    PubMed Central

    Yeager, Ronnie L.; Reisman, Scott A.; Aleksunes, Lauren M.; Klaassen, Curtis D.

    2009-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces genes via the transcription factor aryl hydrocarbon receptor (AhR), including Cyp1a1, NAD(P)H:quinone oxidoreductase 1 (Nqo1), UDP-glucuronosyltransferase 1a6 (Ugt1a6), and glutathione S-transferase a1 (Gsta1). These genes are referred to as the “AhR gene battery.” However, Nqo1 is also considered a prototypical target gene of the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2). In mice, TCDD induction of Nrf2 and Nrf2 target, Nqo1, is dependent on AhR, and thus TCDD induction of drug-processing genes may be routed through an AhR-Nrf2 sequence. There has been speculation that Nrf2 may be involved in the TCDD induction of drug-processing genes; however, the data are not definitive. Therefore, to address whether TCDD induction of Nqo1, Ugts, and Gsts is dependent on Nrf2, we conducted the definitive experiment by administering TCDD (50 μg/kg, ip) to Nrf2-null and wild-type (WT) mice and collecting livers 24 h later to quantify the mRNA of drug-processing genes. TCDD induction of Cyp1a1 and Ugt1a1 was similar in WT and Nrf2-null mice, whereas TCDD induction of Ugt1a5 and 1a9 was blunted in Nrf2-null mice. TCDD induced Nqo1, Ugt1a6, 2b34, 2b35, 2b36, UDP-glucuronic acid–synthesizing gene UDP-glucose dehydrogenase, and Gsta1, m1, m2, m3, m6, p2, t2, and microsomal Gst1 in WT mice but not in Nrf2-null mice. Therefore, the present study demonstrates the novel finding that Nrf2 is required for TCDD induction of classical AhR battery genes Nqo1, Ugt1a6, and Gsta1, as well as most Ugt and Gst isoforms in livers of mice. PMID:19474220

  19. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver

    PubMed Central

    Liu, Wanqing; Ramírez, Jacqueline; Gamazon, Eric R.; Mirkov, Snezana; Chen, Peixian; Wu, Kehua; Sun, Chang; Cox, Nancy J.; Cook, Edwin; Das, Soma; Ratain, Mark J.

    2014-01-01

    The aim of this study was to discover cis- and trans-acting factors significantly affecting mRNA expression and catalytic activity of human hepatic UDP-glucuronosyltransferases (UGTs). Transcription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2B (UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17) genes were quantified in human liver tissue samples (n = 125) using real-time PCR. Glucuronidation activities of 14 substrates were measured in 47 livers. We genotyped 167 tagSNPs (single-nucleotide polymorphisms) in UGT1A (n = 43) and UGT2B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymorphisms. Transcription levels of 15 transcription factors (TFs) known to regulate these UGTs were quantified. We found that UGT expression and activity were highly variable among the livers (median and range of coefficient of variations: 135%, 74–217% and 52%, 39–105%, respectively). CAR, PXR and ESR1 were found to be the most important trans-regulators of UGT transcription (median and range of correlation coefficients: 46%, 6–58%; 47%, 9–58%; and 52%, 24–75%, respectively). Hepatic UGT activities were mainly determined by UGT gene transcription levels. Twenty-one polymorphisms were significantly (FDR-adjusted P < 0.05) associated with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17. We found novel SNPs in the UGT2B17 CNV region accounting for variability in UGT2B17 gene transcription and testosterone glucuronidation rate, in addition to that attributable to the UGT2B17 CNV. Our study discovered novel pharmacogenetic markers and provided detailed insight into the genetic network regulating hepatic UGTs. PMID:24879639

  20. Modeling cell elongation during germ band retraction: cell autonomy versus applied anisotropic stress

    NASA Astrophysics Data System (ADS)

    Lynch, Holley E.; Veldhuis, Jim; Brodland, G. Wayne; Hutson, M. Shane

    2014-05-01

    The morphogenetic process of germ band retraction in Drosophila embryos involves coordinated movements of two epithelial tissues—germ band and amnioserosa. The germ band shortens along its rostral-caudal or head-to-tail axis, widens along its perpendicular dorsal-ventral axis, and uncurls from an initial ‘U’ shape. The amnioserosa mechanically assists this process by pulling on the crook of the U-shaped germ band. The amnioserosa may also provide biochemical signals that drive germ band cells to change shape in a mechanically autonomous fashion. Here, we use a finite-element model to investigate how these two contributions reshape the germ band. We do so by modeling the response to laser-induced wounds in each of the germ band’s spatially distinct segments (T1-T3, A1-A9) during the middle of retraction when segments T1-A3 form the ventral arm of the ‘U’, A4-A7 form its crook, and A8-A9 complete the dorsal arm. We explore these responses under a range of externally applied stresses and internal anisotropy of cell edge tensions—akin to a planar cell polarity that can drive elongation of cells in a direction parallel to the minimum edge tension—and identify regions of parameter space (edge-tension anisotropy versus stress anisotropy) that best match previous experiments for each germ band segment. All but three germ band segments are best fit when the applied stress anisotropy and the edge-tension anisotropy work against one another—i.e., when the isolated effects would elongate cells in perpendicular directions. Segments in the crook of the germ band (A4-A7) have cells that elongate in the direction of maximum external stress, i.e., external stress anisotropy is dominant. In most other segments, the dominant factor is internal edge-tension anisotropy. These results are consistent with models in which the amnioserosa pulls on the crook of the germ band to mechanically assist retraction. In addition, they suggest a mechanical cue for edge

  1. Formation and inhibition of ethyl glucuronide and ethyl sulfate.

    PubMed

    Stachel, Nicole; Skopp, Gisela

    2016-08-01

    Ethyl glucuronide (EtG) und ethyl sulfate (EtS) are widely accepted biomarkers in forensic and clinical settings. Even though, levels of EtG and EtS in blood and urine increase with increasing doses of alcohol, a high inter-individual variability in their production has been noticed. Therefore, we investigated the influence of dietary plant phenols on the formation of EtG and EtS and tentatively estimated the magnitude of in vivo inhibitory interactions from our in vitro results. To address these issues, formation of EtS and EtG was investigated using recombinant glucuronosyl- and sulfotransferases as well as human liver microsomes and liver cytosol. After respective kinetics had been established, inhibition experiments using quercetin, kaempferol and resveratrol were performed. These polyphenols are subject to extensive glucuronidation and/or sulfonation. EtG and EtS were determined by LC-MS/MS following solid phase extraction for EtG due to severe matrix effects and by direct injection for EtS. All enzymes investigated were involved in the conjugation of ethanol. Maximal EtG and EtS formation rates were observed with HLM and SULT1A1, respectively. All kinetics could best be described by Michaelis-Menten kinetics. Resveratrol was a competitive inhibitor of UGT1A1, UGT1A9 and HLM; quercetin and kaempferol were inhibitors of all transferases under investigation except UGT2B15. Findings for quercetin with regard to UGT2B7 and SULT2A1 and for kaempferol with regard to SULT1E1 and SULT2A1 suggested a mechanism based inhibition. Competitive inhibition of the glucuronidation and sulfonation of ethanol was estimated as weak to negligible and as moderate to weak, respectively. Beside the known polymorphisms of the transferases involved in EtG and EtS formation, prediction of the inhibitory potential indicates that polyphenols may contribute to the variable formation rate of EtG and EtS. PMID:26829336

  2. Lithium-bearing fluor-arfvedsonite from Hurricane Mountain, New Hampshire: A crystal-chemical study

    USGS Publications Warehouse

    Hawthorne, F.C.; Oberti, R.; Ottolini, L.; Foord, E.E.

    1996-01-01

    The structures of two crystals of Li-bearing fluor-arfvedsonite (1) (K0.32Na0.68)Na2(Li0.48Fe 2+2.83Mn2+0.10Zn 0.06Fe3+1.46Ti0.07) (Si7.88Al0.12)O22[Fu1.15(OH) 0.85] and (2) (K0.25Na0.75)Na2(Li0.48Fe 2+2.84Mn2+0.11Zn 0.05Fe3+1.45Ti0.07)(Si 7.89Al0.11)O22[F1.35(OH) 0.65] from a granitic pegmatite, Hurricane Mountain, New Hampshire, have been refined to R indices of 1.5(1.6)% based on 1380(1387) reflections measured with MoK?? X-radiation. The unit cell parameters are (1) a 9.838(4), b 17.991(6), c 5.315(2) A??, 103.78(3)??, V 913.7 A??3 and (2) a 9.832(3), b 17.990(7), c 5.316(3) A??, ?? 103.79(3)??, V 913.2 A??3. Site-scattering refinement shows Li to be completely ordered at the M(3) site in these crystals. The amphibole composition is intermediate between fluor-arfvedsonite and fluor-ferro-leakeite with a small component (???10%) of fluor-ferro-ferri-nybo??ite. These amphibole crystals project into miarolitic cavities in a pegmatitic phase of a riebeckite granite. The early-crystallizing amphibole is close to fluor-ferro-leakeite in composition, but becomes progressively depleted in Li and F as crystals project out into miarolitic cavities; the final amphibole to crystallize is a fibrous Li-poor riebeckite. Li plays a significant role in late-stage fractionation involving the crystallization of alkali amphibole in peralkaline granitic environments.

  3. Multiple Introduction and Naturally Occuring Drug Resistance of HCV among HIV-Infected Intravenous Drug Users in Yunnan: An Origin of China’s HIV/HCV Epidemics

    PubMed Central

    Chen, Min; Ma, Yanling; Chen, Huichao; Luo, Hongbing; Dai, Jie; Song, Lijun; Yang, Chaojun; Mei, Jingyuan; Yang, Li; Dong, Lijuan; Jia, Manhong; Lu, Lin

    2015-01-01

    Background The human immunodeficiency virus 1 (HIV-1) epidemic in China historically stemmed from intravenous drug users (IDUs) in Yunnan. Due to a shared transmission route, hepatitis C virus (HCV)/HIV-1 co-infection is common. Here, we investigated HCV genetic characteristics and baseline drug resistance among HIV-infected IDUs in Yunnan. Methods Blood samples of 432 HIV-1/HCV co-infected IDUs were collected from January to June 2014 in six prefectures of Yunnan Province. Partial E1E2 and NS5B genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed. Results Among the 293 specimens successfully genotyped, seven subtypes were identified, including subtypes 3b (37.9%, 111/293), 3a (21.8%, 64/293), 6n (14.0%, 41/293), 1b (10.6%, 31/293), 1a (8.2%, 24/293), 6a (5.1%, 15/293) and 6u (2.4%, 7/293). The distribution of HCV subtypes was mostly related to geographic location. Subtypes 3b, 3a, and 6n were detected in all six prefectures, however, the other four subtypes were detected only in parts of the six prefectures. Phylogeographic analyses indicated that 6n, 1a and 6u originated in the western prefecture (Dehong) and spread eastward and showed genetic relatedness with those detected in Burmese. However, 6a originated in the southeast prefectures (Honghe and Wenshan) bordering Vietnam and was transmitted westward. These subtypes exhibited different evolutionary rates (between 4.35×10−4 and 2.38×10−3 substitutions site-1 year-1) and times of most recent common ancestor (tMRCA, between 1790.3 and 1994.6), suggesting that HCV was multiply introduced into Yunnan. Naturally occurring resistance-associated mutations (C316N, A421V, C445F, I482L, V494A, and V499A) to NS5B polymerase inhibitors were detected in direct-acting antivirals (DAAs)-naïve IDUs. Conclusion This work reveals the temporal-spatial distribution of HCV subtypes and baseline HCV drug resistance among HIV-infected IDUs in Yunnan. The findings enhance our

  4. Molecular and biological characterization of the 5 human-bovine rotavirus (WC3)-based reassortant strains of the pentavalent rotavirus vaccine, RotaTeq.

    PubMed

    Matthijnssens, Jelle; Joelsson, Daniel B; Warakomski, Donald J; Zhou, Tingyi; Mathis, Pamela K; van Maanen, Marc-Henri; Ranheim, Todd S; Ciarlet, Max

    2010-08-01

    RotaTeq is a pentavalent rotavirus vaccine that contains five human-bovine reassortant strains (designated G1, G2, G3, G4, and P1) on the backbone of the naturally attenuated tissue culture-adapted parental bovine rotavirus (BRV) strain WC3. The viral genomes of each of the reassortant strains were completely sequenced and compared pairwise and phylogenetically among each other and to human rotavirus (HRV) and BRV reference strains. Reassortants G1, G2, G3, and G4 contained the VP7 gene from their corresponding HRV parent strains, while reassortants G1 and G2 also contained the VP3 gene (genotype M1) from the HRV parent strain. The P1 reassortant contained the VP4 gene from the HRV parent strain and all the other gene segments from the BRV WC3 strain. The human VP7s had a high level of overall amino acid identity (G1: 95-99%, G2: 94-99% G3: 96-100%, G4: 93-99%) when compared to those of representative rotavirus strains of their corresponding G serotypes. The VP4 of the P1 reassortant had a high identity (92-97%) with those of serotype P1A[8] HRV reference strains, while the BRV VP7 showed identities ranging from 91% to 94% to those of serotype G6 HRV strains. Sequence analyses of the BRV or HRV genes confirmed that the fundamental structure of the proteins in the vaccine was similar to those of the HRV and BRV references strains. Sequences analyses showed that RotaTeq exhibited a high degree of genetic stability as no mutations were identified in the material of each reassortant, which undergoes two rounds of replication cycles in cell culture during the manufacturing process, when compared to the final material used to fill the dosing tubes. The infectivity of each of the reassortant strains of RotaTeq, like HRV strains, did not require the presence of sialic acid residues on the cell surface. The molecular and biologic characterization of RotaTeq adds to the significant body of clinical data supporting the consistent efficacy, immunogenicity, and safety of Rota

  5. Results from a Randomized Clinical Trial of Coadministration of RotaTeq, a Pentavalent Rotavirus Vaccine, and NeisVac-C, a Meningococcal Serogroup C Conjugate Vaccine ▿ †

    PubMed Central

    Vesikari, Timo; Karvonen, Aino; Borrow, Ray; Kitchin, Nick; Baudin, Martine; Thomas, Stéphane; Fiquet, Anne

    2011-01-01

    RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥8 was 100% in both groups). The other responses to MenCC (titer of ≥1:128, ≥4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A[8], GMTs, and ≥3-fold increase in titer) were comparable between groups, including a ≥3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the

  6. Lahnsteinite, Zn4(SO4)(OH)6 · 3H2O, a new mineral from the Friedrichssegen Mine, Germany

    NASA Astrophysics Data System (ADS)

    Chukanov, N. V.; Rastsvetaeva, R. K.; Aksenov, S. M.; Pekov, I. V.; Belakovskiy, D. I.; Blass, G.; Möhn, G.

    2013-12-01

    A new mineral, lahnsteinite, has been found in the dump of the Friedrichssegen Mine, Bad Ems district, Rhineland-Palatinate (Rheinland-Pfalz), Germany. Lahnsteinite, occurring as colorless tabular crystals in the cavities of goethite, is associated with pyromorphite, hydrozincite, quartz, and native copper. The Mohs' hardness is 1.5; the cleavage is perfect parallel to (001). D calc = 2.995 g/cm3, D meas = 2.98(2) g/cm3. The IR spectrum is given. The new mineral is optically biaxial, negative, α = 1.568(2), β = 1.612(2), γ = 1.613(2), 2 V meas = 18(3)°, 2 V calc = 17°. The chemical composition (wt %, electron microprobe data; H2O was determined by gas chromatography of ignition products) is as follows: 3.87 FeO, 1.68 CuO, 57.85 ZnO, 15.83 SO3, 22.3 H2O, total is 101.53. The empirical formula is (Zn3.3Fe0.27Cu0.11)Σ3.91(S0.98O4)(OH)5 · 3H2.10O. The crystal structure has been studied on a single crystal. Lahnsteinite is triclinic, space group P1, a = 8.3125(6), b = 14.545(1), c = 18.504(2) Å, α = 89.71(1), β = 90.05(1), γ = 90.13(1)°, V = 2237.2(3) Å3, Z = 8. The strong reflections in the X-ray powder diffraction pattern [ d, Å ( I, %)] are: 9.30 (100), 4.175 (18), 3.476 (19), 3.290 (19), 2.723 (57), 2.624 (36), 2.503 (35), 1.574 (23). The mineral has been named after its type locality near the town of Lahnstein. The type specimen of lahnsteinite is deposited in the Fersman Mineralogical Museum of the Russian Academy of Sciences, Moscow, registration number 4252/1.

  7. Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses

    PubMed Central

    Russell, Ryan F.; McDonald, Jacqueline U.; Ivanova, Maria; Zhong, Ziyun; Bukreyev, Alexander

    2015-01-01

    ABSTRACT The small hydrophobic (SH) gene of respiratory syncytial virus (RSV), a major cause of infant hospitalization, encodes a viroporin of unknown function. SH gene knockout virus (RSV ΔSH) is partially attenuated in vivo, but not in vitro, suggesting that the SH protein may have an immunomodulatory role. RSV ΔSH has been tested as a live attenuated vaccine in humans and cattle, and here we demonstrate that it protected against viral rechallenge in mice. We compared the immune response to infection with RSV wild type and RSV ΔSH in vivo using BALB/c mice and in vitro using epithelial cells, neutrophils, and macrophages. Strikingly, the interleukin-1β (IL-1β) response to RSV ΔSH infection was greater than to wild-type RSV, in spite of a decreased viral load, and when IL-1β was blocked in vivo, the viral load returned to wild-type levels. A significantly greater IL-1β response to RSV ΔSH was also detected in vitro, with higher-magnitude responses in neutrophils and macrophages than in epithelial cells. Depleting macrophages (with clodronate liposome) and neutrophils (with anti-Ly6G/1A8) demonstrated the contribution of these cells to the IL-1β response in vivo, the first demonstration of neutrophilic IL-1β production in response to viral lung infection. In this study, we describe an increased IL-1β response to RSV ΔSH, which may explain the attenuation in vivo and supports targeting the SH gene in live attenuated vaccines. IMPORTANCE There is a pressing need for a vaccine for respiratory syncytial virus (RSV). A number of live attenuated RSV vaccine strains have been developed in which the small hydrophobic (SH) gene has been deleted, even though the function of the SH protein is unknown. The structure of the SH protein has recently been solved, showing it is a pore-forming protein (viroporin). Here, we demonstrate that the IL-1β response to RSV ΔSH is greater in spite of a lower viral load, which contributes to the attenuation in vivo. This

  8. [H{sub 3}N(CH{sub 2}){sub 4}NH{sub 3}]{sub 2}[Al{sub 4}(C{sub 2}O{sub 4})(H{sub 2}PO{sub 4}){sub 2}(PO{sub 4}){sub 4}].4[H{sub 2}O]: A new layered aluminum phosphate-oxalate

    SciTech Connect

    Peng Li; Li Jiyang; Yu Jihong . E-mail: jihong@mail.jlu.edu.cn; Li Guanghua; Fang Qianrong; Xu Ruren . E-mail: rrxu@mail.jlu.edu.cn

    2005-09-15

    A new layered inorganic-organic hybrid aluminum phosphate-oxalate [H{sub 3}N(CH{sub 2}){sub 4}NH{sub 3}]{sub 2}[Al{sub 4}(C{sub 2}O{sub 4})(H{sub 2}PO{sub 4}){sub 2}(PO{sub 4}){sub 4}].4[H{sub 2}O](AlPO-CJ25) has been synthesized hydrothermally, by using 1,4-diaminobutane (DAB) as structure-directing agent. The structure has been solved by single-crystal X-ray diffraction analysis and further characterized by IR, {sup 31}P MAS NMR, TG-DTA as well as compositional analyses. Crystal data: the triclinic space group P-1, a=8.0484(7) A, b=8.8608(8) A, c=13.2224(11) A, {alpha}=80.830(6) deg. , {beta}=74.965(5) deg. , {gamma}=78.782(6) deg. , Z=2, R {sub 1[} {sub I} {sub >2} {sub {sigma}} {sub (} {sub I} {sub )]}=0.0511 and wR {sub 2(alldata)}=0.1423. The alternation of AlO{sub 4} tetrahedra and PO{sub 4} tetrahedra gives rise to the four-membered corner-sharing chains, which are interconnected through AlO{sub 6} octahedra to form the layered structure with 4,6-net sheet. Interestingly, oxalate ions are bis-bidentately bonded by participating in the coordination of AlO{sub 6}, and bridging the adjacent AlO{sub 6} octahedra. The layers are held with each other through strong H-bondings between the terminal oxygens. The organic ammonium cations and water molecules are located in the large cavities between the interlayer regions. -- Graphical abstract: The alternation of AlO{sub 4} tetrahedra and PO{sub 4} tetrahedra gives rise to the four-membered corner-sharing chains, which are interconnected through AlO{sub 6} octahedra to form the layered structure with 4,6-net sheet. Oxalate ions are bis-bidentately boned by participating in the coordination of AlO{sub 6}, and bridging the adjacent AlO{sub 6} octahedra.

  9. Novel one-dimensional lanthanide acrylic acid complexes: an alternative chain constructed by hydrogen bonding

    SciTech Connect

    Li Hui . E-mail: lihui@bit.edu.cn; Hu Changwen

    2004-12-01

    Novel one-dimensional (1D) chains of three lanthanide complexes La(L{sup 1}){sub 3}(CH{sub 3}OH)].CH{sub 3}OH (L{sup 1}=(E)-3-(2-hydroxyl-phenyl)-acrylic acid) 1, La(L{sup 2}){sub 3}(H{sub 2}O){sub 2}].2.75H{sub 2}O (L{sup 2}=(E)-3-(3-hydroxyl-phenyl)-acrylic acid) 2, and La(L{sup 3}){sub 3}(CH{sub 3}OH){sub 2}(H{sub 2}O)].CH{sub 3}OH (L{sup 3}=(E)-3-(4-hydroxyl-phenyl)-acrylic acid) 3 are reported. The crystal structure data are as follows for 1: C{sub 29}H{sub 29}LaO{sub 11}, monoclinic, P2{sub 1}/n, a=15.4289(12)A, b=7.9585(6)A, c=23.041(2)A, {beta}=99.657(2){sup o}, Z=4, R{sub 1}=0.0637, wR{sub 2}=0.0919; for 2: C{sub 27}H{sub 30.50}LaO{sub 13.75}, triclinic, P-1, a=8.4719(17)A, b=13.719(3)A, c=14.570(3)A, {alpha}=62.19(3){sup o}, {beta}=99.657(2){sup o}, {gamma}=78.22(3){sup o}, Z=2, R{sub 1}=0.0384, wR{sub 2}=0.0820; and for 3: C{sub 30}H{sub 35}LaO{sub 13}, monoclinic, P2(1)/c, a=9.5667(6)A, b=24.3911(15)A, c=14.0448(9)A, {beta}=109.245(2){sup o}, Z=4, R{sub 1}=0.0374, wR{sub 2}=0.0630. All the three structure data were collected using graphite monochromated molybdenum K{alpha} radiation and refined using full-matrix least-squares techniques on F{sup 2}. These structures show that four kinds of the carboxylato bridge modes are included in these chains to link the La(III) ions. It is the first time that it has been found that the intra-chain hydrogen bonding can construct an alternative chain even, when the coordination bridge mode is the same along the chain (complex 2). There are 2D and 3D hydrogen bonding in the crystal lattices of complexes 1-3.

  10. Molecular and biological characterization of the 5 human-bovine rotavirus (WC3)-based reassortant strains of the pentavalent rotavirus vaccine, RotaTeq (registered)

    SciTech Connect

    Matthijnssens, Jelle; Joelsson, Daniel B.; Warakomski, Donald J.; Zhou, Tingyi; Mathis, Pamela K.; Maanen, Marc-Henri van; Ranheim, Todd S.; Ciarlet, Max

    2010-08-01

    RotaTeq (registered) is a pentavalent rotavirus vaccine that contains five human-bovine reassortant strains (designated G1, G2, G3, G4, and P1) on the backbone of the naturally attenuated tissue culture-adapted parental bovine rotavirus (BRV) strain WC3. The viral genomes of each of the reassortant strains were completely sequenced and compared pairwise and phylogenetically among each other and to human rotavirus (HRV) and BRV reference strains. Reassortants G1, G2, G3, and G4 contained the VP7 gene from their corresponding HRV parent strains, while reassortants G1 and G2 also contained the VP3 gene (genotype M1) from the HRV parent strain. The P1 reassortant contained the VP4 gene from the HRV parent strain and all the other gene segments from the BRV WC3 strain. The human VP7s had a high level of overall amino acid identity (G1: 95-99%, G2: 94-99% G3: 96-100%, G4: 93-99%) when compared to those of representative rotavirus strains of their corresponding G serotypes. The VP4 of the P1 reassortant had a high identity (92-97%) with those of serotype P1A[8] HRV reference strains, while the BRV VP7 showed identities ranging from 91% to 94% to those of serotype G6 HRV strains. Sequence analyses of the BRV or HRV genes confirmed that the fundamental structure of the proteins in the vaccine was similar to those of the HRV and BRV references strains. Sequences analyses showed that RotaTeq (registered) exhibited a high degree of genetic stability as no mutations were identified in the material of each reassortant, which undergoes two rounds of replication cycles in cell culture during the manufacturing process, when compared to the final material used to fill the dosing tubes. The infectivity of each of the reassortant strains of RotaTeq (registered) , like HRV strains, did not require the presence of sialic acid residues on the cell surface. The molecular and biologic characterization of RotaTeq (registered) adds to the significant body of clinical data supporting the

  11. Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress

    SciTech Connect

    Cheng, Ya-Hsin; Huang, Su-Chin; Lin, Chun-Ju; Cheng, Li-Chuan; Li, Lih-Ann

    2012-03-15

    Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53–p21–Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity. -- Highlights: ► AhR expression level influences cigarette sidestream smoke-induced ROS production. ► AhR reduces oxidative stress by coordinate regulation of

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

    NASA Astrophysics Data System (ADS)

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

    2008-08-01

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

  13. Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin.

    PubMed

    Larrat, Sylvie; Vallet, Sophie; David-Tchouda, Sandra; Caporossi, Alban; Margier, Jennifer; Ramière, Christophe; Scholtes, Caroline; Haïm-Boukobza, Stéphanie; Roque-Afonso, Anne-Marie; Besse, Bernard; André-Garnier, Elisabeth; Mohamed, Sofiane; Halfon, Philippe; Pivert, Adeline; LeGuillou-Guillemette, Hélène; Abravanel, Florence; Guivarch, Matthieu; Mackiewicz, Vincent; Lada, Olivier; Mourez, Thomas; Plantier, Jean-Christophe; Baazia, Yazid; Alain, Sophie; Hantz, Sebastien; Thibault, Vincent; Gaudy-Graffin, Catherine; Bouvet, Dorine; Mirand, Audrey; Henquell, Cécile; Gozlan, Joel; Lagathu, Gisèle; Pronier, Charlotte; Velay, Aurélie; Schvoerer, Evelyne; Trimoulet, Pascale; Fleury, Hervé; Bouvier-Alias, Magali; Brochot, Etienne; Duverlie, Gilles; Maylin, Sarah; Gouriou, Stéphanie; Pawlotsky, Jean-Michel; Morand, Patrice

    2015-07-01

    The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment. PMID:25926499

  14. Effects of a herbal extract on the bone density, strength and markers of bone turnover of mature ovariectomized rats.

    PubMed

    Xu, Min; Dick, Ian M; Day, Robert; Randall, Drew; Prince, Richard L

    2003-01-01

    For many decades, the Chinese have been using herbal medications to treat bone diseases. To examine effects of an extract of ten medicinal herbs on estrogen deficiency bone loss, ten-month-old female rats were randomly divided into three groups: ovariectomized (OVX), OVX treated with herbs (OVX-M) 4 ml/day by gavage, and OVX treated with estrogen (OVX-E) 10 mg subcutaneously (s.c.) twice per week. The bone mineral density (BMD) of the left femur (fBMD), spine (sBMD) and global body (gBMD) were measured at baseline and at 4, 8 and 12 weeks using a Hologic QDR 2000 dual-energy X-ray densitometer. Tibial strength was tested using the Instron Model 5566 electro-mechanical testing machine. The urinary pyridinoline creatinine ratio (Pyd/Cr), deoxypyridinoline creatinine ratio (Dpd/Cr), plasma alkaline phosphatase (ALP), calcium (CA), phosphorus (P) and albumin (ALB) were also determined. Uterine weight was determined at 12 weeks. The results showed that percent changes of fBMD in the OVX (n = 9), OVX-E (n = 8) and OVX-M (n = 8) rats at the 12-week time point were -11.8 +/- 4.6(c), 1.8 +/- 3.1(a), -7.6 +/- 1.9(abc) (p < 0.05-0.001, a: vs. OVX, b: vs. OVX-E, c: vs. baseline); sBMD were -10.7 +/- 4.6(c), -0.3 +/- 5.5(a), -5.9 +/- 3.5(abc); and gBMD were -4.8 +/- 2.3(c), 0.1 +/- 2.4(a), -2.7 +/- 2.6(abc), respectively. Further, the tibia maximum breaking stress and flexural modulus of elasticity in OVX-M rats (295 +/- 33(a), 18,194 +/- 3,264(a)) were significantly higher (p < 0.005-0.001) than that in OVX rats (189 +/- 83, 10,309 +/- 4,930), and similar to OVX-E rats (298 +/- 35(a), 18,766 +/- 2,620(a)). Additionally, the herbal extract reduced the urinary Pyd/Cr, Dpd/Cr and plasma ALP increment followed OVX and was not associated with a rise in uterine weight. In conclusion, the herbal extract demonstrated a therapeutic effect to inhibit bone resorption and to reduce estrogen-dependent bone loss without uterine stimulation. It may have potential as a new approach in

  15. Energy Efficient Catalytic Activation of Hydrogen peroxide for Green Chemical Processes: Final Report

    SciTech Connect

    Collins, Terrence J.; Horwitz, Colin

    2004-11-12

    A new, highly energy efficient approach for using catalytic oxidation chemistry in multiple fields of technology has been pursued. The new catalysts, called TAML® activators, catalyze the reactions of hydrogen peroxide and other oxidants for the exceptionally rapid decontamination of noninfectious simulants (B. atrophaeus) of anthrax spores, for the energy efficient decontamination of thiophosphate pesticides, for the facile, low temperature removal of color and organochlorines from pulp and paper mill effluent, for the bleaching of dyes from textile mill effluents, and for the removal of recalcitrant dibenzothiophene compounds from diesel and gasoline fuels. Highlights include the following: 1) A 7-log kill of Bacillus atrophaeus spores has been achieved unambiguously in water under ambient conditions within 15 minutes. 2) The rapid total degradation under ambient conditions of four thiophosphate pesticides and phosphonate degradation intermediates has been achieved on treatment with TAML/peroxide, opening up potential applications of the decontamination system for phosphonate structured chemical warfare agents, for inexpensive, easy to perform degradation of stored and aged pesticide stocks (especially in Africa and Asia), for remediation of polluted sites and water bodies, and for the destruction of chemical warfare agent stockpiles. 3) A mill trial conducted in a Pennsylvanian bleached kraft pulp mill has established that TAML catalyst injected into an alkaline peroxide bleach tower can significantly lower color from the effluent stream promising a new, more cost effective, energy-saving approach for color remediation adding further evidence of the value and diverse engineering capacity of the approach to other field trials conducted on effluent streams as they exit the bleach plant. 4) Dibenzothiophenes (DBTs), including 4,6-dimethyldibenzothiophene, the most recalcitrant sulfur compounds in diesel and gasoline, can be completely removed from model gasoline

  16. Extended networks, porous sheets, and chiral frameworks. Thorium materials containing mixed geometry anions: Structures and properties of Th(SeO{sub 3})(SeO{sub 4}), Th(IO{sub 3}){sub 2}(SeO{sub 4})(H{sub 2}O){sub 3}.H{sub 2}O, and Th(CrO{sub 4})(IO{sub 3}){sub 2}

    SciTech Connect

    Sullens, Tyler A.; Almond, Philip M.; Byrd, Jessica A.; Beitz, James V.; Bray, Travis H.; Albrecht-Schmitt, Thomas E. . E-mail: albreth@auburn.edu

    2006-04-15

    Three novel Th(IV) compounds containing heavy oxoanions, Th(SeO{sub 3})(SeO{sub 4}) (1), Th(IO{sub 3}){sub 2}(SeO{sub 4})(H{sub 2}O){sub 3}.H{sub 2}O (2), and Th(CrO{sub 4})(IO{sub 3}){sub 2} (3), have been synthesized under mild hydrothermal conditions. Each of these three distinct structures contain trigonal pyramidal and tetrahedral oxoanions. Compound 1 adopts a three-dimensional structure formed from ThO{sub 9} tricapped trigonal prisms, trigonal pyramidal selenite, SeO{sub 3}{sup 2-}, anions containing Se(IV), and tetrahedral selenate, SeO{sub 4}{sup 2-}, anions containing Se(VI). The structure of 2 contains two-dimensional porous sheets and occluded water molecules. The Th centers are found as isolated ThO{sub 9} tricapped trigonal prisms and are bound by four trigonal pyramidal iodate anions, two tetrahedral selenate anions, and three coordinating water molecules. In the structure of 3, the Th(IV) cations are found as ThO{sub 9} tricapped trigonal prisms. Each Th center is bound by six IO{sub 3}{sup 1-} anions and three CrO{sub 4}{sup 2-} anions forming a chiral three-dimensional structure. Second-harmonic generation of 532nm light from 1064nm radiation by a polycrystalline sample of 3 was observed. Crystallographic data (193K, MoK{alpha}, {lambda}=0.71073): 1; monoclinic, P2{sub 1}/c; a=7.0351(5)A, b=9.5259(7)A, c=9.0266(7)A, {beta}=103.128(1), Z=4, R(F)=2.47% for 91 parameters with 1462 reflections with I>2{sigma}(I); 2, monoclinic, P2{sub 1}/n, a=7.4889(9)A, b=8.002(1)A, c=20.165(3)A, {beta}=100.142(2), Z=4, R(F)=4.71% for 158 parameters with 2934 reflections with I>2{sigma}(I); 3, orthorhombic, P2{sub 1}2{sub 1}2{sub 1}, a=7.3672(5)A, b=9.3617(6)A, c=11.9201(7)A, Z=4, R(F)=2.04% for 129 parameters with 2035 reflections with I>2{sigma}(I)

  17. Synthesis, structure, and optical properties of the quaternary diamond-like compounds I{sub 2}–II–IV–VI{sub 4} (I=Cu; II=Mg; IV=Si, Ge; VI=S, Se)

    SciTech Connect

    Liu, Bin-Wen; Zhang, Ming-Jian; Zhao, Zhong-Yan; Zeng, Hui-Yi Zheng, Fa-Kun; Guo, Guo-Cong Huang, Jin-Shun

    2013-08-15

    Three new diamond-like compounds with the formula of I{sub 2}−II−IV−VI{sub 4} (I=Cu; II=Mg; IV=Si, Ge; VI=S, Se) have been synthesized via traditional high-temperature solid-state reactions and structurally characterized by single crystal X-ray diffraction analysis. All the three compounds crystallize in the space group Pmn2{sub 1} in the wurtzite-type superstructure with a=7.563(4), b=6.448(3), c=6.179(3) Å, Z=2 for Cu{sub 2}MgSiS{sub 4} (1); a=7.953(5), b=6.797(4), c=6.507(4) Å, Z=2 for Cu{sub 2}MgGeS{sub 4} (2); a=7.638(4), b=6.515(4), c=6.225(3) Å, Z=2 for Cu{sub 2}MgSiSe{sub 4} (3). All atoms in these compounds are tetrahedrally coordinated. Optical diffuse reflectance UV/Vis/NIR spectra indicate that compounds 1 and 2 have the band gaps of 3.20 and 2.36 eV, respectively. Electronic structure calculations using the CASTEP code indicate that they are all direct band gap compounds. - Graphical abstract: Three new diamond-like compounds, Cu{sub 2}MgSiS{sub 4}, Cu{sub 2}MgGeS{sub 4}, and Cu{sub 2}MgSiSe{sub 4}, have been synthesized. All the three compounds crystallize in the space group Pmn2{sub 1} and all atoms are tetrahedrally coordinated. Highlights: • Three new diamond-like compounds Cu{sub 2}MgSiS{sub 4}, Cu{sub 2}MgGeS{sub 4} and Cu{sub 2}MgSiSe{sub 4} have been synthesized. • All ions are tetrahedrally coordinated. • Electronic structure calculations indicate that they are all direct band gap compounds.

  18. Evaluation of Meteorology Data for MOPITT Operational Processing

    NASA Astrophysics Data System (ADS)

    Ziskin, D.; Deeter, M. N.; Worden, H. M.; Mao, D.; Dean, V.

    2015-12-01

    Measurements Of Pollution In The Troposphere[1] (MOPITT) is an instrument flying aboard NASA's Terra satellite[2]. It measures CO using correlated spectroscopy[3]. As part of its processing it uses surface temperature, an atmospheric temperature profile and a water vapor profile from analysis. Since there are many analysis products on the market (e.g. GMAO, NCEP, ECMWF etc.) that meet MOPITT's operational requirements, the question arises as to which product is most apt? There is a collection of "validation data" that MOPITT compares its CO retrievals against[4]. The validation dataset has been acquired by in situ air samples taken by aircraft at a series of altitudes. We can run our processing system in "validation mode" which processes the satellite data for only the days that validation data exists and for a spatial subset that corresponds to the region where the validation data has been collected. We will run the MOPITT retrievals in validation mode separately using each variety of analysis data. We will create a cost function that will provide a scalar estimate of the retrieved CO profile error relative to the validation dataset which is assumed to be "the truth". The retrieval errors of each of the input datasets will be compared to each other to provide insight into the best choice for use in operational MOPITT processing. [1] Drummond, J.R., "Measurements of Pollution in the Troposphere (MOPITT)," in The Use of EOS for Studies of Atmospheric Physics, J. C. Gille, G. Visconti, eds. (North Holland, Amsterdam), pp. 77-101, 1992. [2] 1999 EOS Reference Handbook: A Guide to NASA's Earth Science Enterprise and the Earth Observing System; Eds. Michael D. King and Reynold Greenstone; NASA, Greenbelt, MD, 1999. [3] Drummond, J.R., G. P. Brasseur, G. R. Davis, J. C. Gille, J. C. McConnell, G. D. Pesket, H. G. Reichle, N. Roulet, MOPITT Mission Description Document (Department of Physics, University of Toronto, Toronto, Ontario, Canada M5S 1A7), 1993. [4] Deeter, M. N

  19. Effect of age on anthropometric and physical performance measures in professional baseball players.

    PubMed

    Mangine, Gerald T; Hoffman, Jay R; Fragala, Maren S; Vazquez, Jose; Krause, Matthew C; Gillett, Javair; Pichardo, Napoleon

    2013-02-01

    The purpose of this study was to investigate age-related changes in anthropometric and performance variables in professional baseball players. Baseball players (n = 1,157) from several professional baseball organizations were categorized into 7 cohorts based upon age. All adolescent athletes were categorized as age group 1 (AG1), whereas the next 5 groups (AG2-AG6) consisted of players 20-22, 23-25, 26-28, 29-31, and 31-34 years, respectively. The final group (AG7) comprised athletes ≥35 years. All performance assessments were part of the athlete's normal preseason training camp testing routine. Field assessments were used to analyze lower-body power, speed, agility, grip strength, and body composition. The players were heaviest between the ages of 29 and 31 (AG5), and their body mass in that age group was 10.1% (p = 0.004) greater than that of AG1. A 7.0% increase (p = 0.000) in lean body mass occurred between AG1 and AG5. No differences in 10-yd sprint times or agility were seen across any age group or position. A 2.0 seconds (p = 0.001) slower run time for the 300-yd shuttle was seen between AG4 and AG5 for all positions combined. Elevations in grip strength were seen at AG4 compared with AG1 (p = 0.001) and AG2 (p = 0.007) for all positions combined. No other differences were noted. Lower-body power was increased for all positions combined from AG1 to AG3 (p = 0.007). This pattern was similar to that observed in position players, but a 12.4% decrease (p = 0.024) in VJMP was seen between AG7 and AG5 in pitchers. Results of this study indicate that lower-body power is maintained in baseball players until the age of 29-31, whereas speed, agility, and grip strength are maintained in players able to play past the age of 35 years. Age-related differences observed in this study suggest that athletes focus on their strength and conditioning programs to extend the length of their professional careers. PMID:22505124

  20. Diphosphine- and CO-Induced Fragmentation of Chloride-bridged Dinuclear Complex and Cp*Ir(mu-Cl)(3)Re(CO)(3) and Attempted Synthesis of Cp*Ir(mu-Cl)(3)Mn(CO)(3): Spectroscopic Data and X-ray Diffraction Structures of the Pentamethylcyclopentadienyl Compounds [Cp*IrCl{(Z)-Ph2PCH = CHPPh2}][Cl]center dot 2CHCl(3) and Cp*Ir(CO)Cl-2

    SciTech Connect

    Hammons, Casey; Wang, Xiaoping; Nesterov, Vladimir; Richmond, Michael G.

    2010-01-01

    The confacial bioctahedral compound Cp*Ir(mu-Cl)(3)Re(CO)(3) (1) undergoes rapid fragmentation in the presence of the unsaturated diphosphine ligand (Z)-Ph2PCH = CHPPh2 to give the mononuclear compounds [Cp*IrCl {(Z)-Ph2PCH = CHPPh2}][Cl] (2) and fac-ClRe(CO)(3)[(Z)-Ph2PCH = CHPPh2] (3). 2 has been characterized by H-1 and P-31 NMR spectroscopy and X-ray diffraction analysis. 2 center dot 2CHCl(3) crystallizes in the monoclinic space group C2/c, a = 35.023 (8) angstrom, b = 10.189 (2) angstrom, c = 24.003 (6) angstrom, b = 103.340 (3), V = 8,335 (3) angstrom 3, Z = 8, and d(calc) = 1.647 Mg/m(3); R = 0.0383, R-w = 0.1135 for 8,178 reflections with I> 2 sigma(I). The Ir(III) center in 2 exhibits a six-coordinate geometry and displays a chelating diphosphine group. Compound 1 reacts with added CO with fragmentation to yield the known compounds Cp*Ir(CO)Cl-2 (4) and ClRe(CO)(5) (5) in near quantitative yield by IR spectroscopy. Using the protocol established by our groups for the synthesis of 1, we have explored the reaction of [Cp*IrCl2](2) with ClMn(CO)(5) as a potential route to Cp*Ir(mu-Cl)(3)Mn(CO)(3); unfortunately, 4 was the only product isolated from this reaction. The solid-state structure of 4 was determined by X-ray diffraction analysis. 4 crystallizes in the triclinic space group P-1, a = 7.4059 (4) angstrom, b = 7.8940 (4) angstrom, c = 11.8488 (7) angstrom, alpha = 80.020 (1), beta = 79.758 (1), gamma = 68.631 (1), V = 630.34 (6) angstrom(3), Z = 2, and d(calc) = 2.246 Mg/m(3); R = 0.0126, R-w = 0.0329 for 2,754 reflections with I> 2 sigma(I). The expected three-legged piano-stool geometry in 4 has been crystallographically confirmed.

  1. Long-Lasting Effects of Sepsis on Circadian Rhythms in the Mouse

    PubMed Central

    O'Callaghan, Emma K.; Anderson, Sean T.; Moynagh, Paul N.; Coogan, Andrew N.

    2012-01-01

    Daily patterns of activity and physiology are termed circadian rhythms and are driven primarily by an endogenous biological timekeeping system, with the master clock located in the suprachiasmatic nucleus. Previous studies have indicated reciprocal relationships between the circadian and the immune systems, although to date there have been only limited explorations of the long-term modulation of the circadian system by immune challenge, and it is to this question that we addressed ourselves in the current study. Sepsis was induced by peripheral treatment with lipopolysaccharide (5 mg/kg) and circadian rhythms were monitored following recovery. The basic parameters of circadian rhythmicity (free-running period and rhythm amplitude, entrainment to a light/dark cycle) were unaltered in post-septic animals compared to controls. Animals previously treated with LPS showed accelerated re-entrainment to a 6 hour advance of the light/dark cycle, and showed larger phase advances induced by photic stimulation in the late night phase. Photic induction of the immediate early genes c-FOS, EGR-1 and ARC was not altered, and neither was phase-shifting in response to treatment with the 5-HT-1a/7 agonist 8-OH-DPAT. Circadian expression of the clock gene product PER2 was altered in the suprachiasmatic nucleus of post-septic animals, and PER1 and PER2 expression patterns were altered also in the hippocampus. Examination of the suprachiasmatic nucleus 3 months after treatment with LPS showed persistent upregulation of the microglial markers CD-11b and F4/80, but no changes in the expression of various neuropeptides, cytokines, and intracellular signallers. The effects of sepsis on circadian rhythms does not seem to be driven by cell death, as 24 hours after LPS treatment there was no evidence for apoptosis in the suprachiasmatic nucleus as judged by TUNEL and cleaved-caspase 3 staining. Overall these data provide novel insight into how septic shock exerts chronic effects on the

  2. Distribution of serotonin 5-HT1A-binding sites in the brainstem and the hypothalamus, and their roles in 5-HT-induced sleep and ingestive behaviors in rock pigeons (Columba livia).

    PubMed

    dos Santos, Tiago Souza; Krüger, Jéssica; Melleu, Fernando Falkenburger; Herold, Christina; Zilles, Karl; Poli, Anicleto; Güntürkün, Onur; Marino-Neto, José

    2015-12-15

    Serotonin 1A receptors (5-HT1ARs), which are widely distributed in the mammalian brain, participate in cognitive and emotional functions. In birds, 5-HT1ARs are expressed in prosencephalic areas involved in visual and cognitive functions. Diverse evidence supports 5-HT1AR-mediated 5-HT-induced ingestive and sleep behaviors in birds. Here, we describe the distribution of 5-HT1ARs in the hypothalamus and brainstem of birds, analyze their potential roles in sleep and ingestive behaviors, and attempt to determine the involvement of auto-/hetero-5-HT1ARs in these behaviors. In 6 pigeons, the anatomical distribution of [(3)H]8-OH-DPAT binding in the rostral brainstem and hypothalamus was examined. Ingestive/sleep behaviors were recorded (1h) in 16 pigeons pretreated with MM77 (a heterosynaptic 5-HT1AR antagonist; 23 or 69 nmol) for 20 min, followed by intracerebroventricular ICV injection of 5-HT (N:8; 150 nmol), 8-OH-DPAT (DPAT, a 5-HT1A,7R agonist, 30 nmol N:8) or vehicle. 5-HT- and DPAT-induced sleep and ingestive behaviors, brainstem 5-HT neuronal density and brain 5-HT content were examined in 12 pigeons, pretreated by ICV with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (N:6/group). The distribution of brainstem and diencephalic c-Fos immunoreactivity after ICV injection of 5-HT, DPAT or vehicle (N:5/group) into birds provided with or denied access to water is also described. 5-HT1ARs are concentrated in the brainstem 5-HTergic areas and throughout the periventricular hypothalamus, preoptic nuclei and circumventricular organs. 5-HT and DPAT produced a complex c-Fos expression pattern in the 5-HT1AR-enriched preoptic hypothalamus and the circumventricular organs, which are related to drinking and sleep regulation, but modestly affected c-Fos expression in 5-HTergic neurons. The 5-HT-induced ingestivebehaviors and the 5-HT- and DPAT-induced sleep behaviors were reduced by MM77 pretreatment. 5,7-DHT increased sleep per se, decreased tryptophan

  3. Brain and Whole-Body Imaging of Nociceptin/Orphanin FQ Peptide Receptor in Humans Using the PET Ligand 11C-NOP-1A

    PubMed Central

    Lohith, Talakad G.; Zoghbi, Sami S.; Morse, Cheryl L.; Araneta, Maria F.; Barth, Vanessa N.; Goebl, Nancy A.; Tauscher, Johannes T.; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro

    2013-01-01

    Nociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, 11C-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of 11C-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile. Methods After intravenous injection of 11C-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (VT; a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichise’s bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose). Results After 11C-NOP-1A injection, the peak concentration of radioactivity in brain was high (~5–7 standardized uptake values), occurred early (~10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent VT identifiability (~1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional VT values (mL·cm−3) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. VT was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent radioligand, as supported by the fact that all plasma radiometabolites of 11C-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 VT values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. 11C-NOP-1A was significantly

  4. Responsiveness of a Xenopus laevis cell line to the aryl hydrocarbon receptor ligands 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

    PubMed Central

    Laub, Leo B.; Jones, Brian D.; Powell, Wade H.

    2009-01-01

    The aryl hydrocarbon receptor (AHR) mediates the toxic effects of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Frogs are very insensitive to TCDD toxicity, and AHRs from Xenopus laevis (African clawed frog) bind TCDD with >20-fold lower affinity than mouse AHRb-1. Frog AHRs may nonetheless be highly responsive to structurally distinct compounds, especially putative endogenous ligands. We sought to determine the responsiveness of an X. laevis cell line, XLK-WG, to the candidate endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct that exhibits high potency in mammalian systems. FICZ readily induced mRNAs for CYP1A6 and CYP1A7. Cells exposed to FICZ for 3 hours expressed up to 5-fold greater quantities of CYP1A6/7 mRNAs than those exposed for 24 hours, suggesting FICZ is metabolized following rapid enzyme induction. FICZ appeared more potent than TCDD. Following a 3-hr exposure, the EC50 for CYP1A6 mRNA induction by FICZ was ~6 nM, while the TCDD response was greater than 174 nM. These potencies were lower than those determined for mouse hepatoma cells (Hepa1c1c7; EC50 = ~0.06 nM each). The difference in ligand potency between cell lines was confirmed by induction of ethoxyresorufin-O-deethylase (EROD) activity. mRNA from XLK-WG cells treated with 100 nM FICZ, 100 nM TCDD, or vehicle was also analyzed on expression microarrays. FICZ altered the expression of 105 more transcripts than TCDD, and common targets were altered more dramatically by FICZ. Overall, these studies demonstrate that although FICZ is a less potent CYP1A inducer in frog cells than in mouse cells, the reduction is much less than for TCDD. Relative conservation of the FICZ response in a TCDD-insensitive species suggests its physiological importance as an AHR ligand. PMID:19799885

  5. Serotonin directly stimulates cortisol secretion from the interrenals in goldfish.

    PubMed

    Lim, Jan E; Porteus, Cosima S; Bernier, Nicholas J

    2013-10-01

    While serotonin (5-HT) can stimulate the hypothalamic-pituitary-interrenal stress axis in fish, the specific site(s) of 5-HT action are poorly understood. In this study, goldfish (Carassius auratus) were injected intraperitoneally with either saline or the 5-HT1A/7 receptor agonist 8-OH-DPAT at a dose of 100 or 400 μg/kg body weight and sampled 1.5 and 8 h post-injection. Relative to unhandled controls, the saline and 100 μg/kg 8-OH-DPAT treatments elicited similar transient 5- to 7-fold increases in plasma cortisol and the 400 μg/kg 8-OH-DPAT dosage resulted in a sustained 16-fold increase in cortisol levels. Although the 5-HT1A receptor is expressed in the brain preoptic area (POA), the pituitary and the head kidney, neither the saline nor the 8-OH-DPAT treatments affected the mRNA abundance of POA corticotropin-releasing factor and pituitary pro-opiomelanocortin or plasma adrenocorticotropic hormone (ACTH) levels. To assess the direct actions of 5-HT on cortisol secretion relative to those of ACTH, head kidney tissue were superfused with 10(-7)M 5-HT, ACTH or a combined 5-HT/ACTH treatment. Overall, the ACTH and 5-HT/ACTH treatments resulted in higher peak cortisol and total cortisol release than in the 5-HT treatment but the response time to peak cortisol release was shorter in the combined treatment than in either the 5-HT or ACTH alone treatments. Both 8-OH-DPAT and cisapride, a 5-HT4 receptor agonist, also stimulated cortisol release in vitro and their actions were reversed by selective 5-HT1A and 5-HT4 receptor antagonists, respectively. Finally, double-labeling with anti-tyrosine hydroxylase and anti-5-HT revealed that the chromaffin cells of the head kidney contain 5-HT. Thus, in goldfish, 5-HT can directly stimulate cortisol secretion from the interrenals via multiple 5-HT receptor subtypes and the chromaffin cells may be involved in the paracrine regulation of cortisol secretion via 5-HT. PMID:24013027

  6. Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion

    PubMed Central

    Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta

    2015-01-01

    Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs’ wave-like activity lagged behind that of

  7. Microbiota and metabolome of un-started and started Greek-type fermentation of Bella di Cerignola table olives.

    PubMed

    De Angelis, Maria; Campanella, Daniela; Cosmai, Lucrezia; Summo, Carmine; Rizzello, Carlo Giuseppe; Caponio, Francesco

    2015-12-01

    This study aimed to utilize an "omics" approach to evaluate the ability of selected lactobacilli and yeasts to improve the fermentation process of Bella di Cerignola table olives. Four types of fermentations were performed at the pilot-plant scale: un-started fermented olives used as a control (Ctrl); olives started with a commercial Lactobacillus plantarum strain (S); commercial L. plantarum strain and autochthonous yeast Wickeramomyces anomalus DiSSPA73 (SY); and L. plantarum, W. anomalus DiSSPA73, autochthonous L. plantarum DiSSPA1A7 and Lactobacillus pentosus DiSSPA7 (SYL). Compared to Ctrl, S, SY, SYL showed a higher acidification (P < 0.05) of the brine, which reached a pH value of 4.49 after one day of fermentation. The microbiota of unfermented olives and brine after one day of fermentation was primarily composed of Enterobacteria that belonged to Hafnia alvei and Methylobacterium. However, L. plantarum and L. pentosus dominated the total and metabolically active microbiota of the Ctrl brines and olives at the end of the fermentation. The use of lactobacilli and W. anomalus DiSSPA73 as a starter culture markedly affected the microbiota of the brines after one day of fermentation. The number of species (OTU) and the results of an alpha diversity analysis indicated that the microbial diversity of the brines was markedly simplified by the S, SY and, in particular, SYL fermentations. According to the lowest biodiversity, S, SY and SYL samples showed the lowest abundance of Proteobacteria, including Enterobacteriacea, Lactococcus lactis, Propionibacterium acidipropionici and Clostridium. The lactobacilli and W. anomalus DiSSPA73 used in this study markedly affected the amounts of free amino acids, phenolic and volatile organic compounds. Both a texture profile analysis and a sensory evaluation showed the highest appreciation for all of the started table olives. As shown through microbiological, biochemical, and sensory analyses, an accelerated

  8. Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

    PubMed Central

    Vallet, Sophie; David-Tchouda, Sandra; Caporossi, Alban; Margier, Jennifer; Ramière, Christophe; Scholtes, Caroline; Haïm-Boukobza, Stéphanie; Roque-Afonso, Anne-Marie; Besse, Bernard; André-Garnier, Elisabeth; Mohamed, Sofiane; Halfon, Philippe; Pivert, Adeline; LeGuillou-Guillemette, Hélène; Abravanel, Florence; Guivarch, Matthieu; Mackiewicz, Vincent; Lada, Olivier; Mourez, Thomas; Plantier, Jean-Christophe; Baazia, Yazid; Alain, Sophie; Hantz, Sebastien; Thibault, Vincent; Gaudy-Graffin, Catherine; Bouvet, Dorine; Mirand, Audrey; Henquell, Cécile; Gozlan, Joel; Lagathu, Gisèle; Pronier, Charlotte; Velay, Aurélie; Schvoerer, Evelyne; Trimoulet, Pascale; Fleury, Hervé; Bouvier-Alias, Magali; Brochot, Etienne; Duverlie, Gilles; Maylin, Sarah; Gouriou, Stéphanie; Pawlotsky, Jean-Michel; Morand, Patrice

    2015-01-01

    The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment. PMID:25926499

  9. Number and density of equine preantral follicles in different ovarian histological section thicknesses.

    PubMed

    Alves, K A; Alves, B G; Rocha, C D; Visonná, M; Mohallem, R F F; Gastal, M O; Jacomini, J O; Beletti, M E; Figueiredo, J R; Gambarini, M L; Gastal, E L

    2015-04-01

    Regardless of species, advances in preantral follicle culture and cryopreservation and transplant of ovarian tissue techniques are dependent on the number and density of preantral follicles in the ovary. This study tested the effect of different histological section thicknesses on number, classification, and density of equine preantral follicles. An ovarian fragment was obtained from 5- to 10-year-old mares (n = 14) after slaughter, and each fragment was submitted to three histological section thickness treatments: 3, 5, and 7 μm. The area (cm(2)) of each ovarian fragment was measured, and the sections were evaluated by light microscopy. The percentage of morphologically normal follicles (89%) was similar (P > 0.05) among primordial, transitional, and primary follicles and also among histological section thicknesses. A greater (P < 0.05) number of preantral follicles per histological section were seen in the 7-μm (8.0 ± 2.2) than that in the 3-μm (3.4 ± 0.7) treatment. Furthermore, a linear regression analysis reported that the number of preantral follicles increased (P < 0.05) when a thicker section treatment was used. However, no association (P > 0.05) between follicular density and treatment was observed. The mean number of preantral follicles per fragment (45.3 ± 18.8) and the follicular density (3.0 ± 0.5 follicles per cm(2)) were different (P < 0.05) among mares. In conclusion, this study on equine preantral follicles reported that (1) a 7-μm histological section thickness might be recommended because it allowed identification of a greater number of preantral follicles per sample, (2) a large individual variation in follicle population and density was detected regardless of histological section thickness, and (3) mares have a low number and density of preantral follicles when compared with those reported for other species. PMID:25628263

  10. Crystal structures of lazulite-type oxidephosphates Ti{sup III}Ti{sup IV}{sub 3}O{sub 3}(PO{sub 4}){sub 3} and M{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4}){sub 24} (M{sup III}=Ti, Cr, Fe)

    SciTech Connect

    Schoeneborn, M.; Glaum, R. Reinauer, F.

    2008-06-15

    Single crystals of the oxidephosphates Ti{sup III}Ti{sup IV}{sub 3}O{sub 3}(PO{sub 4}){sub 3} (black), Cr{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4}){sub 24} (red-brown, transparent), and Fe{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4}){sub 24} (brown) with edge-lengths up to 0.3 mm were grown by chemical vapour transport. The crystal structures of these orthorhombic members (space group F2dd ) of the lazulite/lipscombite structure family were refined from single-crystal data [Ti{sup III}Ti{sup IV}{sub 3}O{sub 3}(PO{sub 4}){sub 3}: Z=24, a=7.3261(9) A, b=22.166(5) A, c=39.239(8) A, R{sub 1}=0.029, wR{sub 2}=0.084, 6055 independent reflections, 301 variables; Cr{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4}){sub 24}: Z=1, a=7.419(3) A, b=21.640(5) A, c=13.057(4) A, R{sub 1}=0.037, wR{sub 2}=0.097, 1524 independent reflections, 111 variables; Fe{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4}){sub 24}: Z=1, a=7.4001(9) A, b=21.7503(2) A, c=12.775(3) A, R{sub 1}=0.049, wR{sub 2}=0.140, 1240 independent reflections, 112 variables). For Ti{sup III}Ti{sup IV}O{sub 3}(PO{sub 4}){sub 3} a well-ordered structure built from dimers [Ti{sup III,IV}{sub 2}O{sub 9}] and [Ti{sup IV,IV}{sub 2}O{sub 9}] and phosphate tetrahedra is found. The metal sites in the crystal structures of Cr{sub 4}Ti{sub 27}O{sub 24}(PO{sub 4}){sub 24} and Fe{sub 4}Ti{sub 27}O{sub 24}(PO{sub 4}){sub 24}, consisting of dimers [M{sup III}Ti{sup IV}O{sub 9}] and [Ti{sup IV,IV}{sub 2}O{sub 9}], monomeric [Ti{sup IV}O{sub 6}] octahedra, and phosphate tetrahedra, are heavily disordered. Site disorder, leading to partial occupancy of all octahedral voids of the parent lipscombite/lazulite structure, as well as splitting of the metal positions is observed. According to Guinier photographs Ti{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4}){sub 24} (a=7.418(2) A, b=21.933(6) A, c=12.948(7) A) is isotypic to the oxidephosphates M{sup III}{sub 4}Ti{sup IV}{sub 27}O{sub 24}(PO{sub 4

  11. Recent changes detected on two glaciers at the northern part of James Ross Island, Antarctica

    NASA Astrophysics Data System (ADS)

    Nývlt, Daniel; Kopačková, Veronika; Láska, Kamil; Engel, Zbyněk.

    2010-05-01

    2009 repeated mapping of the Davies Dome was carried out and the results showed that the largest retreat ranging from 10 to 20 m occurred in the NW flat part of the glacier. Digital elevation models calculated on bases of aerial stereo-photographs from 1979 and 2006 allowed us to define mass-balance changes of the studied glaciers. Ground Penetrating Radar measurements taken on both glaciers helped with mass-balance investigations, furthermore, made it possible to increase the accuracy of the 3-D models. Annual mass balance measurements on the Davies Dome indicated a mean ablation about 20 cm between 2006 and 2009. On the Whisky Glacier, a network of 20 ablation stakes was established just recently (February 2009). Therefore, another 3-year investigation is necessary to bring comparable results. Acknowledgments: This research has been undertaken within a framework of the project No. 205/09/1876 funded by the Czech Science Foundation and by the R & D project VaV SP II 1a9/23/07.

  12. On the existence of a high-temperature polymorph of Na2Ca6Si4O15—implications for the phase equilibria in the system Na2O-CaO-SiO2

    NASA Astrophysics Data System (ADS)

    Kahlenberg, Volker; Maier, Matthias

    2016-06-01

    Singe crystals of a new high-temperature polymorph of Na2Ca6Si4O15 have been obtained from solid state reactions performed at 1300 °C. The basic crystallographic data of this so-called β-phase at ambient conditions are as follows: space group P1c1, a = 9.0112(5) Å, b = 7.3171(5) Å, c = 10.9723(6) Å, β = 107.720(14)°, V = 689.14(7) Å3, Z = 2. The crystals showed twinning by reticular merohedry (mimicking an orthorhombic C-centred unit cell) which was accounted for during data processing and structure solution. Structure determination was accomplished by direct methods. Least-squares refinements resulted in a residual of R(|F|) = 0.043 for 5811 observed reflections with I > 2σ(I). From a structural point of view β-Na2Ca6Si4O15 can be attributed to the group of mixed-anion silicates containing [Si2O7]-dimers as well as isolated [SiO4]-tetrahedra in the ratio 1:2, i.e. more precisely the formula can be written as Na2Ca6[SiO4]2[Si2O7]. The tetrahedral groups are arranged in layers parallel to (100). Sodium and calcium cations are located between the silicate anions for charge compensation and are coordinated by six to eight nearest oxygen ligands. Alternatively, the structure can be described as a mixed tetrahedral-octahedral framework based on kröhnkite-type [Ca(SiO4)2O2]-chains in which the CaO6-octahedra are corner-linked to bridging SiO4-tetrahedra. The infinite chains are running parallel to [001] and are concentrated in layers parallel to (010). Adjacent layers are shifted relative to each other by an amount of +δ or -δ along a*. Consequently, a …ABABAB… stacking sequence is created. A detailed comparison with related structures such as α-Na2Ca6Si4O15 and other A2B6Si4O15 representatives including topological as well as group theoretical aspects is presented. There are strong indications that monoclinic Na2Ca3Si2O8 mentioned in earlier studies is actually misinterpreted β-Na2Ca6Si4O15. In addition to the detailed crystallographic analysis of the

  13. UDP-Glucuronosyltransferase-mediated Metabolic Activation of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole*

    PubMed Central

    Tang, Yijin; LeMaster, David M.; Nauwelaërs, Gwendoline; Gu, Dan; Langouët, Sophie; Turesky, Robert J.

    2012-01-01

    2-Amino-9H-pyrido[2,3-b]indole (AαC) is a carcinogenic heterocyclic aromatic amine (HAA) that arises in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs. UGTs compete with P450 enzymes, which bioactivate HAAs by N-hydroxylation of the exocyclic amine group; the resultant N-hydroxy-HAA metabolites form covalent adducts with DNA. We have characterized the UGT-catalyzed metabolic products of AαC and the genotoxic metabolite 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC) formed with human liver microsomes, recombinant human UGT isoforms, and human hepatocytes. The structures of the metabolites were elucidated by 1H NMR and mass spectrometry. AαC and HONH-AαC underwent glucuronidation by UGTs to form, respectively, N2-(β-d-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N2-Gl) and N2-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON2-Gl). HONH-AαC also underwent glucuronidation to form a novel O-linked glucuronide conjugate, O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN2-O-Gl). AαC-HN2-O-Gl is a biologically reactive metabolite and binds to calf thymus DNA (pH 5.0 or 7.0) to form the N-(deoxyguanosin-8-yl)-AαC adduct at 20–50-fold higher levels than the adduct levels formed with HONH-AαC. Major UGT isoforms were examined for their capacity to metabolize AαC and HONH-AαC. UGT1A4 was the most catalytically efficient enzyme (Vmax/Km) at forming AαC-N2-Gl (0.67 μl·min−1·mg of protein−1), and UGT1A9 was most catalytically efficient at forming AαC-HN-O-Gl (77.1 μl·min−1·mg of protein−1), whereas UGT1A1 was most efficient at forming AαC-HON2-Gl (5.0 μl·min−1·mg of protein−1). Human hepatocytes produced AαC-N2-Gl and AαC-HN2-O-Gl in abundant quantities, but AαC-HON2-Gl was a minor product. Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, serve as a mechanism of bioactivation of

  14. Seasonal variation of meteorological variables and recent surface ablation / accumulation rates on Davies Dome and Whisky Glacier, James Ross Island, Antarctica

    NASA Astrophysics Data System (ADS)

    Láska, K.; Nývlt, D.; Engel, Z.; Budík, L.

    2012-04-01

    Dome and in 2009 on Whisky Glacier. Since 2009 the surveys cover the whole surface area of both glaciers. The height and position of measurement stakes were measured each year. Preliminary results of mass balance changes suggest the net positive volume balance of the glaciers. Between 2009 and 2010 mass gain was observed on the whole surface of Davies Dome, whereas in 2010-2011 the loss up to 0.25 m took place along southeastern limit of the dome. The net mass gain was identified on the whole Whisky Glacier except for the terminus below 280 m a.s.l., where the surface mass decreased by up to 0.14 m. The repeated measurements reveal the asymmetric pattern of the mass changes with higher accumulation rate on the eastern part of the valley glacier. Acknowledgments: This research is supported by the project of the Czech Grant Agency 205/09/1876 and by the R & D project VaV SP II 1a9/23/07.

  15. Mild hydrothermal synthesis, crystal structure, spectroscopic and magnetic properties of the [M{sub x}{sup II}M{sub 2.5-x}{sup III}(H{sub 2}O){sub 2}(HP{sup III}O{sub 3}){sub y}(P{sup V}O{sub 4}){sub 2-y}F; M=Fe, x=2.08, y=1.58; M=Co, Ni, x=2.5, y=2] compounds

    SciTech Connect

    Orive, Joseba

    2009-08-15

    The [M{sub x}{sup II}M{sub 2.5-x}{sup III}(H{sub 2}O){sub 2}(HP{sup III}O{sub 3}){sub y}(P{sup V}O{sub 4}){sub 2-y}F; M=Fe (1), x=2.08, y=1.58; M=Co (2), x=2.5, y=2; Ni (3), x=2.5, y=2] compounds have been synthesized using mild hydrothermal conditions at 170 deg. C during five days. Single-crystals of (1) and (2), and polycrystalline sample of (3) were obtained. These isostructural compounds crystallize in the orthorhombic system, space group Aba2, with a=9.9598(2), b=18.8149(4) and c=8.5751(2) A for (1), a=9.9142(7), b=18.570(1) and c=8.4920(5) A for (2) and a=9.8038(2), b=18.2453(2) and c=8.4106(1) A for (3), with Z=8 in the three phases. An X-ray diffraction study reveals that the crystal structure is composed of a three-dimensional skeleton formed by [MO{sub 5}F] and [MO{sub 4}F{sub 2}] (M=Fe, Co and Ni) octahedra and [HPO{sub 3}] tetrahedra, partially substituted by [PO{sub 4}] tetrahedra in phase (1). The IR spectra show the vibrational modes of the water molecules and those of the (HPO{sub 3}){sup 2-} tetrahedral oxoanions. The thermal study indicates that the limit of thermal stability of these phases is 195 deg. C for (1) and 315 deg. C for (2) and (3). The electronic absorption spectroscopy shows the characteristic bands of the Fe(II), Co(II) and Ni(II) high-spin cations in slightly distorted octahedral geometry. Magnetic measurements indicate the existence of global antiferromagnetic interactions between the metallic centers with a ferromagnetic transition in the three compounds at 28, 14 and 21 K for (1), (2) and (3), respectively. Compound (1) exhibits a hysteresis loop with remnant magnetization and coercive field values of 0.72 emu/mol and 880 Oe, respectively. - Abstract: Polyhedral view of the crystal structure of the [M{sub x}{sup II}M{sub 2.5-x}{sup III}(H{sub 2}O){sub 2}(HP{sup III}O{sub 3}){sub y}(P{sup IV}O{sub 4}){sub 2-y}F; M=Fe, x=2.08, y=1.58; M=Co, Ni, x=2.5, y=2] compounds showing the sheets along the [001] direction.

  16. Complete Genome Characterization of Recent and Ancient Belgian Pig Group A Rotaviruses and Assessment of Their Evolutionary Relationship with Human Rotaviruses

    PubMed Central

    Heylen, Elisabeth; Zeller, Mark; Roukaerts, Inge D. M.; Desmarets, Lowiese M. B.; Van Ranst, Marc; Nauwynck, Hans J.; Matthijnssens, Jelle

    2014-01-01

    ABSTRACT Group A rotaviruses (RVAs) are an important cause of diarrhea in young pigs and children. An evolutionary relationship has been suggested to exist between pig and human RVAs. This hypothesis was further investigated by phylogenetic analysis of the complete genomes of six recent (G2P[27], G3P[6], G4P[7], G5P[7], G9P[13], and G9P[23]) and one historic (G1P[7]) Belgian pig RVA strains and of all completely characterized pig RVAs from around the globe. In contrast to the large diversity of genotypes found for the outer capsid proteins VP4 and VP7, a relatively conserved genotype constellation (I5-R1-C1-M1-A8-N1-T7-E1-H1) was found for the other 9 genes in most pig RVA strains. VP1, VP2, VP3, NSP2, NSP4, and NSP5 genes of porcine RVAs belonged to genotype 1, which is shared with human Wa-like RVAs. However, for most of these gene segments, pig strains clustered distantly from human Wa-like RVAs, indicating that viruses from both species have entered different evolutionary paths. However, VP1, VP2, and NSP3 genes of some archival human strains were moderately related to pig strains. Phylogenetic analysis of the VP6, NSP1, and NSP3 genes, as well as amino acid analysis of the antigenic regions of VP7, further confirmed this evolutionary segregation. The present results also indicate that the species barrier is less strict for pig P[6] strains but that chances for successful spread of these strains in the human population are hampered by the better adaptation of pig RVAs to pig enterocytes. However, future surveillance of pig and human RVA strains is warranted. IMPORTANCE Rotaviruses are an important cause of diarrhea in many species, including pigs and humans. Our understanding of the evolutionary relationship between rotaviruses from both species is limited by the lack of genomic data on pig strains. In this study, recent and ancient Belgian pig rotavirus isolates were sequenced, and their evolutionary relationship with human Wa-like strains was investigated

  17. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking.

    PubMed

    Monti, Jaime M; Jantos, Héctor

    2008-01-01

    Based on electrophysiological, neurochemical and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) and dopamine (DA) function to promote waking (W) and to inhibit slow wave sleep (SWS) and/or rapid-eye-movement sleep (REMS). Serotonergic neurons of the dorsal raphe nucleus (DRN) fire at a steady rate during W, decrease their firing during SWS and virtually cease activity during REMS. On the other hand, DA cells in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. Available evidence tends to indicate that during W and REMS an increase of burst firing activity of DA neurons occurs together with an enhanced release of DA in the VTA, the nucleus accumbens and several forebrain structures. Recently, DA neurons were characterised in the ventral periaqueductal grey matter (VPAG) that express Fos protein during W. Lesioning of these cells resulted in an increase of SWS and REMS, which led to the proposal that VPAG DA neurons may play a role in the promotion of W. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94,253), 5-HT(2A/2C) (DOI, DOM) and 5-HT(3) (m-chlorophenylbiguanide) receptors increases W and reduces SWS and REMS. On the other hand, microdialysis perfusion or direct infusion of 8-OH-DPAT or flesinoxan into the DRN, where somatodendritic 5-HT(1A) receptors are located, significantly increases REMS. Systemic administration of the selective DA D(1) receptor agonist SKF 38393 induces behavioural arousal together with an increase of W and a reduction of sleep. On the other hand, injection of a DA D(2) receptor agonist (apomorphine, bromocriptine, quinpirole) gives rise to biphasic effects, such that low doses reduce W and augment SWS and REMS

  18. Syntheses, structures, characterizations and charge-density matching of novel amino-templated uranyl selenates

    SciTech Connect

    Ling Jie; Sigmon, Ginger E.; Burns, Peter C.

    2009-02-15

    Five hybrid organic-inorganic uranyl selenates have been synthesized, characterized and their structures have been determined. The structure of (C{sub 2}H{sub 8}N){sub 2}[(UO{sub 2}){sub 2}(SeO{sub 4}){sub 3}(H{sub 2}O)] (EthylAUSe) is monoclinic, P2{sub 1}, a=8.290(1), b=12.349(2), c=11.038(2) A, {beta}=104.439(4){sup o}, V=1094.3(3) A{sup 3}, Z=2, R{sub 1}=0.0425. The structure of (C{sub 7}H{sub 10}N){sub 2}[(UO{sub 2})(SeO{sub 4}){sub 2}(H{sub 2}O)]H{sub 2}O (BenzylAUSe) is orthorhombic, Pna2{sub 1}, a=24.221(2), b=11.917(1), c=7.4528(7) A, V=2151.1(3) A{sup 3}, Z=4, R{sub 1}=0.0307. The structure of (C{sub 2}H{sub 10}N{sub 2})[(UO{sub 2})(SeO{sub 4}){sub 2}(H{sub 2}O)](H{sub 2}O){sub 2} (EDAUSe) is monoclinic, P2{sub 1}/c, a=11.677(2), b=7.908(1), c=15.698(2) A, {beta}=98.813(3){sup o}, V=1432.4(3) A{sup 3}, Z=4, R{sub 1}=0.0371. The structure of (C{sub 6}H{sub 22}N{sub 4})[(UO{sub 2})(SeO{sub 4}){sub 2}(H{sub 2}O)](H{sub 2}O) (TETAUSe) is monoclinic, P2{sub 1}/n, a=13.002(2), b=7.962(1), c=14.754(2) A, {beta}=114.077(2){sup o}, V=1394.5(3) A{sup 3}, Z=4, R{sub 1}=0.0323. The structure of (C{sub 6}H{sub 21}N{sub 4})[(UO{sub 2})(SeO{sub 4}){sub 2}(HSeO{sub 4})] (TAEAUSe) is monoclinic, P2{sub 1}/m, a=9.2218(6), b=12.2768(9), c=9.4464(7) A, {beta}=116.1650(10){sup o}, V=959.88(12) A{sup 3}, Z=2, R{sub 1}=0.0322. The inorganic structural units in these compounds are composed of uranyl pentagonal bipyramids and selenate tetrahedra. In each case, tetrahedra link bipyramids through vertex-sharing, resulting in chain or sheet topologies. The charge-density matching principle is discussed relative to the orientations of the organic molecules between the inorganic structural units. - Graphical abstract: The structures of five new inorganic-organic hybrid uranyl selenates present new structural topologies based upon chains and sheets of uranyl pentagonal bipyramids and selenate tetrahedra.

  19. Fragmentation of doubly-protonated peptide ion populations labeled by H/D exchange with CD3OD

    NASA Astrophysics Data System (ADS)

    Herrmann, Kristin A.; Kuppannan, Krishna; Wysocki, Vicki H.

    2006-03-01

    Doubly-protonated bradykinin (RPPGFSPFR) and an angiotensin III analogue (RVYIFPF) were subjected to hydrogen/deuterium (H/D) exchange with CD3OD in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. A bimodal distribution of deuterium incorporation was present for bradykinin after H/D exchange for 90 s at a CD3OD pressure of 4 × 10-7 Torr, indicating the existence of at least two distinct populations. Bradykinin ion populations corresponding to 0-2 and 5-11 deuteriums (i.e., D0, D1, D2, D5, D6, D7, D8, D9, D10, and D11) were each monoisotopically selected and fragmented via sustained off-resonance irradiation (SORI) collision-induced dissociation (CID). The D0-D2 ion populations, which correspond to the slower exchanging population, consistently require lower SORI amplitude to achieve a similar precursor ion survival yield as the faster-reacting (D5-D11) populations. These results demonstrate that conformation/protonation motif has an effect on fragmentation efficiency for bradykinin. Also, the partitioning of the deuterium atoms into fragment ions suggests that the C-terminal arginine residue exchanges more rapidly than the N-terminal arginine. Total deuterium incorporation in the b1/y8 and b2/y7 ion pairs matches very closely the theoretical values for all ion populations studied, indicating that the ions of a complementary pair are likely formed during the same fragmentation event, or that no scrambling occurs upon SORI. Deuterium incorporation into the y1/a8 pseudo-ion pair does not closely match the expected theoretical values. The other peptide, doubly-protonated RVYIFPF, has a trimodal distribution of deuterium incorporation upon H/D exchange with CD3OD at a pressure of 1 × 10-7 Torr for 600 s, indicating at least three distinct ion populations. After 90 s of H/D exchange where at least two distinct populations are detected, the D0-D7 ion populations were monoisotopically selected and fragmented via SORI-CID over a range of SORI

  20. Affinity of the highly preorganized ligand PDA (1,10-phenanthroline-2,9-dicarboxylic acid) for large metal ions of higher charge. A crystallographic and thermodynamic study of PDA complexes of thorium(IV) and the uranyl(VI) ion.

    PubMed

    Dean, Nolan E; Hancock, Robert D; Cahill, Christopher L; Frisch, Mark

    2008-03-17

    The hydrothermal synthesis and structures of [UO2(PDA)] (1) and [Th(PDA)2(H2O)2].H2O (2) (PDA = 1,10-phenanthroline-2,9-dicarboxylic acid) are reported. 1 is orthorhombic, Pnma, a = 11.1318(7) A, b = 6.6926(4) A, c = 17.3114(12) A, V = 1289.71(14), Z = 4, R = 0.0313; 2 is triclinic, P1, a = 7.6190(15) A, b = 10.423(2) A, c = 17.367(4) A, alpha = 94.93(3) degrees , beta = 97.57(3) degrees , gamma = 109.26(3) degrees , V = 1278.3(4) A (3), Z = 2, R = 0.0654. The local geometry around the U in 1 is a pentagonal bipyramid with the two uranyl oxygens occupying the apical positions. The donor atoms in the plane comprise the four donor atoms from the PDA ligand (average U-N = 2.558 and U-O = 2.351 A) with the fifth site occupied by a bridging carboxylate oxygen from a neighboring UO2/PDA individual. The PDA ligand in 1 is exactly planar, with the U lying in the plane of the ligand. The latter planarity, as well as the near-ideal U-O and U-N bond lengths, and O-U-N and N-U-N bond angles within the chelate rings of 1 suggest that PDA binds to the uranyl cation in a low-strain manner. In 2, there are two PDA ligands bound to the Th (average Th-N = 2.694 and Th-O = 2.430 A) as well as two water molecules (Th-O = 2.473 and 2.532 A) to give the Th a coordination number of 10. The PDA ligands in 2 are bowed, with the Th lying out of the plane of the ligand. Molecular mechanics calculations suggest that the distortion of the PDA ligands in 2 arises because of steric crowding. UV spectroscopic studies of solutions containing 1:1 ratios of PDA and Th(4+) in 0.1 M NaClO4 at 25 degrees C indicate that log K1 for the Th(4+)/PDA complex is 25.7(9). The latter result confirms the previous prediction that complexes of PDA with metal ions of higher charge and an ionic radius of about 1.0 A such as Th(IV) would have remarkably high log K1 values with PDA. The origins of this very high stability are discussed in terms of a synergy between the pyridyl and the carboxylate donor groups of PDA

  1. Synthesis, Hematological, Biochemical, and Neurotoxicity Screening of Some Mannich Base Hydrochlorides

    PubMed Central

    Lahbib, Karima; Aouani, Iyadh; Abdelmelek, Hafedh; Touil, Soufiane

    2013-01-01

    Background: Mannich bases are an important class of compounds in medicinal chemistry with a wide spectrum of biological activities, however, knowledge on their toxicity is limited. Materials and Methods: Two Mannich base hydrochlorides 1a (2-thienyl-β-dimethylaminoethyl ketone hydrochloride) and 1b (β-dimethylaminopropiophenone hydrochloride) were synthesized and characterized on the basis of their infrared and nuclear magnetic resonance spectral data. The potential effects of the synthesized compounds (5 mg/kg, i.p, during 30 days) on relative weight, hematological parameters, biochemical parameters, and neurotoxicity were tested using male Wistar rat. Results: The results showed that compound 1b alters body weight on the first 10 days (182%, P < 0.01) and on the last 10 days (107%, P < 0.01) of treatment. The same treatment decreases food intake (P < 0.01) and increases water intake (P < 0.05). Both compounds induced a deficit on rotarod test manifested by a decrease of grasping time (1a: 65.33%, P < 0.01; 1b: 60.55%, P < 0.01) and fall time (1a: 59.75%, P < 0.01; 1b: 56.81%, P < 0.01) only on the last day of training. Moreover, Mannich base 1b decreases the liver relative weight (22.24%, P < 0.01). It was also observed that both products decrease the total serum cholesterol (Ch) levels (1a: 52.87%, P < 0.01; 1b: 64.70%, P < 0.01). Interestingly, compounds 1a and 1b affect hematological parameters manifested by an increase of the number of white blood cells (1a: 32.29%, P < 0.05; 1b: 20.64%, P < 0.05) and red blood cells (RBCs) (1a: 12.57%, P < 0.05; 1b: 20.11%, P < 0.05), an increase of red cell hemoglobin concentration (1a: 10.48%, P < 0.05; 1b: 16.12%, P < 0.05) and of the volume occupied by RBCs or hematocrit (1a: 18.28%, P < 0.05; 1b: 15.56%, P < 0.05), and an increase of the number of platelets (1a: 16.80%, P < 0.05; 1b: 39.96%, P < 0.05) accompanied by a decrease in hemoglobin level only with the compound 1a (7.41%, P < 0.05). Conclusion: These results

  2. Critical analysis of results after chimney EVAR raises cause for concern

    PubMed Central

    Scali, Salvatore T.; Feezor, Robert J.; Chang, Catherine K.; Waterman, Alyson L.; Berceli, Scott A.; Huber, Thomas S.; Beck, Adam W.

    2014-01-01

    Objective Chimney” techniques used to extend landing zones for endovascular aortic repair(chEVAR) have been increasingly reported; however, concerns about durability and patency remain. The purpose of this analysis was to examine mid-term outcomes of chEVAR. Methods All patients at the University of Florida treated with chEVAR were reviewed. Major adverse events(MAEs) were recorded and defined as any chimney stent thrombosis, type 1a endoleak in follow-up, reintervention, 30-day/in-hospital death and/or ≥ 25% decrease in estimated glomerular filtration rate after discharge. Primary end-points included chimney stent patency and freedom from MAE. Secondary end-points included complications and long-term survival. Results From 2008–2012, 41 patients[age ± standard deviation(SD); 73±8; male 66%(N=27)] were treated with a total of 76 chimney stents(renal, N=51; superior mesenteric artery, N=16 celiac artery, N=9) for a variety of indications: juxtarenal, 42%(N=17, 1 rupture); suprarenal, 17%(N=7), and thoracoabdominal aneurysm, 17%(N=7); aortic anastomotic pseudoaneurysm, 15%(N=6; 3 ruptures), type 1a endoleak after EVAR, 7%(N=3), and atheromatous disease, 2%(N=1). Two patients had a single target vessel abandoned due to cannulation failure and one had a type 1a endoleak at case completion(technical success = 93%). Intraoperative complications occurred in 7 patients(17%), including graft maldeployment with unplanned mesenteric chimney(N=2) and access vessel injury requiring repair(N=5). Major postoperative complications developed in 20%(N=8). 30-day and in-hospital mortality were 5%(N=2) and 7%(N=3), respectively. At median follow-up of 18.2(range 1.4–41.5) months, 28 of 33(85%) patients with available postoperative imaging experienced stabilization or reduction of AAA sac diameters. Nine(32%) patients developed endoleak at some point during follow-up [type 1a, 7%(N=3); type 2, 10%(N=4); indeterminate, 7%(N=3)], and one patient underwent open, surgical

  3. Did the Moon have a dipolar field?

    NASA Astrophysics Data System (ADS)

    Boutin, D.; Arkani-Hamed, J.

    2012-12-01

    Did the Moon have a dipolar core field? Daniel Boutin1 (dboutin003@sympatico.ca) Jafar Arkani-Hamed2 (jafar@physics.utoronto.ca) 1Earth and Planetary Sciences, McGill University, Montreal, QC, H3A-2A7, Canada 2Physics, University of Toronto, Toronto, ON M5S 1A7, Canada The lack of a global scale magnetic field at present and the observed strong magnetic anomalies of the Moon suggest that the magnetic source bodies have been magnetized in the past. The origin of the magnetizing field is poorly understood. Several scenarios have been proposed including a strong core dynamo [1] and the external origin due to giant impacts such as the enhancement of an existing weak field by impact-generated plasmas or a transient field possibly generated during the impacts [2,3]. It is also possible that the existing field was not very strong but the source bodies are highly magnetic [4]. Here we test the hypothesis that the magnetizing field was of internal origin using two sets of data: the 150 degree spherical harmonic representation of the lunar crustal field by Purucker [5] and the raw magnetic data acquired by the Lunar Prospector magnetometer. Although 17 isolated magnetic anomalies are easily identified on the basis of the spherical harmonic representation, we model only 10 anomalies because of the lack of sufficient raw data over others. The isolated magnetic anomalies allow us to model each anomaly by a simple uniformly magnetized elliptical source body. We model the radial component of the magnetic field following the procedure adopted by Boutin and Arkani-Hamed [6] for the martian magnetic anomalies, and determine the three components of the magnetization vector. Seven out of 10 anomalies result in consistent source bodies obtained using the two sets of data. Assuming that each of the source bodies is magnetized by a dipole core field, the paleomagnetic pole of the Moon is determined on the basis of the corresponding magnetization vector. The resulting paleomagnetic pole

  4. New open-framework in the uranyl vanadates A{sub 3}(UO{sub 2}){sub 7}(VO{sub 4}){sub 5}O (A=Li, Ag) with intergrowth structure between A(UO{sub 2}){sub 4}(VO{sub 4}){sub 3} and A{sub 2}(UO{sub 2}){sub 3}(VO{sub 4}){sub 2}O

    SciTech Connect

    Obbade, S. Renard, C.; Abraham, F.

    2009-03-15

    New uranyl vanadates A{sub 3}(UO{sub 2}){sub 7}(VO{sub 4}){sub 5}O (M=Li (1), Na (2), Ag (3)) have been synthesized by solid-state reaction and their structures determined from single-crystal X-ray diffraction data for 1 and 3. The tetragonal structure results of an alternation of two types of sheets denoted S for {sub {infinity}}{sup 2}[UO{sub 2}(VO{sub 4}){sub 2}]{sup 4-} and D for {sub {infinity}}{sup 2}[(UO{sub 2}){sub 2}(VO{sub 4}){sub 3}]{sup 5-} built from UO{sub 6} square bipyramids and connected through VO{sub 4} tetrahedra to {sub {infinity}}{sup 1}[U(3)O{sub 5}-U(4)O{sub 5}]{sup 8-} infinite chains of edge-shared U(3)O{sub 7} and U(4)O{sub 7} pentagonal bipyramids alternatively parallel to a- and b-axis to construct a three-dimensional uranyl vanadate arrangement. It is noticeable that similar {sub {infinity}}[UO{sub 5}]{sup 4-} chains are connected only by S-type sheets in A{sub 2}(UO{sub 2}){sub 3}(VO{sub 4}){sub 2}O and by D-type sheets in A(UO{sub 2}){sub 4}(VO{sub 4}){sub 3}, thus A{sub 3}(UO{sub 2}){sub 7}(VO{sub 4}){sub 5}O appears as an intergrowth structure between the two previously reported series. The mobility of the monovalent ion in the mutually perpendicular channels created in the three-dimensional arrangement is correlated to the occupation rate of the sites and by the geometry of the different sites occupied by either Na, Ag or Li. Crystallographic data: 293 K, Bruker X8-APEX2 X-ray diffractometer equipped with a 4 K CCD detector, MoK{alpha}, {lambda}=0.71073 A, tetragonal symmetry, space group P4-bar m2, Z=1, full-matrix least-squares refinement on the basis of F{sup 2}; 1,a=7.2794(9) A, c=14.514(4) A, R1=0.021 and wR2=0.048 for 62 parameters with 782 independent reflections with I{>=}2{sigma}(I); 3, a=7.2373(3) A, c=14.7973(15) A, R1=0.041 and wR2=0.085 for 60 parameters with 1066 independent reflections with I{>=}2{sigma}(I). - Abstract: A view of the three-dimensional structure of Li{sub 3}(UO{sub 2}){sub 7}(VO{sub 4}){sub 5}O

  5. Batievaite-(Y), Y2Ca2Ti[Si2O7]2(OH)2(H2O)4, a new mineral from nepheline syenite pegmatite in the Sakharjok massif, Kola Peninsula, Russia

    NASA Astrophysics Data System (ADS)

    Lyalina, L. M.; Zolotarev, A. A.; Selivanova, E. A.; Savchenko, Ye. E.; Krivovichev, S. V.; Mikhailova, Yu. A.; Kadyrova, G. I.; Zozulya, D. R.

    2016-05-01

    Batievaite-(Y), Y2Ca2Ti[Si2O7]2(OH)2(H2O)4, is a new mineral found in nepheline syenite pegmatite in the Sakharjok alkaline massif, Western Keivy, Kola Peninsula, Russia. The pegmatite mainly consists of nepheline, albite, alkali pyroxenes, amphiboles, biotite and zeolites. Batievaite-(Y) is a late-pegmatitic or hydrothermal mineral associated with meliphanite, fluorite, calcite, zircon, britholite-group minerals, leucophanite, gadolinite-subgroup minerals, titanite, smectites, pyrochlore-group minerals, zirkelite, cerianite-(Ce), rutile, behoite, ilmenite, apatite-group minerals, mimetite, molybdenite, and nickeline. Batievaite-(Y) is pale-cream coloured with white streak and dull, greasy or pearly luster. Its Mohs hardness is 5-5.5. No cleavage or parting was observed. The measured density is 3.45(5) g/cm3. Batievaite-(Y) is optically biaxial positive, α 1.745(5), β 1.747(5), γ 1.752(5) (λ 589 nm), 2V meas. = 60(5)°, 2V calc. = 65°. Batievaite-(Y) is triclinic, space group P-1, a 9.4024(8), b 5.5623(5), c 7.3784(6) Å, α 89.919(2), β 101.408(2), γ 96.621(2)°, V 375.65(6) Å3 and Z = 1. The eight strongest lines of the X-ray powder diffraction pattern [d(Å)(I)(hkl)] are: 2.991(100)(11-2), 7.238(36)(00-1), 3.061(30)(300), 4.350(23)(0-1-1), 9.145(17)(100), 4.042(16)(11-1), 2.819(16)(3-10), 3.745(13)(2-10). The chemical composition determined by electron probe microanalysis (EPMA) is (wt.%): Nb2O5 2.25, TiO2 8.01, ZrO2 2.72, SiO2 29.96, Al2O3 0.56, Fe2O3 0.43, Y2O3 11.45, La2O3 0.22, Ce2O3 0.33, Nd2O3 0.02, Gd2O3 0.07, Dy2O3 0.47, Er2O3 1.07, Tm2O3 0.25, Yb2O3 2.81, Lu2O3 0.45, CaO 24.98, MnO 1.31, MgO 0.01, Na2O 1.13, K2O 0.02, F 2.88, Cl 0.19, H2O 6.75 (determined on the basis of crystal structure data), O = (F,Cl) -1.25, total 97.09 wt.%. The empirical formula based on the EPMA and single-crystal structure analyses is (Y0.81Ca0.65Mn0.15Zr0.12Yb0.11Er0.04Fe3+ 0.04Ce0.02Dy0.02Lu0.02La0.01Tm0.01)Σ2.00((H2O)0.75Ca0.70□0.55)Σ2.00Ca2.00(□0.61Na0.25( H2O

  6. Formation of Metal Clusters or Nitrogen-Bridged Adducts by Reaction of a Bis(amino)stannylene with Halides of Two-Valent Transition Metals.

    PubMed

    Veith, Michael; Müller, Alice; Stahl, Lothar; Nötzel, Martin; Jarczyk, Maria; Huch, Volker

    1996-06-19

    When the cyclic bis(amino)stannylene Me(2)Si(NtBu)(2)Sn is allowed to react with metal halides MX(2) (M = Cr, Fe, Co, Zn; X = Cl, Br [Zn]) adducts of the general formula [Me(2)Si(NtBu)(2)Sn.MX(2)](n) are obtained. The compounds are generally dimeric (n = 2) except the ZnBr(2) adduct, which is monomeric in benzene. The crystal structures of [Me(2)Si(NtBu)(2)Sn.CoCl(2)](2) (triclinic, space group &Pmacr;1; a = 8.620(9) Å, b = 9.160(9) Å, c = 12.280(9) Å, alpha = 101.2(1) degrees, beta = 97.6(1) degrees, gamma = 105.9(1) degrees, Z = 1) and of [Me(2)Si(NtBu)(2)Sn.ZnCl(2)](2) (monoclinic, space group P2(1)/c; a = 8.156(9) Å, b = 16.835(12) Å, c = 13.206(9) Å, beta = 94.27(6) degrees, Z = 2) were determined by X-ray diffraction techniques. The two compounds form similar polycyclic, centrosymmetrical assemblies of metal atoms bridged by chlorine or nitrogen atoms. While in the case of the cobalt compound Co is pentacoordinated by three chlorine and two nitrogen atoms, in the zinc derivative Zn is almost tetrahedrally coordinated by three chlorine atoms and one nitrogen atom. The iron derivative [Me(2)Si(NtBu)(2)Sn.FeCl(2)](2) seems to be isostructural with the cobalt compound as can be deduced from the crystal data (triclinic, a = 8.622(7) Å, b = 9.158(8) Å, c = 12.353(8) Å, alpha = 101.8(1) degrees, beta = 96.9(1) degrees, gamma = 105.9(1) degrees, Z = 1). If NiBr(2), PdCl(2), or PtCl(2) is combined with the stannylene, the reaction product is totally different: 4 equiv of the stannylene are coordinating per metal halide, forming the molecular compound [Me(2)Si(NtBu)(2)Sn](4)MX(2), which crystallizes with half a mole of benzene per molecular formula. The crystal structures of [Me(2)Si(NtBu)(2)Sn](4).NiBr(2).(1)/(2)C(6)H(6) (tetragonal, space group I4(1)/a, a = b = 43.86(4) Å, c = 14.32(2) Å, Z = 16) and [Me(2)Si(NtBu)(2)Sn](4).PdCl(2).(1)/(2)C(6)H(6) (tetragonal, space group I4(1)/a, a = b = 43.99(4) Å, c = 14.318(14) Å, Z = 16) reveal the two compounds to