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Sample records for 1a fig 1b

  1. CYP1B1: a unique gene with unique characteristics.

    PubMed

    Faiq, Muneeb A; Dada, Rima; Sharma, Reetika; Saluja, Daman; Dada, Tanuj

    2014-01-01

    CYP1B1, a recently described dioxin inducible oxidoreductase, is a member of the cytochrome P450 superfamily involved in the metabolism of estradiol, retinol, benzo[a]pyrene, tamoxifen, melatonin, sterols etc. It plays important roles in numerous physiological processes and is expressed at mRNA level in many tissues and anatomical compartments. CYP1B1 has been implicated in scores of disorders. Analyses of the recent studies suggest that CYP1B1 can serve as a universal/ideal cancer marker and a candidate gene for predictive diagnosis. There is plethora of literature available about certain aspects of CYP1B1 that have not been interpreted, discussed and philosophized upon. The present analysis examines CYP1B1 as a peculiar gene with certain distinctive characteristics like the uniqueness in its chromosomal location, gene structure and organization, involvement in developmentally important disorders, tissue specific, not only expression, but splicing, potential as a universal cancer marker due to its involvement in key aspects of cellular metabolism, use in diagnosis and predictive diagnosis of various diseases and the importance and function of CYP1B1 mRNA in addition to the regular translation. Also CYP1B1 is very difficult to express in heterologous expression systems, thereby, halting its functional studies. Here we review and analyze these exceptional and startling characteristics of CYP1B1 with inputs from our own experiences in order to get a better insight into its molecular biology in health and disease. This may help to further understand the etiopathomechanistic aspects of CYP1B1 mediated diseases paving way for better research strategies and improved clinical management.

  2. MISR Level 1A CCD, 1B1, 1B2, and Browse Products

    Atmospheric Science Data Center

    2013-04-01

    ... 1B1 Radiance, CCD Science;  Local Mode Data (Hi-Res Target Scenes): Terrain/Ellipsoid-Projected Radiance, 1B1 Radiance ... transform fix. ROI Image Matching improvements to blunder detection algorithm and to Image Coordinate Correction. New ancillary ...

  3. Comparison of the Isw1a, Isw1b, and Isw2 nucleosome disrupting activities.

    PubMed

    Krajewski, Wladyslaw A

    2013-10-08

    The three Saccharomyces cerevisiae ISWI chromatin remodeling complexes, Isw1a, Isw1b, and Isw2, are implicated in the regularization of arrayed nucleosomes and regulation of gene activity. Although Isw1a and Isw1b are based on the same catalytic unit, in general, their functions in vivo do not overlap. To better understand the structural consequences of these complexes, we compared the putative nucleosome disrupting activities of the purified Isw1a, Isw1b, and Isw2. To account for the putative effects of nucleosomal environment, we employed reconstituted dinucleosomes in which the histone octamers were specifically positioned by the 146 base pair high-affinity nucleosome sequence "601". We have compared the MNase and deoxyribonuclease I protection patterns of remodeled nucleosome templates and evaluated the nucleosome destabilizing abilities of the Isw1a/b and Isw2 using restriction endonucleases. Although the Isw2 showed little evidence of nucleosome disassembly, the Isw1b remodeled dinucleosomes exhibited some common features with the ySwi-Snf remodeling products. The nuclease digestion data suggest that Isw1a can also promote ATP-dependent distortion of nucleosome structure, although less efficiently than the Isw1b complex.

  4. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms

    PubMed Central

    Hartkoorn, Ruben C; San Kwan, Wai; Shallcross, Victoria; Chaikan, Ammara; Liptrott, Neill; Egan, Deirdre; Enrique Salcedo Sora, J; James, Chloe E; Gibbons, Sara; Bray, Pat G; Back, David J; Khoo, Saye H; Owen, Andrew

    2016-01-01

    OATP1B1 and OATP1B3 are major hepatic drug transporters whilst OATP1A2 is mainly located in the brain but is also located in liver and several other organs. These transporters affect the distribution and clearance of many endo- and xenobiotics and have been reported to have functional SNPs. We have assessed the substrate specificites of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir. SLCO1A2, SLCO1B1 and SLCO1B3 were cloned, verified and used to generate cRNA for use in the Xenopus laevis oocyte transport system. Using the oocyte system, antiretrovirals were tested for their substrate specificities. Plasma samples (n=349) from the Liverpool therapeutic drug monitoring registry were genotyped for SNPs in SLCO1A2, SLCO1B1 and SLCO1B3 and associations between SNPs and lopinavir plasma concentrations were analysed. Antiretroviral protease inhibitors, but not non-nucleoside reverse transcriptase inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3. Furthermore, ritonavir was not an inhibitor of OATP1B1. The 521T>C polymorphism in SLCO1B1 was significantly associated with higher lopinavir plasma concentrations. No associations were observed with functional variants of SLCO1A2 and SLCO1B3. These data add to our understanding of the factors that contribute to variability in plasma concentrations of protease inhibitors. Further studies are now required to confirm the association of SLCO1B1 521T>C with lopinavir plasma concentrations and to assess the influence of other polymorphisms in the SLCO family. PMID:20051929

  5. Biosynthesis of the major brain gangliosides GD1a and GT1b.

    PubMed

    Sturgill, Elizabeth R; Aoki, Kazuhiro; Lopez, Pablo H H; Colacurcio, Daniel; Vajn, Katarina; Lorenzini, Ileana; Majić, Senka; Yang, Won Ho; Heffer, Marija; Tiemeyer, Michael; Marth, Jamey D; Schnaar, Ronald L

    2012-10-01

    Gangliosides-sialylated glycosphingolipids-are the major glycoconjugates of nerve cells. The same four structures-GM1, GD1a, GD1b and GT1b-comprise the great majority of gangliosides in mammalian brains. They share a common tetrasaccharide core (Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-1'Cer) with one or two sialic acids on the internal galactose and zero (GM1 and GD1b) or one (GD1a and GT1b) α2-3-linked sialic acid on the terminal galactose. Whereas the genes responsible for the sialylation of the internal galactose are known, those responsible for terminal sialylation have not been established in vivo. We report that St3gal2 and St3gal3 are responsible for nearly all the terminal sialylation of brain gangliosides in the mouse. When brain ganglioside expression was analyzed in adult St3gal1-, St3gal2-, St3gal3- and St3gal4-null mice, only St3gal2-null mice differed significantly from wild type, expressing half the normal amount of GD1a and GT1b. St3gal1/2-double-null mice were no different than St3gal2-single-null mice; however, St3gal2/3-double-null mice were >95% depleted in gangliosides GD1a and GT1b. Total ganglioside expression (lipid-bound sialic acid) in the brains of St3gal2/3-double-null mice was equivalent to that in wild-type mice, whereas total protein sialylation was reduced by half. St3gal2/3-double-null mice were small, weak and short lived. They were half the weight of wild-type mice at weaning and displayed early hindlimb dysreflexia. We conclude that the St3gal2 and St3gal3 gene products (ST3Gal-II and ST3Gal-III sialyltransferases) are largely responsible for ganglioside terminal α2-3 sialylation in the brain, synthesizing the major brain gangliosides GD1a and GT1b.

  6. Zebrafish ambra1a and ambra1b Knockdown Impairs Skeletal Muscle Development

    PubMed Central

    Skobo, Tatjana; Benato, Francesca; Grumati, Paolo; Meneghetti, Giacomo; Cianfanelli, Valentina; Castagnaro, Silvia; Chrisam, Martina; Di Bartolomeo, Sabrina; Bonaldo, Paolo; Cecconi, Francesco; Valle, Luisa Dalla

    2014-01-01

    The essential role of autophagy in muscle homeostasis has been clearly demonstrated by phenotype analysis of mice with muscle-specific inactivation of genes encoding autophagy-related proteins. Ambra1 is a key component of the Beclin 1 complex and, in zebrafish, it is encoded by two paralogous genes, ambra1a and ambra1b, both required for normal embryogenesis and larval development. In this study we focused on the function of Ambra1, a positive regulator of the autophagic process, during skeletal muscle development by means of morpholino (MO)-mediated knockdown and compared the phenotype of zebrafish Ambra1-depleted embryos with that of Ambra1gt/gt mouse embryos. Morphological analysis of zebrafish morphant embryos revealed that silencing of ambra1 impairs locomotor activity and muscle development, as well as myoD1 expression. Skeletal muscles in ATG-morphant embryos displayed severe histopathological changes and contained only small areas of organized myofibrils that were widely dispersed throughout the cell. Double knockdown of ambra1a and ambra1b resulted in a more severe phenotype whereas defects were much less evident in splice-morphants. The morphants phenotypes were effectively rescued by co-injection with human AMBRA1 mRNA. Together, these results indicate that ambra1a and ambra1b are required for the correct development and morphogenesis of skeletal muscle. PMID:24922546

  7. Biosynthesis of the major brain gangliosides GD1a and GT1b

    PubMed Central

    Sturgill, Elizabeth R; Aoki, Kazuhiro; Lopez, Pablo HH; Colacurcio, Daniel; Vajn, Katarina; Lorenzini, Ileana; Majić, Senka; Yang, Won Ho; Heffer, Marija; Tiemeyer, Michael; Marth, Jamey D; Schnaar, Ronald L

    2012-01-01

    Gangliosides—sialylated glycosphingolipids—are the major glycoconjugates of nerve cells. The same four structures—GM1, GD1a, GD1b and GT1b—comprise the great majority of gangliosides in mammalian brains. They share a common tetrasaccharide core (Galβ1–3GalNAcβ1-4Galβ1-4Glcβ1-1′Cer) with one or two sialic acids on the internal galactose and zero (GM1 and GD1b) or one (GD1a and GT1b) α2–3-linked sialic acid on the terminal galactose. Whereas the genes responsible for the sialylation of the internal galactose are known, those responsible for terminal sialylation have not been established in vivo. We report that St3gal2 and St3gal3 are responsible for nearly all the terminal sialylation of brain gangliosides in the mouse. When brain ganglioside expression was analyzed in adult St3gal1-, St3gal2-, St3gal3- and St3gal4-null mice, only St3gal2-null mice differed significantly from wild type, expressing half the normal amount of GD1a and GT1b. St3gal1/2-double-null mice were no different than St3gal2-single-null mice; however, St3gal2/3-double-null mice were >95% depleted in gangliosides GD1a and GT1b. Total ganglioside expression (lipid-bound sialic acid) in the brains of St3gal2/3-double-null mice was equivalent to that in wild-type mice, whereas total protein sialylation was reduced by half. St3gal2/3-double-null mice were small, weak and short lived. They were half the weight of wild-type mice at weaning and displayed early hindlimb dysreflexia. We conclude that the St3gal2 and St3gal3 gene products (ST3Gal-II and ST3Gal-III sialyltransferases) are largely responsible for ganglioside terminal α2-3 sialylation in the brain, synthesizing the major brain gangliosides GD1a and GT1b. PMID:22735313

  8. Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis

    PubMed Central

    Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

    2016-01-01

    Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39–45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing. PMID:27217144

  9. Adenovirus E1A/E1B Transformed Amniotic Fluid Cells Support Human Cytomegalovirus Replication

    PubMed Central

    Krömmelbein, Natascha; Wiebusch, Lüder; Schiedner, Gudrun; Büscher, Nicole; Sauer, Caroline; Florin, Luise; Sehn, Elisabeth; Wolfrum, Uwe; Plachter, Bodo

    2016-01-01

    The human cytomegalovirus (HCMV) replicates to high titers in primary human fibroblast cell cultures. A variety of primary human cells and some tumor-derived cell lines do also support permissive HCMV replication, yet at low levels. Cell lines established by transfection of the transforming functions of adenoviruses have been notoriously resistant to HCMV replication and progeny production. Here, we provide first-time evidence that a permanent cell line immortalized by adenovirus type 5 E1A and E1B (CAP) is supporting the full HCMV replication cycle and is releasing infectious progeny. The CAP cell line had previously been established from amniotic fluid cells which were likely derived from membranes of the developing fetus. These cells can be grown under serum-free conditions. HCMV efficiently penetrated CAP cells, expressed its immediate-early proteins and dispersed restrictive PML-bodies. Viral DNA replication was initiated and viral progeny became detectable by electron microscopy in CAP cells. Furthermore, infectious virus was released from CAP cells, yet to lower levels compared to fibroblasts. Subviral dense bodies were also secreted from CAP cells. The results show that E1A/E1B expression in transformed cells is not generally repressive to HCMV replication and that CAP cells may be a good substrate for dense body based vaccine production. PMID:26848680

  10. Subtyping of Y-chromosomal haplogroup E-M78 (E1b1b1a) by SNP assay and its forensic application.

    PubMed

    Caratti, S; Gino, S; Torre, C; Robino, C

    2009-07-01

    The continual discovery of new single-nucleotide polymorphisms (SNPs) has led to an increased resolution of the Y chromosome phylogeny. Some of these Y-SNPs have shown to be restricted to small geographical regions and therefore may prove useful in the forensic field as tools for the prediction of population of origin of unknown casework samples. Here, we describe a system for the molecular dissection of haplogroup E-M78 (E1b1b1a), consisting of multiplex polymerase chain reaction and minisequencing of M78 and nine population-informative Y-SNPs (M148, M224, V12, V13, V19, V22, V27, V32, V65) in a single reaction. Sensitivity and admixture studies demonstrated that the SNP protocol allows robust genotyping from as little as 50 pg of male DNA, even in the presence of 500-fold amounts of female DNA. In order to evaluate the suitability of E1b1b1a, subhaplogrouping for population-of-origin prediction, the distribution of E-M78 and its derived variants was determined in an Italian population sample (n = 326).

  11. The HTR1A and HTR1B receptor genes influence stress-related information processing.

    PubMed

    Mekli, Krisztina; Payton, Antony; Miyajima, Fabio; Platt, Hazel; Thomas, Emma; Downey, Darragh; Lloyd-Williams, Kathryn; Chase, Diana; Toth, Zoltan G; Elliott, Rebecca; Ollier, William E; Anderson, Ian M; Deakin, J F William; Bagdy, Gyorgy; Juhasz, Gabriella

    2011-01-01

    The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. We investigated the possible association between depression and anxiety scores and SNPs within the HTR1A and HTR1B genes in a population sample (n=1387). There was no direct SNP-phenotype association, but in interaction with recent stressful life events rs6295 G, rs878567 T alleles and rs6296 C alleles were associated with significantly higher symptom scores. A subset of control subjects (n=101) took part in a computerised face emotion processing task. Healthy rs6295 GG carriers did not show an affective bias to perceive more negative emotions but reacted more quickly to fearful faces. Thus we conclude that the serotonin-1A receptor conveys vulnerability to these psychiatric disorders by modulating threat-related information processing. Our results extend previous findings of an interaction between stressful life events and the serotonin transporter gene to two other genes in the serotonergic pathway and emphasise the possible role of increased threat-related information processing as an intermediate phenotype.

  12. Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo.

    PubMed

    Lee, Sook Y; Brem, Jürgen; Pettinati, Ilaria; Claridge, Timothy D W; Gileadi, Opher; Schofield, Christopher J; McHugh, Peter J

    2016-05-10

    Bacterial metallo-β-lactamases (MBLs) are involved in resistance to β-lactam antibiotics including cephalosporins. Human SNM1A and SNM1B are MBL superfamily exonucleases that play a key role in the repair of DNA interstrand cross-links, which are induced by antitumour chemotherapeutics, and are therefore targets for cancer chemosensitization. We report that cephalosporins are competitive inhibitors of SNM1A and SNM1B exonuclease activity; both the intact β-lactam and their hydrolysed products are active. This discovery provides a lead for the development of potent and selective SNM1A and SNM1B inhibitors.

  13. Digenic Inheritance of Early-Onset Glaucoma: CYP1B1, a Potential Modifier Gene

    PubMed Central

    Vincent, Andrea L.; Billingsley, Gail; Buys, Yvonne; Levin, Alex V.; Priston, Megan; Trope, Graham; Williams-Lyn, Donna; Héon, Elise

    2002-01-01

    “Early-onset glaucoma” refers to genetically heterogeneous conditions for which glaucoma manifests at age 5–40 years and for which only a small subset is molecularly characterized. We studied the role of MYOC, CYP1B1, and PITX2 in a population (n=60) affected with juvenile or early-onset glaucoma from the greater Toronto area. By a combination of single-strand conformation polymorphism and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) of the 60 individuals, CYP1B1 mutations were detected in 3 (5%) of the 60 individuals, and no PITX2 mutations were detected. The range of phenotypic expression associated with MYOC and CYP1B1 mutations was greater than expected. MYOC mutations included cases of juvenile glaucoma with or without pigmentary glaucoma and mixed-mechanism glaucoma. CYP1B1 mutations involved cases of juvenile open-angle glaucoma, as well as cases of congenital glaucoma. The study of a family with autosomal dominant glaucoma showed the segregation of both MYOC and CYP1B1 mutations with disease; however, in this family, the mean age at onset of carriers of the MYOC mutation alone was 51 years (range 48–64 years), whereas carriers of both the MYOC and CYP1B1 mutations had an average age at onset of 27 years (range 23–38 years) (P=.001). This work emphasizes the genetic heterogeneity of juvenile glaucoma and suggests, for the first time, that (1) congenital glaucoma and juvenile glaucoma are allelic variants and (2) the spectrum of expression of MYOC and CYP1B1 mutations is greater than expected. We also propose that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway. PMID:11774072

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

    PubMed

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

    2016-01-01

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

  15. Expression Profile of CYP1A1 and CYP1B1 Enzymes in Colon and Bladder Tumors

    PubMed Central

    Androutsopoulos, Vasilis P.; Spyrou, Ioannis; Ploumidis, Achilles; Papalampros, Alexandros Eystathios; Kyriakakis, Michalis; Delakas, Demetrios; Spandidos, Demetrios A.; Tsatsakis, Aristidis M.

    2013-01-01

    Background The cytochrome P450 CYP1A1 and CYP1B1 enzymes are involved in carcinogenesis via activation of pro-carcinogenic compounds to carcinogenic metabolites. CYP1A1 and CYP1B1 have shown elevated levels in human tumors as determined by qRT-PCR and immunohistochemical studies. However studies that have examined CYP1 expression by enzyme activity assays are limited. Results In the current study the expression of CYP1A1 and CYP1B1 was investigated in a panel of human tumors of bladder and colorectal origin by qRT-PCR and enzyme activity assays. The results demonstrated that 35% (7/20) of bladder tumors and 35% (7/20) of colon tumors overexpressed active CYP1 enzymes. CYP1B1 mRNA was overexpressed in 65% and 60% of bladder and colon tumors respectively, whereas CYP1A1 was overexpressed in 65% and 80% of bladder and colon tumors. Mean mRNA levels of CYP1B1 and CYP1A1 along with mean CYP1 activity were higher in bladder and colon tumors compared to normal tissues (p<0.05). Statistical analysis revealed CYP1 expression levels to be independent of TNM status. Moreover, incubation of tumor microsomal protein in 4 bladder and 3 colon samples with a CYP1B1 specific antibody revealed a large reduction (72.5 ± 5.5 % for bladder and 71.8 ± 7.2% for colon) in catalytic activity, indicating that the activity was mainly attributed to CYP1B1 expression. Conclusions The study reveals active CYP1 overexpression in human tumors and uncovers the potential use of CYP1 enzymes and mainly CYP1B1 as targets for cancer therapy. PMID:24358191

  16. Cytochrome P450 1B1, a novel chemopreventive target for benzo[a]pyrene-initiated human esophageal cancer.

    PubMed

    Wen, Xia; Walle, Thomas

    2007-02-08

    Esophageal cancer is common worldwide, with poor prognosis. Smoking, including exposure to polyaromatic hydrocarbons like benzo[a]pyrene (BaP), is a major risk factor. In human esophageal HET-1A cells, we found that time-dependent BaP-DNA binding was associated with upregulation of CYP1B1, but not CYP1A1, mRNA and protein. The dietary flavonoid 5,7-dimethoxyflavone significantly inhibited BaP-DNA binding and down-regulated BaP-induced CYP1B1 mRNA and protein. 3',4'-Dimethoxyflavone was an even more potent inhibitor of CYP1B1 expression, while resveratrol had no effect. Thus, dietary methoxylated flavones inhibited BaP-induced CYP1B1 transcription in a cell-specific manner and hold promise as chemopreventive agents in esophageal carcinogenesis.

  17. Association between CYP1A2 and CYP1B1 Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis

    PubMed Central

    Liu, Zhi-Zhong; Xie, Jian-Jun; Wang, Wei; Du, Ya-Ping; Chen, Yu; Si, Hui-Qiang; Liu, Qing; Wu, Li-Xia; Wei, Wu

    2014-01-01

    Background The previous published data on the association between CYP1A2*F (rs762551), CYP1B1 Leu432Val (rs1056836), Asn453Ser (rs180040), and Arg48Gly (rs10012) polymorphisms and colorectal cancer risk remained controversial. Methodology/Principal Findings The purpose of this study is to evaluate the role of CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly genotypes in colorectal cancer susceptibility. We performed a meta-analysis on all the eligible studies that provided 5,817 cases and 6,544 controls for CYP1A2*F (from 13 studies), 9219 cases and 10406 controls for CYP1B1 Leu432Val (from 12 studies), 6840 cases and 7761 controls for CYP1B1 Asn453Ser (from 8 studies), and 4302 cases and 4791 controls for CYP1B1Arg48Gly (from 6 studies). Overall, no significant association was found between CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly and colorectal cancer risk when all the eligible studies were pooled into the meta-analysis. And in the subgroup by ethnicity and source of controls, no evidence of significant association was observed in any subgroup analysis. Conclusions/Significance In summary, this meta-analysis indicates that CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly polymorphisms do not support an association with colorectal cancer, and further studies are needed to investigate the association. In addition, our work also points out the importance of new studies for CYP1A2*F polymorphism in Asians, because high heterogeneity was found (dominant model: I2 = 81.3%; heterozygote model: I2 = 79.0). PMID:25115775

  18. BmRobo1a and BmRobo1b control axon repulsion in the silkworm Bombyx mori.

    PubMed

    Li, Xiao-Tong; Yu, Qi; Zhou, Qi-Sheng; Zhao, Xiao; Liu, Zhao-Yang; Cui, Wei-Zheng; Liu, Qing-Xin

    2016-02-15

    The development of the nervous system is based on the growth and connection of axons, and axon guidance molecules are the dominant regulators during this course. Robo, as the receptor of axon guidance molecule Slit, plays a key role as a conserved repellent cue for axon guidance during the development of the central nervous system. However, the function of Robo in the silkworm Bombyx mori is unknown. In this study, we cloned two novel robo genes in B. mori (Bmrobo1a and Bmrobo1b). BmRobo1a and BmRobo1b lack an Ig and a FNIII domain in the extracellular region and the CC0 and CC2 motifs in the intracellular region. BmRobo1a and BmRobo1b were colocalized with BmSlit in the neuropil. Knock-down of Bmrobo1a and Bmrobo1b by RNA interference (RNAi) resulted in abnormal development of axons. Our results suggest that BmRobo1a and BmRobo1b have repulsive function in axon guidance, even though their structures are different from Robo1 of other species.

  19. Structural and functional differences between KRIT1A and KRIT1B isoforms: a framework for understanding CCM pathogenesis.

    PubMed

    Francalanci, Floriana; Avolio, Maria; De Luca, Elisa; Longo, Dario; Menchise, Valeria; Guazzi, Paolo; Sgrò, Francesco; Marino, Marco; Goitre, Luca; Balzac, Fiorella; Trabalzini, Lorenza; Retta, Saverio Francesco

    2009-01-15

    KRIT1 is a disease gene responsible for Cerebral Cavernous Malformations (CCM). It encodes for a protein containing distinct protein-protein interaction domains, including three NPXY/F motifs and a FERM domain. Previously, we isolated KRIT1B, an isoform characterized by the alternative splicing of the 15th coding exon and suspected to cause CCM when abnormally expressed. Combining homology modeling and docking methods of protein-structure and ligand binding prediction with the yeast two-hybrid assay of in vivo protein-protein interaction and cellular biology analyses we identified both structural and functional differences between KRIT1A and KRIT1B isoforms. We found that the 15th exon encodes for the distal beta-sheet of the F3/PTB-like subdomain of KRIT1A FERM domain, demonstrating that KRIT1B is devoid of a functional PTB binding pocket. As major functional consequence, KRIT1B is unable to bind Rap1A, while the FERM domain of KRIT1A is even sufficient for this function. Furthermore, we found that a functional PTB subdomain enables the nucleocytoplasmic shuttling of KRIT1A, while its alteration confers a restricted cytoplasmic localization and a dominant negative role to KRIT1B. Importantly, we also demonstrated that KRIT1A, but not KRIT1B, may adopt a closed conformation through an intramolecular interaction involving the third NPXY/F motif at the N-terminus and the PTB subdomain of the FERM domain, and proposed a mechanism whereby an open/closed conformation switch regulates KRIT1A nuclear translocation and interaction with Rap1A in a mutually exclusive manner. As most mutations found in CCM patients affect the KRIT1 FERM domain, the new insights into the structure-function relationship of this domain may constitute a useful framework for understanding molecular mechanisms underlying CCM pathogenesis.

  20. 5-HT 1A/1B receptor-mediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice.

    PubMed

    Monaca, Christelle; Boutrel, Benjamin; Hen, René; Hamon, Michel; Adrien, Joëlle

    2003-05-01

    Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT(1A) and 5-HT(1B) types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT(1A) or 5-HT(1B) receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT(1A) or 5-HT(1B) receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT(1B)-/- mice, but not in 5-HT(1A)-/- mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT(1A) antagonist WAY 100635, but only partially with the 5-HT(1B) antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT(1A) receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT(1A) antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs.

  1. Characterisation of iron regulatory protein 1A and 1B in the blood-feeding copepod Lepeophtheirus salmonis.

    PubMed

    Tröße, Christiane; Kongshaug, Heidi; Dondrup, Michael; Nilsen, Frank

    2015-10-01

    During its parasitic life stages, the marine ectoparasitic copepod Lepeophtheirus salmonis ingests large amounts of host blood, which contains high amounts of iron. Iron is an essential micronutrient, but also toxic in high dosages, and blood-feeding parasites like the salmon louse must thus possess an efficient system to handle the excess iron. Iron regulatory protein 1 and 2 (IRP1 and IRP2) are known to play crucial roles in this process, by regulating several proteins involved in iron transport and storage, depending on the cellular iron concentration. To gain knowledge about the regulation of the iron metabolism in salmon lice, two IRP homologues (LsIRP1A and LsIRP1B) were identified by sequence and predicted structure similarity to known IRPs in other species. In situ hybridisation revealed that LsIRP1A and LsIRP1B mRNAs were expressed in the ovaries, oviducts and vitellogenic oocytes of adult females. Transcription levels of LsIRP1A and LsIRP1B mRNAs did not differ significantly between the different developmental stages of the salmon louse. Adults in the absence of blood as a feed source had decreased levels of LsIRP1A, but not LsIRP1B mRNA. RNA binding experiments indicated the presence of functioning IRP in salmon lice. In order to explore the biological functions of LsIRP1A and LsIRP1B, the mRNAs of both proteins were knocked down by RNA interference (RNAi) in preadult females. The knockdown was confirmed by qRT-PCR. LsIRP1B knockdown lice produced less offspring than control lice due to slightly shorter egg strings and had decreased levels of transcripts involved in egg development. Knockdown of both LsIRP1A and LsIRP1B caused increased expression of a salmon louse Ferritin (LsFer). These results confirm that salmon lice have two IRP1 homologues, LsIRP1A and LsIRP1B, and might suggest a function in cellular iron regulation in the reproductive organs and eggs.

  2. Yeast Isw1a and Isw1b exhibit similar nucleosome mobilization capacities for mononucleosomes, but differently mobilize dinucleosome templates.

    PubMed

    Krajewski, Wladyslaw A

    2014-03-15

    Nucleosome remodeling studies in vitro have primarily focused on the use of mononucleosome templates, which, however, can provide only limited information on how nucleosome mobilization occurs in the context of chromatin, in which internucleosome interactions might influence remodeling. We tried to evaluate whether nucleosome mobilization by yeast Isw1a, Isw1b and Isw2 could be affected by neighboring nucleosomes. We compared mono- and dinucleosomes positioned by the '601' sequence, the studied constructs contain variation in linker length between nucleosomes and variation in the length of flanking sequences. The data characterizing the remodeling were based on gel retardation of the mono and dinucleosomes, keeping in mind the observation that the relative position of the nucleosome will change the mobility of the complex in well defined ways. We found that Isw1a, Isw1b and Isw2 process nucleosomes differently whether they exist as mononucleosomes or dinucleosomes, such as, the Isw1a and Isw1b nucleosome repositioning patterns, which were very similar for mononucleosomes, appeared to be profoundly different in case of dinucleosome templates. We also examined the DNase I protection patterns of remodeled mono- and dinucleosomes. The data suggest that nucleosome mobilizing activity of Isw1a, Isw1b and Isw2 complexes could be significantly influenced by neighboring nucleosomes.

  3. 39 CFR 3010.13 - Proceedings for Type 1-A and Type 1-B rate adjustment filings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... rate adjustments are found consistent with applicable law by the Commission, they may take effect... with applicable law by the Commission, the Postal Service will submit an amended notice of rate... 39 Postal Service 1 2012-07-01 2012-07-01 false Proceedings for Type 1-A and Type 1-B...

  4. Flood monitoring and damage assessment in Thailand using multi-temporal HJ-1A/1B and MODIS images

    NASA Astrophysics Data System (ADS)

    Zhou, S. L.; Zhang, W. C.

    2017-02-01

    Flood is one of the most serious natural disasters in South Asia. How to monitor floods and assess damage caused is the most urgent problem for the government and disaster experts. With the advances of remote sensing, images acquired before the beginning of disaster to the very end or after the disaster from Earth-observing satellites benefit the decision making for reduction and protection of disaster dramatically. By using multi-temporal HJ-1A/1B and MODIS remote sensing data, applicability of different algorithms for flood monitoring and damage assessing was investigated in 2011 Thailand floods. Three different algorithms were adopted to monitor flood disaster events with water indices. Comparisons on the flood disaster monitoring and damage assessing by means of HJ-1A/1B and MODIS images suggested that multi-temporal HJ-1A/1B is much useful for the purpose, which demonstrated with the analysis of the thresholds estimated and problems in data post-processing. The variations of the inundated areas in the process of 2011 Thailand floods revealed were presented in this paper, and the damage caused by flooding was evaluated in three aspects, the population in the inundated region, the inundated information of different provinces and land use areas. Compared with MODIS, HJ-1A/1B images can provide more rapid and accurate flood extent and damage assessment for the disaster prevention, damage mitigation and disaster relief.

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

    PubMed

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

    2004-10-01

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

  6. Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

    PubMed Central

    Doucet-Beaupré, Hélène; Gilbert, Catherine; Profes, Marcos Schaan; Chabrat, Audrey; Pacelli, Consiglia; Giguère, Nicolas; Rioux, Véronique; Deng, Qiaolin; Laguna, Ariadna; Ericson, Johan; Perlmann, Thomas; Ang, Siew-Lan; Cicchetti, Francesca; Parent, Martin; Trudeau, Louis-Eric; Lévesque, Martin

    2016-01-01

    The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson’s disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein+ inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. PMID:27407143

  7. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner.

    PubMed

    Wang, Tao; Chen, Keshi; Zeng, Xiaoming; Yang, Jianguo; Wu, Yun; Shi, Xi; Qin, Baoming; Zeng, Lingwen; Esteban, Miguel Angel; Pan, Guangjin; Pei, Duanqing

    2011-12-02

    Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenome to an embryonic-like state. Vitamin C enhances the reprogramming process, but the underlying mechanisms are unclear. Here we show that the histone demethylases Jhdm1a/1b are key effectors of somatic cell reprogramming downstream of vitamin C. We first observed that vitamin C induces H3K36me2/3 demethylation in mouse embryonic fibroblasts in culture and during reprogramming. We then identified Jhdm1a/1b, two known vitamin-C-dependent H3K36 demethylases, as potent regulators of reprogramming through gain- and loss-of-function approaches. Furthermore, we found that Jhdm1b accelerates cell cycle progression and suppresses cell senescence during reprogramming by repressing the Ink4/Arf locus. Jhdm1b also cooperates with Oct4 to activate the microRNA cluster 302/367, an integral component of the pluripotency machinery. Our results therefore reveal a role for H3K36me2/3 in cell fate determination and establish a link between histone demethylases and vitamin-C-induced reprogramming.

  8. Immunogenicity of an inactivated Chinese bovine viral diarrhea virus 1a (BVDV 1a) vaccine cross protects from BVDV 1b infection in young calves.

    PubMed

    Wang, Wei; Shi, Xinchuan; Wu, Yongwang; Li, Xiaoxin; Ji, Ye; Meng, Qingsen; Zhang, Shucheng; Wu, Hua

    2014-08-15

    Bovine viral diarrhea virus (BVDV) 1a and 1b strains are the predominant subgenotypes in China. Because of the genetic and antigenic variability among different BVDV strains, a vaccine effective in one region may fail to protect against infections caused by different virus strains in another region. No BVDV vaccine developed with the predominant strains in China are available. In this study, the immunogenicity of an inactivated Chinese BVDV 1a NM01 vaccine strain was evaluated by challenging with a Chinese BVDV 1b JL strain. Ten 2-4-month-old calves were intramuscularly vaccinated with a single dose of the vaccine strain and boosted with same dose three weeks after the first vaccination, with five mock immunized calves serving as a control group. The average titer of neutralization antibody to BVDV 1a and BVDV 1b of immunized calves reached 1:410 and 1:96, respectively, at 21 days post the second vaccination. Twenty-one days post the second vaccination, all calves were challenged with strain JL. The clinical signs, such as the temperature and leukopenia of the immunized calves and viral shedding, were significantly less than the mock immunized calves after challenging with the virulent BVDV 1b strain, indicating that the BVDV 1a vaccine strain elicited efficacious protection against the endemic BVDV 1b strain in China. To the best of our knowledge, this is the first report of an inactivated BVDV vaccine which demonstrated effective cross-protection against BVDV type 1b infection in China.

  9. Antidepressant effects on serotonin 1A/1B receptors in the rat brain using a gene x environment model.

    PubMed

    Shrestha, Stal Saurav; Pine, Daniel S; Luckenbaugh, David A; Varnäs, Katarina; Henter, Ioline D; Innis, Robert B; Mathé, Aleksander A; Svenningsson, Per

    2014-01-24

    A gene-environment (GxE) interaction is implicated in both the pathophysiology and treatment of major depressive disorder (MDD). This study modeled the effects of genetic vulnerability by using the Flinders sensitive line (FSL), a rat model of depression and its control counterpart-the Flinders resistant line (FRL). The effects of environmental vulnerability (e.g., early-life stress) were modeled by using maternal separation. Rats (n=105) were drawn from four groups reflecting experimental crossing of strain (FSL vs. FRL) and early-life stress (high vs. low) to assess the effects of two antidepressants (escitalopram or nortriptyline) compared to vehicle. Quantitative in vitro autoradiography was performed using [(125)I]MPPI (5-HT1A) and [(125)I]CYP (5-HT1B) in prefrontal cortex (PFC) and hippocampus. Stringent, Bonferroni-corrected statistical analyses showed significant strain-by-rearing-by-treatment (three-way) interactions in PFC 5-HT1A and hippocampal 5-HT1B receptors. Either vulnerability reduced serotonergic binding; no additive effects were associated with the two vulnerabilities. Both antidepressants increased hippocampal 5-HT1B receptor binding; however, only nortriptyline selectively increased PFC 5-HT1A receptor binding. Taken together, our findings demonstrate that antidepressant effects on the serotonergic system are shaped by a GxE interaction that depends on antidepressant class and brain region.

  10. Polymorphic variation of CYP1A1 and CYP1B1 genes in a Haryana population.

    PubMed

    Giri, Shiv Kumar; Yadav, Anita; Kumar, Anil; Dev, Kapil; Gulati, Sachin; Gupta, Ranjan; Aggarwal, Neeraj; Gautam, Sanjeev Kumar

    2013-12-01

    Cytochrome P450 (CYP) 1A1 and CYP1B1 are important phase I xenobiotic metabolizing enzymes involved in the metabolism of numbers of toxins, endogenous hormones, and pharmaceutical drugs. Polymorphisms in these phase I genes can alter enzyme activity and are known to be associated with cancer susceptibility related to environmental toxins and hormone exposure. Their genotypes may also display ethnicity-dependent population frequencies. The present study was aimed to determine the frequencies of commonly known functional polymorphisms of CYP1A1 and CYP1B1 genes in a Haryana state population of North India. The allelic frequency of CYP1A1 polymorphism m1 (MspI) was 29.65% and m2 (Ile(462)Val) was 24.85%. The frequency of CYP1B1 polymorphism m1 (Val(432)Leu) was 45.85% and m2 (Asn(453)Ser) was 16.2%. We observed inter- and intra-ethnic variation in the frequency distribution of these polymorphisms. Analysis of polymorphisms in these genes might help in predicting the risk of cancer. Our results emphasize the need for more such studies in high-risk populations.

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

    PubMed Central

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

    2009-01-01

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

  12. ASD and Genetic Associations with Receptors for Oxytocin and Vasopressin—AVPR1A, AVPR1B, and OXTR

    PubMed Central

    Francis, Sunday M.; Kim, Soo-Jeong; Kistner-Griffin, Emily; Guter, Stephen; Cook, Edwin H.; Jacob, Suma

    2016-01-01

    Background: There are limited treatments available for autism spectrum disorder (ASD). Studies have reported significant associations between the receptor genes of oxytocin (OT) and vasopressin (AVP) and ASD diagnosis, as well as ASD-related phenotypes. Researchers have also found the manipulation of these systems affects social and repetitive behaviors, core characteristics of ASD. Consequently, research involving the oxytocin/vasopressin pathways as intervention targets has increased. Therefore, further examination into the relationship between these neuropeptides and ASD was undertaken. In this study, we examined associations between variants in the receptor genes of vasopressin (AVPR1A, AVPR1B), oxytocin (OXTR), and ASD diagnosis along with related subphenotypes. Methods: Probands were assessed using Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and clinical DSM-IV-TR criteria. Single nucleotide polymorphisms (SNPs) in AVPR1B and OXTR, and microsatellites in AVPR1A were genotyped in ~200 families with a proband with ASD. Family-based association testing (FBAT) was utilized to determine associations between variants and ASD. Haplotypes composed of OXTR SNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations. Results: Using the additive inheritance model in FBAT we found associations between AVPR1B SNPs (rs28632197, p = 0.005, rs35369693, p = 0.025) and diagnosis. As in other studies, OXTR rs2268493 (p = 0.050) was associated with diagnosis. rs2268493 was also associated with ASD subphenotypes of social withdrawal (p = 0.013) and Insistence on Sameness (p = 0.039). Further analyses demonstrated that the haplotype, rs2254298–rs2268493 was found to be significantly associated with diagnosis (A-T; p = 0.026). FBAT was also used to analyze AVPR1A microsatellites (RS1 and RS3). Both length variants were found to be associated with restrictive, repetitive behaviors, but not overall diagnosis

  13. Protein expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 in young patients with oral squamous cell carcinoma.

    PubMed

    Kaminagakura, E; Caris, A; Coutinho-Camillo, C; Soares, F A; Takahama-Júnior, A; Kowalski, L P

    2016-06-01

    The purpose of this study was to evaluate the expression of the enzymes involved in the biotransformation of tobacco and alcohol. A study group of 41 young patients (≤40 years old) with oral squamous cell carcinoma (OSCC) was compared to 59 control subjects (≥50 years old) with tumours of similar clinical stages and topographies. The immunohistochemical expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 was evaluated using the tissue microarray technique. There was a predominance of males, smokers, and alcohol drinkers in both groups. Most tumours were located in the tongue (43.9% vs. 50.8%), were well-differentiated (63.4% vs. 56.6%), and were in clinical stages III or IV (80.5% vs. 78.0%). No difference was observed in the expression of CYP1A1, ALDH1A1, or ALDH2 between the two groups. CYP1A1 and ALDH2 protein expression had no influence on the prognosis. The immunoexpression of CYP1B1 was significantly higher in the control group than in the young group (P<0.001). The 5-year relapse-free survival was better in patients with CYP1B1 overexpression vs. protein underexpression (64% vs. 25%; P<0.05), regardless of age. ALDH1A1 expression improved relapse-free survival in young patients. These results suggest a lower risk of recurrence with increased metabolism of carcinogens by CYP1B1. Further studies involving other genes and proteins are necessary to complement the results of this research.

  14. Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c.

    PubMed

    Lei, K J; Shelly, L L; Lin, B; Sidbury, J B; Chen, Y T; Nordlie, R C; Chou, J Y

    1995-01-01

    Glycogen storage disease (GSD) type 1, which is caused by the deficiency of glucose-6-phosphatase (G6Pase), is an autosomal recessive disease with heterogenous symptoms. Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-catalytic unit model proposes that five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), and glucose (1d) translocases. Conversely, the conformation-substrate-transport model suggests that G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities. We have recently demonstrated that mutations in the G6Pase catalytic unit cause GSD type 1a. To elucidate whether mutations in the G6Pase gene are responsible for other GSD type 1 subgroups, we characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP patients. Our results show that the G6Pase gene of GSD type 1b and 1c patients is normal, consistent with the translocase-catalytic unit model of G6Pase catalysis. However, a mutation in exon 2 that converts an Arg at codon 83 to a Cys (R83C) was identified in both G6Pase alleles of the type 1aSP patient. The R83C mutation was also demonstrated in one homozygous and five heterogenous GSD type 1a patients, indicating that type 1aSP is a misclassification of GSD type 1a. We have also analyzed the G6Pase gene of seven additional type 1a patients and uncovered two new mutations that cause GSD type 1a.

  15. HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b

    PubMed Central

    2012-01-01

    Background The impact of viral subtype on the rate of sustained virological response (SVR) to antiviral therapy in patients chronically infected with hepatitis C genotype 1 subtype 1a and 1b has not been extensively investigated. The aim of this study is to determine whether the HCV genotype 1 subtypes 1a and 1b respond differently to treatment with PEGylated interferon (PEG-IFN) plus ribavirin. Methods For 48 weeks, 388 “naïve”genotype 1 patients were treated weekly with PEG-IFN α-2a or PEG-INF α-2b combined with daily ribavirin (1000–1200 mg/day). The numbers of patients in whom HCV-RNA was undetectable were compared after 4 (rapid virological response, RVR), 12 (early virological response, EVR), and 48 (end treatment virological response, ETR) weeks of treatment as well as 24 weeks after the last treatment (sustained virological response, SVR). Results The rate of SVR was higher in subtype 1a patients than subtype 1b patients (55% vs. 43%; p < 0.02). Multiple logistic regression analysis showed that infection with genotype 1a (odds ratio(OR) : 1.8; 95% confidence interval (CI): 1.4 to 4.1), age < 50 years (OR:7.0; 95% CI 1.1 to 21.2), alanine aminotransferase level (ALT)<100 IU/ml (OR:2.1; 95% CI: 1.3 to3.5), HCV-RNA < 5.6 log10 IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9) and fibrosis score < S3 (OR: 3.8; 95% CI:3.2 to 7.4), were all independent predictors of SVR. Conclusion Dual antiviral therapy is more effective against HCV subtype 1a than against subtype 1b and this difference is independent of other factors that may favour viral clearance. Trial registration ClinicalTrials.gov Identifier: NCT01342003 PMID:23157720

  16. Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice

    PubMed Central

    Nishio, Miki; Sugimachi, Keishi; Goto, Hiroki; Wang, Jia; Morikawa, Takumi; Miyachi, Yosuke; Takano, Yusuke; Hikasa, Hiroki; Itoh, Tohru; Suzuki, Satoshi O.; Kurihara, Hiroki; Aishima, Shinichi; Leask, Andrew; Sasaki, Takehiko; Nakano, Toru; Nishina, Hiroshi; Nishikawa, Yuji; Sekido, Yoshitaka; Nakao, Kazuwa; Shin-ya, Kazuo; Mimori, Koshi; Suzuki, Akira

    2016-01-01

    Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs. PMID:26699479

  17. Identification, characterization, and quantitative expression analysis of rainbow trout myostatin-1a and myostatin-1b genes.

    PubMed

    Garikipati, Dilip K; Gahr, Scott A; Rodgers, Buel D

    2006-09-01

    Myostatin is a potent negative regulator of skeletal muscle growth. Although several cDNA clones have been characterized in different vertebrates, the genomic organization and bioactivity of non-mammalian homologs have not. The intron/exon organization and promoter subsequence analysis of two rainbow trout myostatin genes, rtMSTN-1a and rtMSTN-1b (formerly 1 and 2 respectively), as well as a quantitative assessment of their embryonic, larval, and adult tissue expression profiles are reported herein. Each gene was similarly organized into three exons of 490, 368, and 1600 bp for MSTN-1a and 486, 386, and 1419 bp for MSTN-1b. Comparative mapping of coding regions from several vertebrate myostatin genes revealed a common organization between species, including conserved pre-mRNA splice sites; the first among the fishes and the second across all vertebrate species. In silico subsequence analysis of the promoter regions identified E-boxes and other putative myogenic response elements. However, the number and diversity of elements were considerably less than those found in mammalian promoters or in the recently characterized zebrafish MSTN-2 gene. A quantitative analysis of the embryonic expression profile for both genes indicates that rtMSTN-1a expression is consistently greater than that of rtMSTN-1b and neither gene is significantly expressed throughout gastrulation. Expression of both steadily increases fourfold during somitogenesis and subsides as this period ends. After eyeing, however, rtMSTN-1a mRNA levels ultimately rise 20-fold by day 49 and peak before hatching and yolk sac absorption (YSA). Levels of rtMSTN-1b rise similarly, but do not peak before YSA. An analysis of adult (2-year-old fish) tissue expression indicates that both transcripts are present in most tissues although levels are highest in brain, testes, eyes, muscle, and surprisingly spleen. These studies suggest that strong selective pressures have preserved the genomic organization of myostatin

  18. CYP1A1 and CYP1B1 genetic polymorphisms and uterine leiomyoma risk in Chinese women

    PubMed Central

    Ye, Yi; Cheng, Xiao; Luo, Hai-Bo; Liu, Li; Li, Ying-Bi

    2008-01-01

    Purpose The aim of the study was to evaluate the association of CYP1A1 and CYP1B1 polymorphisms with uterine leiomyoma in Chinese women. Methods We investigated 100 women with clinically diagnosed uterine leiomyoma and 110 healthy normal subjects from Chinese women. The genetic distribution of two CYP1A1 polymorphisms at MspI, Ile462Val and four CYP1B1 polymorphisms at Arg48Gly, Ala119Ser, Leu432Val, Asp449Asp were analyzed by polymerase chain reaction–restriction fragment length polymorphism and DNA sequencing method. Results All the SNPs showed polymorphisms in Chinese women. The genotype A/G and the allele G on Ile462Val was significantly different between uterine leiomyoma patients and controls (P < 0.05). Conclusion These results suggest that the genotype of CYP1A1 Ile462Val was associated with the increased risk of uterine leiomyomas in Chinese women. PMID:18763031

  19. Characterization of hERG1a and hERG1b potassium channels-a possible role for hERG1b in the I (Kr) current.

    PubMed

    Larsen, Anders Peter; Olesen, Søren-Peter; Grunnet, Morten; Jespersen, Thomas

    2008-09-01

    I (Kr) is the fast component of the delayed rectifier potassium currents responsible for the repolarization of the cardiac muscle. The molecular correlate underlying the I (Kr) current has been identified as the hERG1 channel. Recently, two splice variants of the hERG1 alpha-subunit, hERG1a and hERG1b, have been shown to be co-expressed in human cardiomyocytes. In this paper, we present the electrophysiological characterization of hERG1a, hERG1b, and co-expressed hERG1a/b channels in a mammalian expression system using the whole-cell patch clamp technique. We also quantified the messenger RNA (mRNA) levels of hERG1a and hERG1b in human cardiac tissue, and based on the expressed ratios, we evaluated the resulting currents in Xenopus laevis oocytes. Compared to hERG1a channels, activation was faster for both hERG1b and hERG1a/b channels. The deactivation kinetics was greatly accelerated in the presence of hERG1b, whereas no difference in the time constant of inactivation was observed. The voltage-dependent recovery from inactivation was also similar. However, the time constant of recovery from inactivation was significantly faster for hERG1b channels compared to hERG1a and hERG1a/b. Quantification of hERG1a and hERG1b mRNA in the human heart showed that hERG1b mRNA constitutes, on average, 19% in the right atrium and 12% in the left ventricle of the total hERG1 mRNA. Expression of the observed ratios of hERG1a to hERG1b in X. laevis oocytes showed that these ratios are indeed sufficient to change the deactivation phenotype markedly. The present work suggests that hERG1b is likely to play a role in the formation of the native I (Kr) current.

  20. Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene.

    PubMed

    Hadjighassem, Mahmoud R; Galaraga, Kimberly; Albert, Paul R

    2011-01-01

    The serotonin-1A (5-HT1A) receptor functions as a pre-synaptic autoreceptor in serotonin neurons that regulates their activity, and is also widely expressed on non-serotonergic neurons as a post-synaptic heteroreceptor to mediate serotonin action. The 5-HT1A receptor gene is strongly repressed by a dual repressor element (DRE), which is recognized by two proteins: Freud-1/CC2D1A and another unknown protein. Here we identify mouse Freud-2/CC2D1B as the second repressor of the 5-HT1A-DRE. Freud-2 shares 50% amino acid identity with Freud-1, and contains conserved structural domains. Mouse Freud-2 bound specifically to the rat 5-HT1A-DRE adjacent to, and partially overlapping, the Freud-1 binding site. By supershift assay using nuclear extracts from L6 myoblasts, Freud-2-DRE complexes were distinguished from Freud-1-DRE complexes. Freud-2 mRNA and protein were detected throughout mouse brain and peripheral tissues. Freud-2 repressed 5-HT1A promoter-reporter constructs in a DRE-dependent manner in non-neuronal (L6) or 5-HT1A-expressing neuronal (NG108-15, RN46A) cell models. In NG108-15 cells, knockdown of Freud-2 using a specific short-interfering RNA reduced endogenous Freud-2 protein levels and decreased Freud-2 bound to the 5-HT1A-DRE as detected by chromatin immunoprecipitation assay, but increased 5-HT1A promoter activity and 5-HT1A protein levels. Taken together, these data show that Freud-2 is the second component that, with Freud-1, mediates dual repression of the 5-HT1A receptor gene at the DRE.

  1. Heterozygous mutation of eEF1A1b resulted in spermatogenesis arrest and infertility in male tilapia, Oreochromis niloticus

    PubMed Central

    Chen, Jinlin; Jiang, Dongneng; Tan, Dejie; Fan, Zheng; Wei, Yingying; Li, Minghui; Wang, Deshou

    2017-01-01

    Eukaryotic elongation factor 1 alpha (eEF1A) is an essential component of the translational apparatus. In the present study, eEF1A1b was isolated from the Nile tilapia. Real-time PCR and Western blot revealed that eEF1A1b was expressed highly in the testis from 90 dah (days after hatching) onwards. In situ hybridization and immunohistochemistry analyses showed that eEF1A1b was highly expressed in the spermatogonia of the testis. CRISPR/Cas9 mediated mutation of eEF1A1b resulted in spermatogenesis arrest and infertility in the F0 XY fish. Consistently, heterozygous mutation of eEF1A1b (eEF1A1b+/−) resulted in an absence of spermatocytes at 90 dah, very few spermatocytes, spermatids and spermatozoa at 180 dah, and decreased Cyp11b2 and serum 11-ketotestosterone level at both stages. Further examination of the fertilization capacity of the sperm indicated that the eEF1A1b+/− XY fish were infertile due to abnormal spermiogenesis. Transcriptomic analyses of the eEF1A1b+/− testis from 180 dah XY fish revealed that key elements involved in spermatogenesis, steroidogenesis and sperm motility were significantly down-regulated compared with the control XY. Transgenic overexpression of eEF1A1b rescued the spermatogenesis arrest phenotype of the eEF1A1b+/− testis. Taken together, our data suggested that eEF1A1b is crucial for spermatogenesis and male fertility in the Nile tilapia. PMID:28266557

  2. Utility of Oatp1a/1b-knockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein.

    PubMed

    Higgins, J William; Bao, Jing Q; Ke, Alice B; Manro, Jason R; Fallon, John K; Smith, Philip C; Zamek-Gliszczynski, Maciej J

    2014-01-01

    Although organic anion transporting polypeptide (OATP)-mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and ≤74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice; distributional attenuation was less notable in kidney, brain, cardiac, and skeletal muscle. Knockin of OATP1B1 or OATP1B3 partially restored control clearance, volume, and bioavailability values (24%-142% increase, ≤47% increase, and ≤77% decrease vs. knockout, respectively), such that knockin pharmacokinetic profiles were positioned between knockout and wild-type mice. Consistent with liver-specific humanization, only hepatic drug distribution was partially restored (1.3- to 6.5-fold increase vs. knockout). Exposure and liver distribution changes in OATP1B1-humanized versus knockout mice predicted the clinical impact of OATP1B1 on oral exposure and contribution to human hepatic uptake of statins within 1.7-fold, but only after correcting for human/humanized mouse liver relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).

  3. Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells: trimodal distribution of Japanese population according to induction of CYP1B1 mRNA by environmental dioxins.

    PubMed

    Toide, Kenji; Yamazaki, Hiroshi; Nagashima, Rikako; Itoh, Keisuke; Iwano, Shunsuke; Takahashi, Yoshiki; Watanabe, Shaw; Kamataki, Tetsuya

    2003-03-01

    The expression level of mRNAs for cytochrome P450 (CYP) 1A1 and 1B1 in freshly prepared white cells from 72 subjects exposed to dioxins at waste incinerators was investigated. The amounts of CYP1B1 mRNA ranged from 0.16 to 671 molecules/10(7) molecules of 18S rRNA, whereas the amounts of CYP1A1 mRNA were <6 molecules/10 ng total RNA, indicating that CYP1A1 was not induced to a detectable level by environmentally exposed dioxins. The inducibility of CYP1B1 mRNA in leukocytes, defined as the ratio of CYP1B1 mRNA to the plasma concentration of dioxins, varied among the subjects. It was found that the subjects showed trimodal distribution according to inducibility: 39 (54.2%), 25 (34.7%), and 8 (11.1%) of 72 subjects were judged as poor, intermediate, and high responders to environmental dioxins, respectively. The amounts of CYP1B1 mRNA in leukocytes of the intermediate and high responders were highly correlated with the plasma concentrations of dioxins (P < 0.05 and <0.01). These results suggest that CYP1B1 with polymorphic inducibility by dioxins is involved in aromatic hydrocarbon hydroxylase activities in human lymphocytes.

  4. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

    PubMed Central

    Sausen, Mark; Leary, Rebecca J.; Jones, Siân; Wu, Jian; Reynolds, C. Patrick; Liu, Xueyuan; Blackford, Amanda; Parmigiani, Giovanni; Diaz, Luis A.; Papadopoulos, Nickolas; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.; Hogarty, Michael D.

    2012-01-01

    Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3–70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients. PMID:23202128

  5. A simple method for the simultaneous detection of E1A and E1B in adenovirus stocks.

    PubMed

    Suzuki, Erika; Murata, Takehide; Watanabe, Sanae; Kujime, Yukari; Hirose, Megumi; Pan, Jianzhi; Yamazaki, Takahito; Ugai, Hideyo; Yokoyama, Kazunari K

    2004-01-01

    Recombinant adenoviral vectors have been developed for use as therapeutic agents and for the introduction of exogenous genes into living cells. However, the occurrence of replication-competent adenoviruses (RCA) in adenovirus stocks produced in 293 cells remains a major problem in terms of the safe use of such vectors. To overcome the problems associated with the occurrence of RCA, we have established a simple method for the simultaneous detection of amplified E1A and E1B from RCA that might contaminate adenoviral stocks. The products amplified by polymerase chain reaction (PCR) were fractionated by regular electrophoresis on agarose gels and visualized by staining with ethidium bromide. This method is rapid and inexpensive for detection of RCA in the preparation of adenoviruses.

  6. Early HIV RNA decay during raltegravir-containing regimens exhibits two distinct subphases (1a and 1b)

    PubMed Central

    Andrade, Adriana; Guedj, Jeremie; Rosenkranz, Susan L.; Lu, Darlene; Mellors, John; Kuritzkes, Daniel R.; Perelson, Alan S.; Ribeiro, Ruy M.

    2015-01-01

    Background We analyzed the early kinetics with integrase inhibitor treatment to gain new insights into viral dynamics. Methodology We analyzed data from 39 HIV-1 infected, treatment-naïve, participants; 28 treated with raltegravir (RAL; multiple doses) monotherapy for 9 days, and 11 with RAL 400 mg BID and emtricitabine (200 mg QD)/tenofovir disoproxil fumarate (300 mg QD). Plasma HIV-1 RNA was measured frequently; the data was fitted using a mathematical model of viral dynamics distinguishing between infected cells with unintegrated HIV DNA and productively infected cells. Parameters were estimated using mixed-effect models. Results RAL treatment led to a biphasic viral decline with a rapid first phase (1a) lasting ~5 days followed by a slower phase (1b). Phase 1a is attributed to the rapid elimination of productively infected cells. Phase 1b reflects the loss of infected cells with non-integrated provirus due to cell loss and integration of HIV DNA. The half-life of productively infected cells and of infected cells that had completed reverse transcription but had not yet integrated HIV DNA were ~19 h and between 3.6 and 5.8 days, respectively. The effectiveness of RAL in preventing HIV-1 integration was 94% and 99.7%, for the combination therapy and monotherapy groups, respectively. Conclusion We found that the first phase of viral decay with RAL therapy was composed of 2 subphases corresponding to the half-lives of infected cells with integrated proviruses and with unintegrated HIV-1 DNA. PMID:26558541

  7. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans

    PubMed Central

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C.

    2013-01-01

    Background The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene–environment interactions in relation to health risks is needed. Objectives The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. Results The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p′-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Conclusion Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies. PMID:23785672

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

    PubMed

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

    2015-05-01

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

  9. Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells

    PubMed Central

    Wei, Fang; Wang, Huiping; Chen, Xiafang; Li, Chuanyuan; Huang, Qian

    2014-01-01

    Oncolytic viruses have recently received widespread attention for their potential in innovative cancer therapy. Many telomerase promoter-regulated oncolytic adenoviral vectors retain E1A and E1B. However, the functions of E1A and E1B proteins in the oncolytic role of replication-competent adenovirus (RCAd) and RCAd enhanced transduction of replication defective adenoviruses (RDAd) have not been addressed well. In this study, we constructed viruses expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa. We then tested their roles in oncolysis and replication of RCAd as well as their roles in RCAd enhanced transfection rate and transgene expression of RDAd in various cancer cells in vitro and in xenografted human NCI-H460 tumors in nude mice. We demonstrated that RCAds expressing E1A alone and plus E1B-19 kDa exhibited an obvious ability in replication and oncolytic effects as well as enhanced RDAd replication and transgene expression, with the former showed more effective oncolysis, while the latter exhibited superior viral replication and transgene promotion activity. However, RCAd expressing both E1A and E1B-19 kDa/55 kDa was clearly worst in all these abilities. The effects of E1A and E1B observed through using RCAd were further validated by using plasmids expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa proteins. Our study provided evidence that E1A was essential for inducing replication and oncolytic effects of RCAd as well as RCAd enhanced RDAd transduction, and expression of E1B-19 kDa other than E1B-55 kDa could promote these effects. E1B-55 kDa is not necessary for the oncolytic effects of adenoviruses and somehow inhibits RCAd-mediated RDAd replication and transgene expression. PMID:25019940

  10. Vaccination with a modified-live bovine viral diarrhea virus (BVDV) type 1a vaccine completely protected calves against challenge with BVDV type 1b strains.

    PubMed

    Xue, Wenzhi; Mattick, Debra; Smith, Linda; Umbaugh, Jerry; Trigo, Emilio

    2010-12-10

    Vaccination plays a significant role in the control of bovine viral diarrhea virus (BVDV) infection and spread. Recent studies revealed that type 1b is the predominant BVDV type 1 subgenotype, representing more than 75% of field isolates of BVDV-1. However, nearly all current, commercially available BVDV type 1 vaccines contain BVDV-1a strains. Previous studies have indicated that anti-BVDV sera, induced by BVDV-1a viruses, show less neutralization activity to BVDV-1b isolates than type 1a. Therefore, it is critically important to evaluate BVDV-1a vaccines in their ability to prevent BVDV-1b infection in calves. In current studies, calves were vaccinated subcutaneously, intradermally or intranasally with a single dose of a multivalent, modified-live viral vaccine containing a BVDV-1a strain, and were challenged with differing BVDV-1b strains to determine the efficacy and duration of immunity of the vaccine against these heterologous virus strains. Vaccinated calves, in all administration routes, were protected from respiratory disease caused by the BVDV-1b viruses, as indicated by significantly fewer clinical signs, lower rectal temperatures, reduced viral shedding and greater white blood cell counts than non-vaccinated control animals. The BVDV-1a vaccine elicited efficacious protection in calves against each BVDV-1b challenge strain, with a duration of immunity of at least 6 months.

  11. A rationally-designed chimeric KDM1A/KDM1B histone demethylase tower domain deletion mutant retaining enzymatic activity.

    PubMed

    Burg, Jonathan M; Makhoul, Alan T; Pemble, Charles W; Link, Jennifer E; Heller, Frederick J; McCafferty, Dewey G

    2015-08-19

    A target with therapeutic potential, lysine-specific demethylase 1A (KDM1A) is a regulator of gene expression whose tower domain is a protein-protein interaction motif. This domain facilitates the interaction of KDM1A with coregulators and multiprotein complexes that direct its activity to nucleosomes. We describe the design and characterization of a chimeric 'towerless' KDM1A, termed nΔ150 KDM1AΔTower KDM1B chimera (chKDM1AΔTower), which incorporates a region from the paralog lysine-specific demethylase 1B (KDM1B). This chimera copurifies with FAD and displays demethylase activity, but fails to bind the partner protein corepressor of the RE1-silencing transcription factor (CoREST). We conclude that KDM1A catalysis can be decoupled from tower-dependent interactions, lending chKDM1AΔTower useful for dissecting molecular contributions to KDM1A function.

  12. Chromosomal localization of the human genes for {alpha}{sub 1A}, {alpha}{sub 1B}, and {alpha}{sub 1E} voltage-dependent Ca{sup 2+} channel subunits

    SciTech Connect

    Diriong, S.; Lory, P.; Taviaux, S.

    1995-12-10

    The {alpha}{sub 1} subunit genes encoding voltage-dependent Ca{sup 2+} channels are members of a gene family. We have used human brain cDNA probes to localize the neuronal isoform genes CACNL1A4 ({alpha}{sub 1A}), CACNL1A5 ({alpha}{sub 1B}), and CACNL1A6 ({alpha}{sub 1E}) to 19p13, 9q34, and 1q25-q31, respectively, using fluorescene in situ hybridization on human chromosomes. These genes are particularly interesting gene candidates in the pathogenesis of neuronal disorders. Although genetic disorders have been linked to loci 9q34 and 19p13, no genetic disease related to Ca{sup 2+} signaling defects has yet been linked to these loci. 22 refs., 2 figs., 1 tab.

  13. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    SciTech Connect

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho; Chung, Young Chul; Jeong, Tae Cheon; Jeong, Hye Gwang

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression.

  14. 5-HT1A and 5-HT1B receptors differentially modulate rate and timing of auditory responses in the mouse inferior colliculus

    PubMed Central

    Ramsey, Lissandra Castellan Baldan; Sinha, Shiva R.; Hurley, Laura M.

    2010-01-01

    Serotonin is a physiological signal that translates both internal and external information about behavioral context into changes in sensory processing through a diverse array of receptors. The details of this process, particularly how receptors interact to shape sensory encoding, are poorly understood. In the inferior colliculus, a midbrain auditory nucleus, serotonin (5-HT) 1A receptors have suppressive and 5-HT1B receptors have facilitatory effects on evoked responses of neurons. We explored how these two receptor classes interact by testing three hypotheses: that they 1) affect separate neuron populations, 2) affect different response properties, or 3) have different endogenous patterns of activation. The first two hypotheses were tested by iontophoretic application of 5-HT1A and 5-HT1B receptor agonists individually and together to neurons in vivo. 5-HT1A and 5-HT1B agonists affected overlapping populations of neurons. During co-application, 5-HT1A and 5-HT1B agonists influenced spike rate and frequency bandwidth additively, with each moderating the effect of the other. In contrast, although both agonists individually influenced latencies and interspike intervals, the 5-HT1A agonist dominated these measurements during co-application. The third hypothesis was tested by applying antagonists of the 5-HT1A and 5-HT1B receptors. Blocking 5-HT1B receptors was complementary to activation of the receptor, but blocking 5-HT1A receptors was not, suggesting the endogenous activation of additional receptor types. These results suggest that cooperative interactions between 5-HT1A and 5-HT1B receptors shape auditory encoding in the IC, and that the effects of neuromodulators within sensory systems may depend nonlinearly on the specific profile of receptors that are activated. PMID:20646059

  15. Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

    PubMed Central

    Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.

    2015-01-01

    Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex. Here we report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A1 and APL1B form a stable complex with LRIM1. These results support a model in which APL1A1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens. PMID:25775123

  16. Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

    SciTech Connect

    Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.; Kobe, Bostjan

    2015-03-16

    Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex. We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.

  17. Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

    DOE PAGES

    Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.; ...

    2015-03-16

    Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex.more » We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.« less

  18. AP-1/σ1A and AP-1/σ1B adaptor-proteins differentially regulate neuronal early endosome maturation via the Rab5/Vps34-pathway

    PubMed Central

    Candiello, Ermes; Kratzke, Manuel; Wenzel, Dirk; Cassel, Dan; Schu, Peter

    2016-01-01

    The σ1 subunit of the AP-1 clathrin-coated-vesicle adaptor-protein complex is expressed as three isoforms. Tissues express σ1A and one of the σ1B and σ1C isoforms. Brain is the tissue with the highest σ1A and σ1B expression. σ1B-deficiency leads to severe mental retardation, accumulation of early endosomes in synapses and fewer synaptic vesicles, whose recycling is slowed down. AP-1/σ1A and AP-1/σ1B regulate maturation of these early endosomes into multivesicular body late endosomes, thereby controlling synaptic vesicle protein transport into a degradative pathway. σ1A binds ArfGAP1, and with higher affinity brain-specific ArfGAP1, which bind Rabex-5. AP-1/σ1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. Formation of AP-1/σ1A-ArfGAP1-Rabex-5 complexes is prevented by σ1B binding of Rabex-5 and the amount of endosomal Rabex-5 is reduced. AP-1 complexes differentially regulate endosome maturation and coordinate protein recycling and degradation, revealing a novel molecular mechanism by which they regulate protein transport besides their established function in clathrin-coated-vesicle formation. PMID:27411398

  19. AP-1/σ1A and AP-1/σ1B adaptor-proteins differentially regulate neuronal early endosome maturation via the Rab5/Vps34-pathway.

    PubMed

    Candiello, Ermes; Kratzke, Manuel; Wenzel, Dirk; Cassel, Dan; Schu, Peter

    2016-07-14

    The σ1 subunit of the AP-1 clathrin-coated-vesicle adaptor-protein complex is expressed as three isoforms. Tissues express σ1A and one of the σ1B and σ1C isoforms. Brain is the tissue with the highest σ1A and σ1B expression. σ1B-deficiency leads to severe mental retardation, accumulation of early endosomes in synapses and fewer synaptic vesicles, whose recycling is slowed down. AP-1/σ1A and AP-1/σ1B regulate maturation of these early endosomes into multivesicular body late endosomes, thereby controlling synaptic vesicle protein transport into a degradative pathway. σ1A binds ArfGAP1, and with higher affinity brain-specific ArfGAP1, which bind Rabex-5. AP-1/σ1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5(GTP)-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. Formation of AP-1/σ1A-ArfGAP1-Rabex-5 complexes is prevented by σ1B binding of Rabex-5 and the amount of endosomal Rabex-5 is reduced. AP-1 complexes differentially regulate endosome maturation and coordinate protein recycling and degradation, revealing a novel molecular mechanism by which they regulate protein transport besides their established function in clathrin-coated-vesicle formation.

  20. GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization.

    PubMed

    Fritschy, J M; Meskenaite, V; Weinmann, O; Honer, M; Benke, D; Mohler, H

    1999-03-01

    GABAB (gamma-aminobutyric acid)-receptors have been implicated in central nervous system (CNS) functions, e.g. cognition and pain perception, and dysfunctions including spasticity and absence epilepsy. To permit an analysis of the two known GABAB-receptor splice variants GABAB-R1a (GB1a) and GABAB-R1b (GB1b), their distribution pattern has been differentiated in the rat brain, using Western blotting and immunohistochemistry with isoform-specific antisera. During postnatal maturation, the expression of the two splice variants was differentially regulated with GB1a being preponderant at birth. In adult brain, GB1b-immunoreactivity (-IR) was predominant, and the two isoforms largely accounted for the pattern of GABAB-receptor binding sites in the brain. Receptor heterogeneity was pronounced in the hippocampus, where both isoforms occurred in CA1, but only GB1b in CA3. Similarly, in the cerebellum, GB1b was exclusively found in Purkinje cells in a zebrin-like pattern. The staining was most pronounced in Purkinje cell dendrites and spines. Using electron microscopy, over 80% of the spine profiles in which a synaptic contact with a parallel fibre was visible contained GB1b-IR at extrasynaptic sites. This subcellular localization is unrelated to GABAergic inputs, indicating that the role of GABAB-receptors in vivo extends beyond synaptic GABAergic neurotransmission and may, in the cerebellum, involve taurine as a ligand.

  1. Cytochrome P450 1B1, a new keystone in gene-environment interactions related to human head and neck cancer?

    PubMed

    Thier, Ricarda; Brüning, Thomas; Roos, Peter H; Bolt, Hermann M

    2002-06-01

    Alcohol consumption and tobacco smoking are major causes of head and neck cancers, and regional differences point to the importance of research into gene-environment interactions. Much interest has been focused on polymorphisms of CYP1A1 and of GSTM1 and GSTT1, but a number of studies have not demonstrated significant effects. This has mostly been ascribed to small sample sizes. In general, the impact of polymorphisms of metabolic enzymes appears inconsistent, with some reports of weak-to-moderate associations, and with others of no elevation of risks. The classical cytochrome P450 isoenzyme considered for metabolic activation of polycyclic aromatic hydrocarbons (PAH) is CYP1A1. A new member of the CYP1 family, CYP1B1, was cloned in 1994, currently representing the only member of the CYP1B subfamily. A number of single nucleotide polymorphisms of the CYP1B1 gene have been reported. The amino acid substitutions Val432Leu ( CYP1B1*3) and Asn453Ser ( CYP1B1*4), located in the heme binding domain of CYP1B1, appear as likely candidates to be linked with biological effects. CYP1B1 activates a wide range of PAH, aromatic and heterocyclic amines. Very recently, the CYP1B1 codon 432 polymorphism ( CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squamous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has pointed to interactive effects. This provides new molecular evidence that tobacco smoke-specific compounds relevant to head and neck carcinogenesis are metabolically activated through CYP1B1 and is consistent with a major pathogenetic relevance of PAH as ingredients of tobacco smoke.

  2. Basolateral sorting of the Mg²⁺ transporter CNNM4 requires interaction with AP-1A and AP-1B.

    PubMed

    Hirata, Yusuke; Funato, Yosuke; Miki, Hiroaki

    2014-12-12

    Ancient conserved domain protein/cyclin M (CNNM) 4 is an evolutionarily conserved Mg(2+) transporter that localizes at the basolateral membrane of the intestinal epithelia. Here, we show the complementary importance of clathrin adaptor protein (AP) complexes AP-1A and AP-1B in basolateral sorting of CNNM4. We first confirmed the basolateral localization of both endogenous and ectopically expressed CNNM4 in Madin-Darby Canine Kidney cells, which form highly polarized epithelia in culture. Single knockdown of μ1B, a cargo-recognition subunit of AP-1B, did not affect basolateral localization, but simultaneous knockdown of the μ1A subunit of AP-1A abrogated localization. Mutational analyses showed the importance of three conserved dileucine motifs in CNNM4 for both basolateral sorting and interaction with μ1A and μ1B. These results imply that CNNM4 is sorted to the basolateral membrane by the complementary function of AP-1A and AP-1B.

  3. Interactions between genetic polymorphism of cytochrome P450-1B1, sulfotransferase 1A1, catechol-o-methyltransferase and tobacco exposure in breast cancer risk.

    PubMed

    Saintot, Monique; Malaveille, Christian; Hautefeuille, Agnès; Gerber, Mariette

    2003-11-20

    Genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and estrogens might play a role in breast carcinogenesis related to environmental exposures. In a case-only study on 282 women with breast cancer, we studied the interaction effects (ORi) between smoking habits and the gene polymorphisms of Cytochrome P450 1B1 (Val432Leu CYP1B1), Phenol-sulfotransferase 1A1 (Arg213His SULT1A1) and Catechol-O-methyltransferase (Val158Met COMT). The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38). Also, the smokers carrying the His SULT1A1 allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SULT1A1 common genotype (ORi= 2.55, 95%CI: 1.21-5.36). The His SULT1A1 allele increased the risk only in premenopausal patients. The Met COMT allele with a lower methylation activity than Val COMT did not modify the risk among smokers. The excess risk due to joint effect could result from a higher exposure to activated tobacco-compounds for women homo/heterozygous for the Val CYP1B1 allele. Also, a lower sulfation of the tobacco carcinogens among women with His SULT1A1 could increase exposure to genotoxic compounds. Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers. Our study showed that gene polymorphisms of CYP1B1 and SULT1A1 induce an individual susceptibility to breast cancer among current smokers.

  4. SUMO E3 Ligases GmSIZ1a and GmSIZ1b regulate vegetative growth in soybean† 

    PubMed Central

    Cai, Bin; Kong, Xiangxiong; Zhong, Chao; Sun, Suli; Zhou, Xiao Feng; Jin, Yin Hua; Wang, Youning; Li, Xia; Zhu, Zhendong

    2017-01-01

    Abstract SIZ1 is a small ubiquitin‐related modifier (SUMO) E3 ligase that mediates post‐translational SUMO modification of target proteins and thereby regulates developmental processes and hormonal and environmental stress responses in Arabidopsis. However, the role of SUMO E3 ligases in crop plants is largely unknown. Here, we identified and characterized two Glycine max (soybean) SUMO E3 ligases, GmSIZ1a and GmSIZ1b. Expression of GmSIZ1a and GmSIZ1b was induced in response to salicylic acid (SA), heat, and dehydration treatment, but not in response to cold, abscisic acid (ABA), and NaCl treatment. Although GmSIZ1a was expressed at higher levels than GmSIZ1b, both genes encoded proteins with SUMO E3 ligase activity in vivo. Heterologous expression of GmSIZ1a or GmSIZ1b rescued the mutant phenotype of Arabidopsis siz1‐2, including dwarfism, constitutively activated expression of pathogen‐related genes, and ABA‐sensitive seed germination. Simultaneous downregulation of GmSIZ1a and GmSIZ1b (GmSIZ1a/b) using RNA interference (RNAi)‐mediated gene silencing decreased heat shock‐induced SUMO conjugation in soybean. Moreover, GmSIZ1RNAi plants exhibited reduced plant height and leaf size. However, unlike Arabidopsis siz1‐2 mutant plants, flowering time and SA levels were not significantly altered in GmSIZ1RNAi plants. Taken together, our results indicate that GmSIZ1a and GmSIZ1b mediate SUMO modification and positively regulate vegetative growth in soybean. PMID:27762067

  5. B-1a, B-1b and B-2 B cells display unique VHDJH repertoires formed at different stages of ontogeny and under different selection pressures.

    PubMed Central

    Tornberg, U C; Holmberg, D

    1995-01-01

    Analyses of VHDJH rearrangements isolated from murine peritoneal B-1a cells (CD5+, IgMhi, B220lo), peritoneal B-1b cells (CD5-, IgMhi, B220lo), and conventional splenic B cells provide evidence that a unique repertoire of VH regions is displayed by each of these B-cell subsets. The B-1a subset is characterized by a low N-region diversity, by a high frequency of sequence homologies in the VH-D and D-JH junctions, and by a limited exonuclease nibbling of the terminals of the joining gene segments. Through expansion in ageing mice, B-1a clones with these properties are favoured. B-1b cells are similar to conventional B-2 cells with respect to N-region diversity, but are unique in terms of D gene expression. Thus, while most murine pre-B and B cells preferentially use DSP and DFL gene segments in a given reading frame (RF1), B-1b cells frequently express D genes in another reading frame (RF2). Together, these findings provide structural evidence for a model where B-1a, B-1b and B-2 cells are produced by separate progenitors that are active at different stages of ontogeny. Images PMID:7737121

  6. Expression of FcFT1, a FLOWERING LOCUS T-like gene, is regulated by light and associated with inflorescence differentiation in fig (Ficus carica L.)

    PubMed Central

    2013-01-01

    Background Because the floral induction occurs in many plants when specific environmental conditions are satisfied, most plants bloom and bear fruit during the same season each year. In fig, by contrast, the time interval during which inflorescence (flower bud, fruit) differentiation occurs corresponds to the shoot elongation period. Fig trees thus differ from many species in their reproductive growth characteristics. To date, however, the molecular mechanisms underlying this unorthodox physiology of floral induction and fruit setting in fig trees have not been elucidated. Results We isolated a FLOWERING LOCUS T (FT)-like gene from fig and examined its function, characteristics, and expression patterns. The isolated gene, F. carica FT (FcFT1), is single copy in fig and shows the highest similarity at the amino acid level (93.1%) to apple MdFT2. We sequenced its upstream region (1,644 bp) and identified many light-responsive elements. FcFT1 was mainly expressed in leaves and induced early flowering in transgenic tobacco, suggesting that FcFT1 is a fig FT ortholog. Real-time reverse-transcription PCR analysis revealed that FcFT1 mRNA expression occurred only in leaves at the lower nodes, the early fruit setting positions. mRNA levels remained a constant for approximately 5 months from spring to autumn, corresponding almost exactly to the inflorescence differentiation season. Diurnal variation analysis revealed that FcFT1 mRNA expression increased under relative long-day and short-day conditions, but not under continuous darkness. Conclusion These results suggest that FcFT1 activation is regulated by light conditions and may contribute to fig’s unique fruit-setting characteristics. PMID:24341499

  7. CYP1A1 and CYP1B1 polymorphisms and their association with estradiol and estrogen metabolites in women who are premenopausal and perimenopausal.

    PubMed

    Sowers, MaryFran R; Wilson, Angela L; Kardia, Sharon R; Chu, Jian; McConnell, Daniel S

    2006-09-01

    The purpose of this study was to relate measured concentrations of estradiol (E2) and the urinary estrogen metabolites 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1) to single nucleotide polymorphisms (SNPs) from CYP1A1 and CYP1B1, the primary genes involved in estrogen catabolism. We investigated the association of 4 CYP1A1 SNPs (CYP1A1 rs4646903, CYP1A1 rs1531163, CYP1A1 rs2606345, and CYP1A1 rs1048943) and 2 CYP1B1 SNPs (CYP1B1 rs162555 and CYP1B1 rs1056836) to circulating serum E2 concentrations and the urinary estrogen metabolites 2-OHE1 and 16alpha-OHE1. The associations were evaluated in 1,340 participants of 4 racial/ethnic groups from the Study of Women's Health Across the Nation (SWAN) who were premenopausal and perimenopausal. There was substantial variation in the allele frequencies of the SNPs for African American and Caucasian women. There was, however, remarkable comparability between Chinese and Japanese women; their CYP1A1 and CYP1B1 allele frequencies differed by only < or =11%. There was significant variation in E2 concentrations by genotype within racial/ethnic group for CYP1A1 rs2606345. In particular, Japanese women with the CC genotype had lower E2 concentrations than did Japanese women with the AC genotype. Chinese women with the CC genotype had higher 2-OHE1 concentrations than did Chinese women with the AC genotype. Further, African American women with the CC genotype had higher 16alpha-OHE1 concentrations than did those with other genotypes. CYP1A1 rs2606345 may play an important role in estrogen metabolism in women who are premenopausal and perimenopausal.

  8. On the process of cellular division in Escherichia coli: isolation and characterization of penicillin-binding proteins 1a, 1b, and 3.

    PubMed Central

    Tamura, T; Suzuki, H; Nishimura, Y; Mizoguchi, J; Hirota, Y

    1980-01-01

    Multiple mutants of Escherichia coli defective in penicillin-binding proteins (PBPs) were constructed, and into these strains Co1E1 plasmids carrying the genes for PBP-1a, -1b, or -3 were introduced. From these plasmid-carrying strains, PBP-1a and -1b were purified by ampicillin-Sepharose affinity chromatography and PBP-3 by cephalexin-Sepharose affinity chromatography. Improved purification was achieved by differential elution with NH2OH. Purified PBP-1b synthesized murein when added to the membrane fraction of a PBP-1b-defective mutant, which by itself failed to support murein synthesis in vitro. The PBP-1b preparation was able to synthesize murein from the lipid intermediate extracted with chloroform/methanol but was unable to utilize UDP-linked precursors for murein synthesis. Murein synthesis was inhibited by vancomysin, ristocetin, moenomycin, and enduracidin, but not by beta-lactam antibiotics. The synthesized murein was shown to contain crosslinked muropeptides. Their crosslinking was abolished by action of beta-lactam antibiotics. The PBP-1a and -3 preparations showed substantially no activity for murein synthesis in the same reaction system. None of the three PBPs showed D-alanine carboxypeptidase activity with UDP-N-acetylmuramoyl-pentapeptide as substrate or endopeptidase activity with bis(disaccharide-peptide) as substrate. Images PMID:7001458

  9. Basal and 3,3',4,4',5-pentachlorobiphenyl-induced expression of cytochrome P450 1A, 1B and 1C genes in zebrafish

    SciTech Connect

    Joensson, Maria E. . E-mail: mjonsson@whoi.edu; Orrego, Rodrigo; Woodin, Bruce R.; Goldstone, Jared V.; Stegeman, John J.

    2007-05-15

    The cytochrome P4501C (CYP1C) gene subfamily was recently discovered in fish, and zebrafish (Danio rerio) CYP1C1 transcript has been cloned. Here we cloned the paralogous CYP1C2, showing that the amino acid sequence is 78% identical to CYP1C1, and examined gene structure and expression of CYP1A, CYP1B1, CYP1C1, and CYP1C2. Xenobiotic response elements were observed upstream of the coding regions in all four genes. Zebrafish adults and embryos were exposed (24 h) to 100 nM 3,3',4,4',5-polychlorinated biphenyl (PCB126) or 20 ppm acetone and subsequently held in clean water for 24 h (adults) or 48 h (embryos). All adult organs examined (eye, gill, heart, liver, kidney, brain, gut, and gonads) and embryos showed basal expression of the four genes. CYP1A was most strongly expressed in liver, whereas CYP1B1, CYP1C1, and CYP1C2 were most strongly expressed in heart and eye. CYP1B1 and the CYP1C genes showed an expression pattern similar to one another and to mammalian CYP1B1. In embryos CYP1C1 and CYP1C2 tended to have a higher basal expression than CYP1A and CYP1B1. PCB126 induced CYP1A in all organs, and CYP1B1 and CYP1C1 in all organs except gonads, or gonads and brain, respectively. CYP1C2 induction was significant only in the liver. However, in embryos all four genes were induced strongly by PCB126. The results are consistent with CYP1C1 and CYP1C2, as well as CYP1A and CYP1B1, being regulated by the aryl hydrocarbon receptor. While CYP1A may have a protective role against AHR agonists in liver and gut, CYP1B1, CYP1C1, and CYP1C2 may also play endogenous roles in eye and heart and possibly other organs, as well as during development.

  10. Carnosol, a Constituent of Zyflamend, Inhibits Aryl Hydrocarbon Receptor-Mediated Activation of CYP1A1 and CYP1B1 Transcription and Mutagenesis

    PubMed Central

    Mohebati, Arash; Guttenplan, Joseph B.; Kochhar, Amit; Zhao, Zhong-Lin; Kosinska, Wieslawa; Subbaramaiah, Kotha; Dannenberg, Andrew J.

    2012-01-01

    The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic-helix-loop-helix family of transcription factors, plays a significant role in polycyclic aromatic hydrocarbon (PAH) induced carcinogenesis. In the upper aerodigestive tract of humans, tobacco smoke, a source of PAHs, activates the AhR leading to increased expression of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. Inhibitors of Hsp90 ATPase cause a rapid decrease in levels of AhR, an Hsp90 client protein, and thereby block PAH-mediated induction of CYP1A1 and CYP1B1. The main objective of this study was to determine whether Zyflamend, a polyherbal preparation, suppressed PAH-mediated induction of CYP1A1 and CYP1B1 and inhibited DNA adduct formation and mutagenesis. We also investigated whether carnosol, one of multiple phenolic antioxidants in Zyflamend, had similar inhibitory effects. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) and skin (HaCaT) with benzo[a]pyrene (B[a]P), a prototypic PAH, induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Both Zyflamend and carnosol suppressed these effects of B[a]P. Notably, both Zyflamend and carnosol inhibited Hsp90 ATPase activity and caused a rapid reduction in AhR levels. The formation of B[a]P induced DNA adducts and mutagenesis were also inhibited by Zyflamend and carnosol. Collectively, these results show that Zyflamend and carnosol inhibit Hsp90 ATPase leading to reduced levels of AhR, suppression of B[a]P-mediated induction of CYP1A1 and CYP1B1 and inhibition of mutagenesis. Carnosol-mediated inhibition of Hsp90 ATPase activity can help explain the chemopreventive activity of herbs such as Rosemary, which contain this phenolic antioxidant. PMID:22374940

  11. Relationships of common polymorphisms in IL-6, IL-1A, and IL-1B genes with susceptibility to osteoarthritis: a meta-analysis.

    PubMed

    Cai, Hao; Sun, Huan-Jian; Wang, You-Hua; Zhang, Zhe

    2015-08-01

    Observational and experimental studies have arrived at inconsistent conclusions about whether common polymorphisms in IL-6, IL-1A, and IL-1B genes are associated with an increased risk of osteoarthritis (OA). Therefore, we undertook a comprehensive meta-analysis to more systematically summarize the relationships of IL-6, IL-1A, and IL-1B genetic polymorphisms with susceptibility to OA. We screened the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases up to 31 March 2014. We used STATA software to analyze statistical data. Odds ratios (ORs) and their corresponding 95 % confidence intervals (95 % CIs) were calculated. Seventeen independent case-control studies were included in this meta-analysis with a total number of 7,491 subjects, comprised of 3,293 OA patients and 4,729 healthy controls. Our results indicate that IL-6, IL-1A, and IL-1B genetic polymorphisms are statistically correlated with an increased risk of OA under the allele and dominant models. According to a subgroup analysis based on disease, a higher frequency of IL-6 genetic polymorphisms was observed among knee OA and hand OA patients, but not among hip OA and DIP OA patients. A higher frequency of IL-1A genetic polymorphisms were found among hip OA patients, hand OA, hip OA and DIP OA patients. Furthermore, we observed a higher IL-1B polymorphism frequency among knee OA and hip OA patients, but not among hand OA patients. Our findings provide evidence that IL-6, IL-1A, and IL-1B genetic polymorphisms may be correlated with susceptibility to OA.

  12. CYP1A1 and CYP1B1 genetic polymorphisms, smoking and breast cancer risk in a Finnish Caucasian population.

    PubMed

    Sillanpää, Pia; Heikinheimo, Liisa; Kataja, Vesa; Eskelinen, Matti; Kosma, Veli-Matti; Uusitupa, Matti; Vainio, Harri; Metsola, Katja; Hirvonen, Ari

    2007-09-01

    We investigated the associations between two CYP1A1 polymorphisms (Ile462Val and Thr461Asn) and one CYP1B1 polymorphism (Leu432Val) and breast cancer risk. The study population consisted of 483 breast cancer patients and 482 healthy population controls, all of homogenous Finnish origin. No statistically significant overall associations were found between the CYP1A1 and CYP1B1 genotypes and breast cancer risk. However, a significant increase in the breast cancer risk was seen for women who had smoked 1-9 cigarettes/day and carried the CYP1B1 432Val allele; the OR was 2.6 (95% CI 1.07-6.46) for women carrying the Leu/Val genotype and 5.1 (95% CI 1.30-19.89, P for trend 0.005) for women with the Val/Val genotype compared to similarly smoking women homozygous for the 432Leu allele. Furthermore, when CYP1B1 genotypes were combined with the previously analyzed N-acetyl transferase (NAT2) genotypes, a significant increase in breast cancer risk was found among women who had at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype (OR 1.52; 95% CI 1.03-2.24) compared to women carrying a combination of CYP1B1 Leu/Leu and NAT2 rapid acetylator genotypes. This risk was seen to be confined to ever smokers; the OR was 2.46 (95% CI 1.11-5.45) for ever smokers carrying at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype compared to ever smokers with the CYP1B1 Leu/Leu and NAT2 rapid acetylator genotype combination. Our results suggest that the CYP1B1 polymorphism may be an important modifier of breast cancer risk in Finnish Caucasian women who have been exposed to tobacco smoke and/or carry the NAT2 slow acetylator genotype.

  13. Soy isoflavones, CYP1A1, CYP1B1, and COMT polymorphisms, and breast cancer: a case-control study in southwestern China.

    PubMed

    Wang, Qiong; Li, Hui; Tao, Ping; Wang, Yuan-Ping; Yuan, Ping; Yang, Chun-Xia; Li, Jia-Yuan; Yang, Fei; Lee, Hui; Huang, Yuan

    2011-08-01

    CYP1A1, CYP1B1, and COMT are key enzymes involved in estrogen metabolism. Soy isoflavones, phytoestrogens found in soy foods, may modify the activity of these enzymes. A case-control study was conducted to assess the associations between soy isoflavone intake and the CYP1A1 Ile462Val, CYP1B1 Val432Leu, and COMT Val158Met polymorphisms and breast cancer, as well as their combined effects on breast cancer. A total of 400 newly diagnosed breast cancer cases and 400 healthy controls were recruited. Participants' daily intake of soy isoflavones (DISI [mg/day]) was calculated and transformed to energy-adjusted DISI by the residual method. Gene sequencing was used to analyze CYP1A1, CYP1B1, and COMT polymorphisms. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated by conditional logistic regression. A strong protective dose-dependent effect of energy-adjusted DISI on breast cancer was found in both pre- and postmenopausal women (P(trend) < 0.05). Among all women and in the postmenopausal subgroup, COMT Met/Met and CYP1B1 Leu/Leu susceptible genotype carriers had higher risk of breast cancer (aORs > 1, OR 95% CIs exclude 1). In premenopausal women, only carrying CYP1B1 Leu/Leu was associated with breast cancer risk (aOR = 2.05, 95% CI: 1.11-3.79). Carrying CYP1A1 Val/Val was related to breast cancer risk only among all women. A stratified analysis was performed at two levels of energy-adjusted DISI, with wildtype homozygous genotypes and low energy-adjusted DISI as the reference. In the high energy-adjusted DISI subgroup, carrying the CYP1B1 Leu/Leu genotype did not affect breast cancer risk in either all women or in the menopausal subgroups, compared with the reference. Overall, in Han Chinese women, carrying CYP1A1 Val/Val and COMT Met/Met appears to be associated with breast cancer risk, especially in postmenopausal women. CYP1B1 susceptible genotypes (Val/Leu or Leu/Leu) also contribute to increased breast cancer risk

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  15. The Human Adenovirus Type 5 E4orf6/E1B55K E3 Ubiquitin Ligase Complex Enhances E1A Functional Activity

    PubMed Central

    Dallaire, Frédéric; Schreiner, Sabrina; Blair, G. Eric; Dobner, Thomas; Branton, Philip E.

    2015-01-01

    ABSTRACT Human adenovirus (Ad) E1A proteins have long been known as the central regulators of virus infection as well as the major source of adenovirus oncogenic potential. Not only do they activate expression of other early viral genes, they make viral replication possible in terminally differentiated cells, at least in part, by binding to the retinoblastoma (Rb) tumor suppressor family of proteins to activate E2F transcription factors and thus viral and cellular DNA synthesis. We demonstrate in an accompanying article (F. Dallaire et al., mSphere 1:00014-15, 2016) that the human adenovirus E3 ubiquitin ligase complex formed by the E4orf6 and E1B55K proteins is able to mimic E1A activation of E2F transactivation factors. Acting alone in the absence of E1A, the Ad5 E4orf6 protein in complex with E1B55K was shown to bind E2F, disrupt E2F/Rb complexes, and induce hyperphosphorylation of Rb, leading to induction of viral and cellular DNA synthesis, as well as stimulation of early and late viral gene expression and production of viral progeny. While these activities were significantly lower than those exhibited by E1A, we report here that this ligase complex appeared to enhance E1A activity in two ways. First, the E4orf6/E1B55K complex was shown to stabilize E1A proteins, leading to higher levels in infected cells. Second, the complex was demonstrated to enhance the activation of E2F by E1A products. These findings indicated a new role of the E4orf6/E1B55K ligase complex in promoting adenovirus replication. IMPORTANCE Following our demonstration that adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins is able to mimic the activation of E2F by E1A, we conducted a series of studies to determine if this complex might also promote the ability of E1A to do so. We found that the complex both significantly stabilizes E1A proteins and also enhances their ability to activate E2F. This finding is of significance because it represents an entirely new

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

    PubMed Central

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

    2016-01-01

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

  17. Comparative Transcriptome Analysis between the Cytoplasmic Male Sterile Line NJCMS1A and Its Maintainer NJCMS1B in Soybean (Glycine max (L.) Merr.)

    PubMed Central

    Li, Jiajia; Han, Shaohuai; Ding, Xianlong; He, Tingting; Dai, Jinying; Yang, Shouping; Gai, Junyi

    2015-01-01

    Background The utilization of soybean heterosis is probably one of the potential approaches in future yield breakthrough as was the situation in rice breeding in China. Cytoplasmic male sterility (CMS) plays an important role in the production of hybrid seeds. However, the molecular mechanism of CMS in soybean remains unclear. Results The comparative transcriptome analysis between cytoplasmic male sterile line NJCMS1A and its near-isogenic maintainer NJCMS1B in soybean was conducted using Illumina sequencing technology. A total of 88,643 transcripts were produced in Illumina sequencing. Then 56,044 genes were obtained matching soybean reference genome. Three hundred and sixty five differentially expressed genes (DEGs) between NJCMS1A and NJCMS1B were screened by threshold, among which, 339 down-regulated and 26 up-regulated in NJCMS1A compared to in NJCMS1B. Gene Ontology (GO) annotation showed that 242 DEGs were annotated to 19 functional categories. Clusters of Orthologous Groups of proteins (COG) annotation showed that 265 DEGs were classified into 19 categories. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 46 DEGs were assigned to 33 metabolic pathways. According to functional and metabolic pathway analysis combined with reported literatures, the relations between some key DEGs and the male sterility of NJCMS1A were discussed. qRT-PCR analysis validated that the gene expression pattern in RNA-Seq was reliable. Finally, enzyme activity assay showed that energy supply was decreased in NJCMS1A compared to in NJCMS1B. Conclusions We concluded that the male sterility of NJCMS1A might be related to the disturbed functions and metabolism pathways of some key DEGs, such as DEGs involved in carbohydrate and energy metabolism, transcription factors, regulation of pollen development, elimination of reactive oxygen species (ROS), cellular signal transduction, and programmed cell death (PCD) etc. Future research will focus on cloning and transgenic

  18. Functional evaluation of novel single nucleotide polymorphisms and haplotypes in the promoter regions of CYP1B1 and CYP1A1 genes.

    PubMed

    Han, Weiguo; Pentecost, Brian T; Spivack, Simon D

    2003-07-01

    Interindividual variation in the expression of the carcinogen- and estrogen-metabolizing enzymes cytochrome P4501B1 and 1A1 (CYP1B1 and CYP1A1) has been detected in human lung. To search for polymorphisms with functional consequences for CYP1B1 and CYP1A1 gene expression, we examined 1.5 kb of the promoter region of each gene. Genomic DNA from 21 Caucasian individuals was amplified by polymerase chain reaction (PCR) for direct cycle sequencing. Eight single nucleotide polymorphisms (SNPs) for CYP1B1 and 13 SNPs for CYP1A1 were found. The majority of polymorphisms occurred as multiSNP combinations for individual subjects. The wild-type sequences were cloned into a luciferase reporter construct. The most frequent polymorphisms were then recreated by iterative site-directed mutagenesis, replicating single polymorphisms and multiSNP combinations. These wild-type and variant constructs were functionally evaluated in transient transfection experiments employing exposures to either the index polycyclic aromatic hydrocarbon (PAH) inducer benzo[a]pyrene (B[a]P), a composite mixture of cigarette smoke extract (CSE), or the repressor chemopreventive agent trans-3,4,5-trihydroxystilbene (reseveratrol). Results indicated that all wild-type and variant constructs responded in qualitatively concordant fashion to the inducers and to the repressor. The CYP1B1 haplotypes and the majority of CYP1A1 haplotypes were shown to have no functional consequence, as compared to those of the wild-type promoter sequences. Two constructs of composite polymorphisms of CYP1A1 appeared to result in a statistically significant increase in basal promoter activity (1.38- and 1.50-fold, respectively), but the degree of functional impact was judged unlikely to be biologically important in vivo. We conclude that the observed promoter region polymorphisms in these genes are common, but are of unclear functional consequence.

  19. Photoabsorption Assignments for the C̃(1)B2 ← X̃(1)A1 Vibronic Transitions of SO2, Using New Ab Initio Potential Energy and Transition Dipole Surfaces.

    PubMed

    Kumar, Praveen; Jiang, Bin; Guo, Hua; Kłos, Jacek; Alexander, Millard H; Poirier, Bill

    2017-02-09

    The high resolution spectroscopy of the SO2 molecule is of great topical interest, in a wide variety of contexts ranging from origins of higher life, to astrophysics of the interstellar medium, to environmental chemistry. In particular, the C̃(1)B2 ← X̃(1)A1 UV photoabsorption spectrum has received considerable attention. This spectrum exhibits a highly regular progression of ∼20 or so strong peaks, spaced roughly 350 cm(-1) apart, which is comparable to the C̃(1)B2 bending vibrational frequency. Accordingly, they have for decades been largely attributed to the (1, v2('), 2) ← (0, 0, 0) bend progression. Using a highly accurate new ab initio potential energy surface (PES) for the C̃(1)B2 state, we compute vibrational energy levels and wave functions, and compare with a photoabsorption calculation obtained using the same PES and corresponding C̃(1)B2 ← X̃(1)A1 transition dipole surface (TDS). We find that the above putative assignment is incorrect, contradicting even general qualitative trends-thus necessitating a very different dynamical picture for this highly unusual molecule.

  20. Cellular expression of isoforms of endothelin-converting enzyme-1 (ECE-1c, ECE-1b and ECE-1a) and endothelin-converting enzyme-2.

    PubMed

    Davenport, A P; Kuc, R E

    2000-11-01

    Our aim was to compare the cellular expression of endothelin-converting enzyme-1 (ECE-1) isoforms and ECE-2 using immunocytochemistry in normal and diseased human tissue. Intense ECE-1b immunoreactivity was present within renal and pulmonary epithelial cells with lower levels of staining displayed by ECE-1c, ECE-1a and ECE-2 antisera. Staining was detected with all antisera (except ECE-1a) within the endothelium of renal and pulmonary vessels having a range of lumen diameters as well as pial arteries and intracerebral vessels penetrating brain. ECE-1b, ECE-1c and ECE-2 immunoreactivity was localized to perivascular astrocytes and neuronal processes in the cerebral cortex. In diseased vessels, ECE-1c, ECE-1b and ECE-2 antisera stained macrophages infiltrating atherosclerotic plaques within coronary arteries. These results suggest ECE-1b and ECE-2 may be widely expressed in normal tissue from humans and inhibition of ECE-1 isoforms and ECE-2 expressed by cells such as macrophages in pathophysiological tissue may be an additional therapeutic target in cardiovascular disease.

  1. Discovery of Western European R1b1a2 Y chromosome variants in 1000 genomes project data: an online community approach.

    PubMed

    Rocca, Richard A; Magoon, Gregory; Reynolds, David F; Krahn, Thomas; Tilroe, Vincent O; Op den Velde Boots, Peter M; Grierson, Andrew J

    2012-01-01

    The authors have used an online community approach, and tools that were readily available via the Internet, to discover genealogically and therefore phylogenetically relevant Y-chromosome polymorphisms within core haplogroup R1b1a2-L11/S127 (rs9786076). Presented here is the analysis of 135 unrelated L11 derived samples from the 1000 Genomes Project. We were able to discover new variants and build a much more complex phylogenetic relationship for L11 sub-clades. Many of the variants were further validated using PCR amplification and Sanger sequencing. The identification of these new variants will help further the understanding of population history including patrilineal migrations in Western and Central Europe where R1b1a2 is the most frequent haplogroup. The fine-grained phylogenetic tree we present here will also help to refine historical genetic dating studies. Our findings demonstrate the power of citizen science for analysis of whole genome sequence data.

  2. In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B.

    PubMed

    Reid, Janet C; Bennett, Nigel C; Stephens, Carson R; Carroll, Melanie L; Magdolen, Viktor; Clements, Judith A; Hooper, John D

    2016-12-01

    Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5-10 nm, KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, KLK14 generates HAI-1A and HAI-1B fragments known to inhibit pro-HGF activating serine proteases. These in vitro data suggest that increased KLK14 activity could contribute at multiple levels to HGF/Met-mediated processes in prostate and other cancers.

  3. RPRD1A and RPRD1B Are Human RNA Polymerase II C-Terminal Domain Scaffolds for Ser5 Dephosphorylation

    PubMed Central

    Guo, Xinghua; Hunter, Gerald O.; Kuznetsova, Olga V.; Tempel, Wolfram; Marcon, Edyta; Zhong, Guoqing; Guo, Hongbo; Kuo, Wei-Hung William; Li, Joyce; Young, Peter; Olsen, Jonathan B.; Wan, Cuihong; Loppnau, Peter; El Bakkouri, Majida; Senisterra, Guillermo A.; He, Hao; Huang, Haiming; Sidhu, Sachdev S.; Emili, Andrew; Murphy, Shona; Mosley, Amber L.; Arrowsmith, Cheryl H.; Min, Jinrong; Greenblatt, Jack F.

    2014-01-01

    SUMMARY The RNA polymerase II (RNAPII) carboxyl-terminal domain (CTD) heptapeptide repeats (Y1-S2-P3-T4-S5-P6-S7) undergo dynamic phosphorylation and dephosphorylation during the transcription cycle to recruit factors that regulate transcription, RNA processing and chromatin modification. We show here that RPRD1A and RPRD1B form homodimers and heterodimers through their coiled-coil domains and interact preferentially via CTD interaction domains (CIDs) with CTD repeats phosphorylated at S2 and S7. Our high resolution crystal structures of the RPRD1A, RPRD1B and RPRD2 CIDs, alone and in complex with CTD phosphoisoforms, elucidate the molecular basis of CTD recognition. In an interesting example of cross-talk between different CTD modifications, our data also indicate that RPRD1A and RPRD1B associate directly with RPAP2 phosphatase and, by interacting with CTD repeats where phospho-S2 and/or phospho-S7 bracket a phospho-S5 residue, serve as CTD scaffolds to coordinate the dephosphorylation of phospho-S5 by RPAP2. PMID:24997600

  4. Cell-cycle-regulated control of VSG expression site silencing by histones and histone chaperones ASF1A and CAF-1b in Trypanosoma brucei.

    PubMed

    Alsford, Sam; Horn, David

    2012-11-01

    Antigenic variation in African trypanosomes involves monoallelic expression and reversible silencing of variant surface glycoprotein (VSG) genes found adjacent to telomeres in polycistronic expression sites (ESs). We assessed the impact on ES silencing of five candidate essential chromatin-associated factors that emerged from a genome-wide RNA interference viability screen. Using this approach, we demonstrate roles in VSG ES silencing for two histone chaperones. Defects in S-phase progression in cells depleted for histone H3, or either chaperone, highlight in particular the link between chromatin assembly and DNA replication control. S-phase checkpoint arrest was incomplete, however, allowing G2/M-specific VSG ES derepression following knockdown of histone H3. In striking contrast, knockdown of anti-silencing factor 1A (ASF1A) allowed for derepression at all cell cycle stages, whereas knockdown of chromatin assembly factor 1b (CAF-1b) revealed derepression predominantly in S-phase and G2/M. Our results support a central role for chromatin in maintaining VSG ES silencing. ASF1A and CAF-1b appear to play constitutive and DNA replication-dependent roles, respectively, in the recycling and assembly of chromatin. Defects in these functions typically lead to arrest in S-phase but defective cells can also progress through the cell cycle leading to nucleosome depletion and derepression of telomeric VSG ESs.

  5. SKF-96365 attenuates toxin-induced neuronal injury through opposite regulatory effects on Homer1a and Homer1b/c in cultured rat mesencephalic cells.

    PubMed

    Zeng, Xuan; Pan, Zhi-Guo; Shao, Yu; Wu, Xiao-Na; Liu, Shen-Xi; Li, Nan-Lin; Wang, Wei-Min

    2013-05-24

    Disturbances in Ca(2+) homeostasis have been implicated in a variety of neuro-pathological conditions including Parkinson's disease (PD). In the present study, we investigated the potential protective effect of SKF-96365, an originally identified blocker of receptor-mediated calcium entry, on MPP(+) induced neuronal injury in cultured rat mesencephalic cells. We found that pretreatment with SKF-96365 30 min before injury significantly reduced nuclear damage, decreased LDH release and inhibited apoptotic neuronal death. The results of calcium image also showed that SKF-96365 inhibited the increase of intracellular calcium induced by MPP(+), which was not dependent on the expression and function of TRPC1. In addition, SKF-96365 increased the expression of Homer1a, but decreased the expression of Homer1b/c in the presence or absence of MPP(+). Furthermore, overexpression of Homer1a by using recombinant lentivirus and knockdown of Homer1b/c by short interfering RNA (siRNA) further enhanced protective effects of SKF-96365 against MPP(+) injury. Taken together, these data suggest that SKF-96365 protects cultured rat mesencephalic cells against MPP(+) induced cytotoxicity, and this protection may be at least in part dependent on attenuating intracellular calcium overload, opposite regulatory effects on Homer1a and Homer1b/c expressions.

  6. Mmp1a and Mmp1b are not functional orthologs to human MMP1 in cigarette smoke induced lung disease.

    PubMed

    Carver, Phillip I; Anguiano, Vincent; D'Armiento, Jeanine M; Shiomi, Takayuki

    2015-02-01

    Matrix Metalloproteinase 1 (MMP1, collagenase-1) expression is implicated in a number of diseased states including emphysema and malignant tumors. The cigarette-smoke induced expression of this interstitial collegenase has been studied extensively and its inhibition proposed as a novel therapeutic treatment for tobacco related diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. However, a limitation in MMP1 research is the inability to take advantage of natural in vivo studies as most research has been performed in vitro or via animal models expressing human forms of the gene due to the lack of a rodent ortholog of MMP1. The present study examines the function of two possible mouse orthologs of human MMP1 known as Mmp1a and Mmp1b. Using genomic sequence analysis and expression analysis of these enzymes, the data demonstrate that neither MMP1a nor MMP1b behave in the same manner as human MMP1 in the presence of cigarette smoke. These findings establish that the two commonly proposed orthologs of MMP1, Mmp1a and Mmp1b, provide substantial limitations for use in examining MMP1 induced lung disease in mouse models of cigarette smoke emphysema.

  7. Comparison of HCV NS3 protease and NS5B polymerase inhibitor activity in 1a, 1b and 2a replicons and 2a infectious virus.

    PubMed

    Paulson, Matthew S; Yang, Huiling; Shih, I-hung; Feng, Joy Y; Mabery, Eric M; Robinson, Margaret F; Zhong, Weidong; Delaney, William E

    2009-08-01

    The hepatitis C virus infection system represents an important new tool for drug discovery. In this study, we compared the in vitro antiviral efficacy of several NS3 and NS5B inhibitors in genotype 1a, 1b, and 2a replicons and in the 2a infectious virus system. The nucleoside inhibitor 2'-C-methyl adenosine showed similar efficacy in each system tested. Three non-nucleoside inhibitors had small differences in potency between genotype 1a and 1b. In contrast, there was a dramatic loss of potency for these non-nucleoside inhibitors in the genotype 2a replicon, 2a infectious virus, and 2a NS5B biochemical assays. The protease inhibitor BILN-2061 had similar efficacy against 1a and 1b replicons but was 61-109-fold less potent against the 2a replicon and virus, respectively. VX-950, a covalent protease inhibitor, had similar efficacy (<3-fold changes in EC(50)) regardless of genotype or subtype. Importantly, we observed a significant correlation (p<0.0001) in antiviral potency between the 2a replicon and 2a infectious virus for all classes of compounds tested.

  8. Photoperiod regulates lung-associated immunological parameters and melatonin receptor (Mel1a and Mel1b) in lungs of a tropical bird, Perdicula asiatica.

    PubMed

    Kharwar, Rajesh Kumar; Haldar, Chandana

    2011-01-01

    We accessed the effects of different photoperiodic regimes, i.e. long (LP; 20L:4D), short (SP; 4L:20D) and natural day photoperiod during reproductively inactive and reproductively active phase on immune parameters of lungs and general immunity of Perdicula asiatica. SP increased bronchus-associated lymphoid tissue (BALT) and non-BALT nodule size, total leukocyte count, lymphocyte count, plasma melatonin level, percent stimulation ratio of lymphocytes and decreased testicular activity (weight and testosterone level). LP during both the reproductive phases decreased the above-mentioned immune parameters suggesting that photoperiod might be regulating lung-associated immune system (LAIS) via melatonin. We also extended our study to note the expression of melatonin receptor types Mel(1a) and Mel(1b) in lung tissue to support our above statement. Western blot analysis showed significant increase in expression of Mel(1a) and Mel(1b) receptor types under SP conditions and decreased expression under LP condition when compared with control group of both reproductive phases. This suggests the probable involvement of Mel(1a) and Mel(1b) receptors in mediation of photoperiodic signals to LAIS. P. asiatica is a photoperiodic bird hence photoperiodically regulated melatonin hormone and its receptors in the lung might be responsible for modulation of lung-associated immunity.

  9. Different pathways of ( sup 3 H)inositol phosphate formation mediated by. alpha. 1a- and. alpha. 1b-adrenergic receptors

    SciTech Connect

    Wilson, K.M.; Minneman, K.P. )

    1990-10-15

    The types of inositol phosphates (InsPs) formed in response to activation of alpha 1-adrenergic receptor subtypes were determined in collagenase-dispersed renal cells and hepatocytes by high pressure liquid chromatography separation. In hepatocytes, which contain only the alpha 1b subtype, norepinephrine stimulated rapid (10-s) formation of (3H)Ins(1,4,5)P3 and (3H)Ins(1,3,4)P3 and slower (5-min) formation of Ins(1,4)P2 and Ins(1)P. Selective inactivation of alpha 1b receptors by chloroethylclonidine almost completely blocked the effects of norepinephrine in hepatocytes. In renal cells, which contain both alpha 1a and alpha 1b receptors in a 60:40 ratio, norepinephrine did not significantly increase the size of any peaks until 5 min after agonist activation. At this time, only a peak eluting with Ins(1)P and one eluting shortly after Ins(1,4)P2 were significantly elevated. Incubation with norepinephrine for 2 h caused small but significant increases in peaks co-eluting with Ins(1)P and Ins(1,4,5)P3 in renal cells; however, only the increase in Ins(1)P was inhibited by chloroethylclonidine pretreatment. Extraction under neutral conditions suggested that cyclic InsPs may be the primary compounds formed in response to norepinephrine in renal cells. Removal of extracellular Ca2+ caused a 60% reduction in the InsP response to norepinephrine in renal cells but had no effect in hepatocytes. These results suggest that activation of alpha 1a and alpha 1b receptor subtypes results in formation of different InsPs and that the response to alpha 1a activation may require influx of extracellular Ca2+.

  10. Serotonin 1A, 1B, and 7 receptors of the rat medial nucleus accumbens differentially regulate feeding, water intake, and locomotor activity.

    PubMed

    Clissold, Kara A; Choi, Eugene; Pratt, Wayne E

    2013-11-01

    Serotonin (5-HT) signaling has been widely implicated in the regulation of feeding behaviors in both humans and animal models. Recently, we reported that co-stimulation of 5-HT1&7 receptors of the anterior medial nucleus accumbens with the drug 5-CT caused a dose-dependent decrease in food intake, water intake, and locomotion in rats (Pratt et al., 2009). The current experiments sought to determine which of three serotonin receptor subtypes (5-HT1A, 5-HT1B, or 5-HT7) might be responsible for these consummatory and locomotor effects. Food-deprived rats were given 2-h access to rat chow after stimulation of nucleus accumbens 5-HT1A, 5-HT1B, or 5-HT7 receptors, or blockade of the 5-HT1A or 5-HT1B receptors. Stimulation of 5-HT1A receptors with 8-OH-DPAT (at 0.0, 2.0, 4.0, and 8.0 μg/0.5 μl/side) caused a dose-dependent decrease in food and water intake, and reduced rearing behavior but not ambulation. In contrast, rats that received the 5-HT1B agonist CP 93129 (at 0.0, 1.0, 2.0 and 4.0 μg/0.5 μl/side) showed a significant dose-dependent decrease in water intake only; stimulation of 5-HT7 receptors (AS 19; at 0.0, 1.0, and 5.0 μg/0.5 μl/side) decreased ambulatory activity but did not affect food or water consumption. Blockade of 5-HT1A or 5-HT1B receptors had no lasting effects on measures of food consumption. These data suggest that the food intake, water intake, and locomotor effects seen after medial nucleus accumbens injections of 5-CT are due to actions on separate serotonin receptor subtypes, and contribute to growing evidence for selective roles of individual serotonin receptors within the nucleus accumbens on motivated behavior.

  11. 5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

    PubMed Central

    Wu, Hua-Li; Pang, Si-Lin; Liu, Qiong-Zhen; Wang, Qian; Cai, Min-Xuan; Shang, Jing

    2014-01-01

    Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A

  12. CYP1A1 and CYP1B1 polymorphisms as modifying factors in patients with pneumoconiosis and occupationally related tumours: A pilot study.

    PubMed

    Schneider, Joachim; Bernges, Ulrike

    2009-01-01

    CYP1A1 and CYP1B1 are involved in the metabolism of carcinogens. The effect of CYP1A1 and CYP1B1 polymorphisms as genetic modifiers of risk was investigated in individuals with asbestos, silica dust or ionizing radiation-induced occupational tumours compared to exposed non-cancer subjects suffering from pneumoconiosis, particularly in relation to tobacco smoking. CYP1A1 T6235C, CYP1A1 A4889G and CYP1B1 codon 432 polymorphisms were determined by real-time PCR analysis in patients with asbestos-related lung cancer (n=39), patients with diffuse malignant mesotheliomas (n=19), lung cancer in silicosis patients (n=7), uranium miners with lung cancer (UMLC) (n=40), patients with asbestosis (n=181), and silicosis patients (n=204). The results were compared to those from a healthy unexposed control group (n=50) not exposed to carcinogenic (or fibrogenic) agents in the workplace. An additional healthy control group (n=134) comprised smokers and ex-smokers. Allele frequencies were within the range described for Caucasians. Multivariate analysis revealed that patients with occupational diseases with the susceptible CYP1A1 T6235C genotype had a calculated risk ranging from OR=0.5 (95% CI 0.18-1.36) for UMLC to OR=1.23 (95% CI 0.39-4.05) for uranium miners with silicosis. The risk for patients with the susceptible CYP1A1 A4889G allele was calculated as being between OR=0.39 (95% CI 0.10-1.54) for mesothelioma patients and OR=1.54 (95% CI 0.49-4.89) for UMLC. CYP1B1 Val432Leu polymorphisms were associated with a risk of OR=0.56 (95% CI 0.2-1.55) for UMLC and OR=1.52 (95% CI 0.68-3.39) for asbestos-exposed lung cancer patients. By analyzing the interaction between tobacco smoking, type of exposure to carcinogens and the genotypes, it was determined that smoking and the presence of the susceptible genotypes did not have a combined effect. In this pilot study, the analyzed polymorphism had no consistent modifying effect on pneumoconiosis or occupationally related tumours.

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

    PubMed Central

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

    2013-01-01

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

  14. Association of genetic variants of xenobiotic and estrogen metabolism pathway (CYP1A1 and CYP1B1) with gallbladder cancer susceptibility.

    PubMed

    Sharma, Kiran Lata; Agarwal, Akash; Misra, Sanjeev; Kumar, Ashok; Kumar, Vijay; Mittal, Balraj

    2014-06-01

    Gallbladder carcinoma is a highly aggressive cancer with female predominance. Interindividual differences in the effectiveness of the activation/detoxification of environmental carcinogens and endogenous estrogens may play a crucial role in cancer susceptibility. The present study included 410 patients with carcinoma of the gallbladder (GBC) and 230 healthy subjects. This study examined association of CYP1A1-MspI, CYP1A1-Ile462Val, and CYP1B1-Val432Leu with GBC susceptibility. CYP1A1-MspI [CC] and CYP1A1-Ile462Val [iso/val] genotypes were found to be significantly associated with GBC (p=0.006 and p=0.03, respectively), as compared to healthy controls, while CYP1B1-Val432Leu was not associated with GBC. The CYP1A1 haplotype [C-val] showed a significant association with GBC (p=0.006). On stratification based on gender, the CYP1A1-MspI [CC] genotype showed an increased risk of GBC in females (p=0.018). In case-only analysis, tobacco users with CYP1A1-MspI [CT] genotypes were at a higher risk of GBC (p=0.008). Subdividing the GBC patients on the basis of gallstone status, the CYP1A1 haplotype [C-val] imparted a higher risk in patients without stones when compared to controls (p=0.001). The results remained significant even after applying Bonferroni correction. Multivariate analysis revealed an increased risk of CYP1A1 iso/val and val/val genotypes in GBC patients having BMI >25 (p=0.021). The CYP1A1 polymorphisms may confer increased risk of GBC, probably due to impaired xenobiotic or hormone metabolism through a gallstone-independent pathway.

  15. Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

    PubMed Central

    Harkitis, P.; Lang, M. A.; Marselos, M.; Fotopoulos, A.; Albucharali, G.; Konstandi, M.

    2015-01-01

    Dopaminergic systems regulate the release of several hormones including growth hormone (GH), thyroid hormones, insulin, glucocorticoids and prolactin (PRL) that play significant roles in the regulation of various Cytochrome P450 (CYP) enzymes. The present study investigated the role of dopamine D2-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR) and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D2-receptors with sulpiride (SULP) significantly repressed the constitutive and benzo[a]pyrene (B[a]P)-induced CYP1A1, CYP1A2 and CYP1B expression in the rat liver. The expression of AhR, heat shock protein 90 (HSP90) and AhR nuclear translocator (ARNT) was suppressed by SULP in B[a]P-treated livers, whereas the AhRR expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D2-mediated down-regulation of constitutive CYP1A1/2 and CYP1B1 expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 genes, may also participate in the SULP-mediated repression of both, the constitutive and induced CYP1 expression. The present findings indicate that drugs acting as D2-dopamine receptor antagonists can modify several hormone systems that regulate the expression of CYP1A1, CYP1A2 and CYP1B1, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens. PMID:26466350

  16. Geophysical logs and water-quality data collected for boreholes Kimama-1A and -1B, and a Kimama water supply well near Kimama, southern Idaho

    USGS Publications Warehouse

    Twining, Brian V.; Bartholomay, Roy C.

    2011-01-01

    In September 2010, a research consortium led by scientists from Utah State University began drilling the first of three continuously cored boreholes on the Snake River Plain in southern Idaho. The goals of this effort, the Snake River Scientific Drilling Project, are to study the interaction between the Earth's crust and mantle, to identify potential geothermal energy sources, and to track the evolution of the Yellowstone hotspot on the Snake River Plain. The first borehole, located near Kimama, Idaho, is about 50 miles southwest of the U.S. Department of Energy's Idaho National Laboratory. Because geohydrologic data are scarce for that area of the central Snake River Plain, the Kimama borehole, completed in January 2011, provided a unique opportunity to collect geophysical and water-chemistry data from the eastern Snake River Plain aquifer system, downgradient of the laboratory. Therefore, in conjunction with the Snake River Scientific Drilling Project, scientists from the U.S. Geological Survey's Idaho National Laboratory Project Office conducted geophysical logging and collected water samples at the Kimama site. Wireline geophysical logs were collected for the diverging borehole, Kimama-1A and -1B, from land surface to 976 and 2,498 feet below land surface (BLS), respectively. Water samples were collected from Kimama-1A at depths near 460 and 830 feet BLS, and from the Kimama Water Supply (KWS) well located about 75 feet away. Geophysical log data included a composite of natural gamma, neutron, gamma-gamma dual density, and gyroscopic analysis for boreholes Kimama-1A and -1B. Geophysical logs depicted eight sediment layers (excluding surficial sediment) ranging from 4 to 60 feet in thickness. About 155 individual basalt flows were identified, ranging from less than 3 feet to more than 175 feet in thickness (averaging 15 feet) for borehole Kimama-1B (0 to 2,498 feet BLS). Sediment and basalt contacts were selected based on geophysical traces and were confirmed

  17. Mapping the genomic diversity of HCV subtypes 1a and 1b: Implications of structural and immunological constraints for vaccine and drug development

    PubMed Central

    Cuypers, Lize; Li, Guangdi; Neumann-Haefelin, Christoph; Piampongsant, Supinya; Libin, Pieter; Van Laethem, Kristel; Vandamme, Anne-Mieke; Theys, Kristof

    2016-01-01

    Despite significant progress in hepatitis C (HCV) treatment, global viral eradication remains a challenge. An in-depth map of its genome diversity within the context of structural and immunological constraints could contribute to the design of pan-genotypic antivirals and preventive vaccines. For such analyses, extensive information is only available for the highly prevalent HCV genotypes (GT) 1a and 1b. Using 647 GT1a and 408 GT1b full-genome sequences obtained from the Los Alamos database, we found that respectively 3 per cent and 82 per cent of all codon positions are under positive and negative selective pressure, suggesting variation mainly accumulates due to random genetic drift. An association between conservation and both structured RNA and secondary protein structures confirmed the important role of structural elements at nucleotide and at amino acid level. Remarkably, CD8+ T-cell epitopes in HCV GT1a were significantly more conserved, while at the same time containing more sites under positive selection. Similarly, CD4+ T-cell epitopes were significantly more conserved in both HCV subtypes, but under less positive selective pressure in GT1b and more negative selective pressure in GT1a. In contrast, B-cell epitopes in both subtypes were less conserved and under less stringent negative selection. These findings argue against immune selective pressure as the main force of between-host diversifying evolution. Despite its high variability, HCV is under strict evolutionary constraints, most probably to keep its genes and proteins functional during the replication cycle. These are encouraging findings for vaccine and drug design, which could consider these newly established genetic diversity profiles. PMID:27774307

  18. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations

    PubMed Central

    Howe, J; Sayed, M; Ahmed, A; Ringold, J; Larsen-Haidle, J; Merg, A; Mitros, F; Vaccaro, C; Petersen, G; Giardiello, F; Tinley, S; Aaltonen, L; Lynch, H

    2004-01-01

    Background: Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-ß superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients. Methods: DNA was extracted from the blood of JP patients and used for PCR amplification of each exon of these five genes, using primers flanking each intron–exon boundary. Mutations were determined by comparison to wild type sequences using sequence analysis software. A total of 77 JP cases were sequenced for mutations in the MADH4, BMPR1A, BMPR1B, BMPR2, and/or ACVR1 (activin A receptor) genes. The latter three genes were analysed when MADH4 and BMPR1A sequencing found no mutations. Results: Germline MADH4 mutations were found in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B, BMPR2, or ACVR1 in 32 MADH4 and BMPR1A mutation negative cases. Discussion: In the largest series of JP patients reported to date, the prevalence of germline MADH4 and BMPR1A mutations is approximately 20% for each gene. Since mutations were not found in more than half the JP patients, either additional genes predisposing to JP remain to be discovered, or alternate means of inactivation of the two known genes are responsible for these JP cases. PMID:15235019

  19. Competitive inhibition of carcinogen-activating CYP1A1 and CYP1B1 enzymes by a standardized complex mixture of PAH extracted from coal tar

    SciTech Connect

    Mahadevan, B.; Marston, C.P.; Luch, A.; Dashwood, W.M.; Brooks, E.; Pereira, C.; Doehmer, J.; Baird, W.M.

    2007-03-15

    A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, the Standard Reference Material (SRM) 1597, was recently shown to decrease the levels of DNA binding of the 2 strong carcinogens benzo(a)pyrene (BP) and dibenzo(a,l)pyrene (DBP) in the human mammary carcinoma-derived cell line MCF-7. The present study was designed to further elucidate the biochemical mechanisms involved in this inhibition process. We examined the effects of SRM 1597 on the metabolic activation of BP and DBP toward DNA-binding derivatives in Chinese hamster cells expressing either human cytochrome P450 (CYP) 1A1 or CYP1B1. The data obtained from biochemical experiments revealed that SRM 1597 competitively inhibited the activity of both human enzymes as analyzed by 7-ethoxyresorufin O-deethylation assays. While the Michaelis-Menten constant (K-M) was {lt} 0.4 {mu}M in the absence of SRM 1597, this value increased up to 1.12 (CYP1A1) or 4.45 {mu}M (CYP1B1) in the presence of 0.1 {mu} g/ml SRM 1597. Hence the inhibitory effects of the complex mixture on human CYP1B1 were much stronger when compared to human CYP1A1 Taken together, the decreases in PAH-DNA adduct formation on co-treatment with SRM 1597 revealed inhibitory effects on the CYP enzymes that convert carcinogenic PAH into DNA-binding metabolites. The implications for the tumorigenicity of complex environmental PAR mixtures are discussed.

  20. Role of 5-HT(1A) and 5-HT(1B) receptors in the antidepressant-like effect of piperine in the forced swim test.

    PubMed

    Mao, Qing-Qiu; Huang, Zhen; Ip, Siu-Po; Xian, Yan-Fang; Che, Chun-Tao

    2011-10-24

    Our previous studies have showed that treating mice with piperine significantly decreased the immobility time of the animals in the forced swim test and tail suspension test, which was related to up-regulation of serotonin (5-HT) level in the brain. The purpose of this study is to explore the contribution of 5-HT receptors in the antidepressant-like effect of piperine. The results showed that pre-treating mice with methiothepin (a non-selective 5-HT receptor antagonist, 0.1mg/kg, intraperitoneally), 4-(2'-methoxy-phenyl)-1-[2'-(n-2″-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (a selective 5-HT(1A) receptor antagonist, 1mg/kg, subcutaneously) or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (a 5-HT(1B) receptor antagonist, 2.5mg/kg, intraperitoneally) was found to abolish the anti-immobility effect of piperine (10mg/kg, intraperitoneally) in the forced swim test. On the other hand, a sub-effective dose of piperine (1mg/kg, intraperitoneally) produced a synergistic antidepressant-like effect with (+)-8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT(1A) receptor agonist, 1mg/kg, intraperitoneally) or anpirtoline (a 5-HT(1B) receptor agonist, 0.25mg/kg, intraperitoneally). Taken together, these results suggest that the antidepressant-like effect of piperine in the mouse forced swim test may be mediated, at least in part, by the activation of 5-HT(1A) and 5-HT(1B) receptors.

  1. The 3A2, 1A2, 3B2, and 1B2 electronic states of CH2: Small bond angle states

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Yukio; Schaefer, Henry F., III

    1997-02-01

    Molecular structures with very small bond angles are a curiosity in chemistry. The two triplet (3A2 and 3B2) and two singlet (1A2 and 1B2) excited states of CH2 have been investigated systematically using ab initio electronic structure theory. For these four states total energies and physical properties including geometries, dipole moments, harmonic vibrational frequencies, and associated infrared intensities were determined with the single and double excitation configuration interaction (CISD) method using four different basis sets. It is confirmed in this study that the four states of CH2 all have bent structures with longer CH bond lengths and smaller bond angles than the four lower-lying (X˜, ã, b˜, and c˜) states of CH2. At the CISD optimized geometries single point energies were determined with complete active space self-consistent-field (CASSCF) and CASSCF second-order configuration interaction (SOCI) levels of theory. For the triplet excited states single point energies were also determined employing coupled cluster with single and double excitations (CCSD) and CCSD with perturbative triple excitations methods. At the CISD level with the largest basis set, the triple zeta plus triple polarizations with two sets of higher angular momentum and two sets of diffuse functions basis set [TZ3P(2 f,2d)+2diff], the bond angles were predicted to be 40.6° (3A2), 46.1° (1A2), 76.3° (3B2), and 81.3° (1B2), while the dipole moments were determined to be 2.35 (3A2), 2.26 (1A2), 1.69 (3B2), and 1.60 debye (1B2), respectively. With the most accurate method in this study, the CASSCF-SOCI level with the TZ3P(2 f,2d)+2diff basis set, the energy separations (Te value) between the ground state (X˜ 3B1) and the four excited states were predicted to be 73.7 kcal/mol (3.20 eV, 25 800 cm-1) for the 3A2 state, 96.8 kcal/mol (4.20 eV, 33 800 cm-1) for the 1A2 state, 151.0 kcal/mol (6.55 eV, 52 800 cm-1) for the 3B2 state, and 182.5 kcal/mol (7.91 eV, 63 800 cm-1) for the 1B2

  2. Polycomb RING1A- and RING1B-dependent histone H2A monoubiquitylation at pericentromeric regions promotes S-phase progression.

    PubMed

    Bravo, Mónica; Nicolini, Fabio; Starowicz, Katarzyna; Barroso, Sonia; Calés, Carmela; Aguilera, Andrés; Vidal, Miguel

    2015-10-01

    The functions of polycomb products extend beyond their well-known activity as transcriptional regulators to include genome duplication processes. Polycomb activities during DNA replication and DNA damage repair are unclear, particularly without induced replicative stress. We have used a cellular model of conditionally inactive polycomb E3 ligases (RING1A and RING1B), which monoubiquitylate lysine 119 of histone H2A (H2AK119Ub), to examine DNA replication in unperturbed cells. We identify slow elongation and fork stalling during DNA replication that is associated with the accumulation of mid and late S-phase cells. Signs of replicative stress and colocalisation of double-strand breaks with chromocenters, the sites of coalesced pericentromeric heterocromatic (PCH) domains, were enriched in cells at mid S-phase, the stage at which PCH is replicated. Altered replication was rescued by targeted monoubiquitylation of PCH through methyl-CpG binding domain protein 1. The acute senescence associated with the depletion of RING1 proteins, which is mediated by p21 (also known as CDKN1A) upregulation, could be uncoupled from a response to DNA damage. These findings link cell proliferation and the polycomb proteins RING1A and RING1B to S-phase progression through a specific function in PCH replication.

  3. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.

    PubMed

    Chicas, Agustin; Kapoor, Avnish; Wang, Xiaowo; Aksoy, Ozlem; Evertts, Adam G; Zhang, Michael Q; Garcia, Benjamin A; Bernstein, Emily; Lowe, Scott W

    2012-06-05

    Cellular senescence is a tumor-suppressive program that involves chromatin reorganization and specific changes in gene expression that trigger an irreversible cell-cycle arrest. Here we combine quantitative mass spectrometry, ChIP deep-sequencing, and functional studies to determine the role of histone modifications on chromatin structure and gene-expression alterations associated with senescence in primary human cells. We uncover distinct senescence-associated changes in histone-modification patterns consistent with a repressive chromatin environment and link the establishment of one of these patterns--loss of H3K4 methylation--to the retinoblastoma tumor suppressor and the H3K4 demethylases Jarid1a and Jarid1b. Our results show that Jarid1a/b-mediated H3K4 demethylation contributes to silencing of retinoblastoma target genes in senescent cells, suggesting a mechanism by which retinoblastoma triggers gene silencing. Therefore, we link the Jarid1a and Jarid1b demethylases to a tumor-suppressor network controlling cellular senescence.

  4. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence

    PubMed Central

    Chicas, Agustin; Kapoor, Avnish; Wang, Xiaowo; Aksoy, Ozlem; Evertts, Adam G.; Zhang, Michael Q.; Garcia, Benjamin A.; Bernstein, Emily; Lowe, Scott W.

    2012-01-01

    Cellular senescence is a tumor-suppressive program that involves chromatin reorganization and specific changes in gene expression that trigger an irreversible cell-cycle arrest. Here we combine quantitative mass spectrometry, ChIP deep-sequencing, and functional studies to determine the role of histone modifications on chromatin structure and gene-expression alterations associated with senescence in primary human cells. We uncover distinct senescence-associated changes in histone-modification patterns consistent with a repressive chromatin environment and link the establishment of one of these patterns—loss of H3K4 methylation—to the retinoblastoma tumor suppressor and the H3K4 demethylases Jarid1a and Jarid1b. Our results show that Jarid1a/b-mediated H3K4 demethylation contributes to silencing of retinoblastoma target genes in senescent cells, suggesting a mechanism by which retinoblastoma triggers gene silencing. Therefore, we link the Jarid1a and Jarid1b demethylases to a tumor-suppressor network controlling cellular senescence. PMID:22615382

  5. Triclosan activates aryl hydrocarbon receptor (AhR)-dependent apoptosis and affects Cyp1a1 and Cyp1b1 expression in mouse neocortical neurons.

    PubMed

    Szychowski, Konrad A; Wnuk, Agnieszka; Kajta, Małgorzata; Wójtowicz, Anna K

    2016-11-01

    Triclosan (TCS) is an antimicrobial agent that is used extensively in personal care and in sanitizing products, such as soaps, toothpastes, and hair products. A number of studies have revealed the presence of TCS in human tissues, such as fat, liver and brain, in addition to blood and breast milk. The aim of the present study was to investigate the impact of TCS on AhR and Cyp1a1/Cyp1b1 signaling in mouse neocortical neurons in primary cultures. In addition to the use of selective ligands and siRNAs, expression levels of mRNA and proteins as well as caspase-3 activity, reactive oxygen species (ROS) formation, and lactate dehydrogenase (LDH) release have been measured. We also studied the involvement of the AhR in TCS-induced LDH release and caspase-3 activation as well as the effect of TCS on ROS generation. Cultures of neocortical neurons were prepared from Swiss mouse embryos on day 15/16 of gestation. The cells were cultured in phenol red-free Neurobasal medium with B27 and glutamine, and the neurons were exposed to 1 and 10µM TCS. Our experiments showed that the expression of AhR and Cyp1a1 mRNA decreased in cells exposed to 10µM TCS for 3 or 6h. In the case of Cyp1b1, mRNA expression remained unchanged compared with the control group following 3h of exposure to TCS, but after 6h, the mRNA expression of Cyp1b1 was decreased. Our results confirmed that the AhR is involved in the TCS mechanism of action, and our data demonstrated that after the cells were transfected with AhR siRNA, the cytotoxic and pro-apoptotic properties of TCS were decreased. The decrease in Cyp1a1 mRNA and protein expression levels accompanied by a decrease in its activity. The stimulation of Cyp1a1 activity produced by the application of an AhR agonist (βNF) was attenuated by TCS, whereas the addition of AhR antagonist (αNF) reversed the inhibitory effects of TCS. In our experiments, TCS diminished Cyp1b1 mRNA and enhanced its protein expression. In case of Cyp1a1 we observed

  6. The CIDA Variability Survey of Orion OB1. I. The Low-Mass Population of Ori OB1a and 1b

    NASA Astrophysics Data System (ADS)

    Briceño, Cesar; Calvet, Nuria; Hernández, J.; Vivas, A. K.; Hartmann, Lee; Downes, J. J.; Berlind, Perry

    2005-02-01

    We present results of a large-scale, multiepoch optical survey of the Orion OB1 association, carried out with the QUEST camera at the Venezuela National Astronomical Observatory. We identify for the first time the widely spread low-mass, young population in the Ori OB1a and OB1b subassociations. Candidate members were picked up by their variability in the V band and position in color-magnitude diagrams. We obtained spectra to confirm membership. In a region spanning ~68 deg2, we found 197 new young stars; of these, 56 are located in the Ori OB1a subassociation and 141 in Ori OB1b. The spatial distribution of the low-mass young stars is spatially coincident with that of the high-mass members but suggests a much sharper edge to the association. Comparison with the spatial extent of molecular gas and extinction maps indicates that the subassociation Ori OB1b is concentrated within a ringlike structure of radius ~2°(~15 pc at 440 pc), centered roughly on the star ɛ Ori in the Orion belt. The ring is apparent in 13CO and corresponds to a region with an extinction AV>=1. The stars exhibiting strong Hα emission, an indicator of active accretion, are found along this ring, whereas the center is populated with weak Hα-emitting stars. In contrast, Ori OB1a is located in a region devoid of gas and dust. We identify a grouping of stars within a ~3 deg2 area located in Ori OB1a, roughly clustered around the B2 star 25 Ori. The Herbig Ae/Be star V346 Ori is also associated with this grouping, which could be an older analog of σ Ori. Using several sets of evolutionary tracks, we find an age of 7-10 Myr for Ori OB1a and of ~4-6 Myr for Ori OB1b, consistent with previous estimates from OB stars. Indicators such as the equivalent width of Hα and near-IR excesses show that the number of accreting low-mass stars decreases sharply between Ori OB1b and Ori OB1a. These results indicate that although a substantial fraction of accreting disks remain at ages ~5 Myr, inner disks are

  7. Smyd1b_tv1, a Key Regulator of Sarcomere Assembly, Is Localized on the M-Line of Skeletal Muscle Fibers

    PubMed Central

    Li, Huiqing; Xu, Jin; Bian, Yue-Hong; Rotllant, Pep; Shen, Tiansheng; Chu, Wuying; Zhang, Jianshe; Schneider, Martin; Du, Shao Jun

    2011-01-01

    Background Smyd1b is a member of the Smyd family that plays a key role in sarcomere assembly during myofibrillogenesis. Smyd1b encodes two alternatively spliced isoforms, smyd1b_tv1 and smyd1b_tv2, that are expressed in skeletal and cardiac muscles and play a vital role in myofibrillogenesis in skeletal muscles of zebrafish embryos. Methodology/Principal Findings To better understand Smyd1b function in myofibrillogenesis, we analyzed the subcellular localization of Smyd1b_tv1 and Smyd1b_tv2 in transgenic zebrafish expressing a myc-tagged Smyd1b_tv1 or Smyd1b_tv2. The results showed a dynamic change of their subcellular localization during muscle cell differentiation. Smyd1b_tv1 and Smyd1b_tv2 were primarily localized in the cytosol of myoblasts and myotubes at early stage zebrafish embryos. However, in mature myofibers, Smyd1b_tv1, and to a small degree of Smyd1b_tv2, exhibited a sarcomeric localization. Double staining with sarcomeric markers revealed that Smyd1b_tv1was localized on the M-lines. The sarcomeric localization was confirmed in zebrafish embryos expressing the Smyd1b_tv1-GFP or Smyd1b_tv2-GFP fusion proteins. Compared with Smyd1b_tv1, Smyd1b_tv2, however, showed a weak sarcomeric localization. Smyd1b_tv1 differs from Smyd1b_tv2 by a 13 amino acid insertion encoded by exon 5, suggesting that some residues within the 13 aa insertion may be critical for the strong sarcomeric localization of Smyd1b_tv1. Sequence comparison with Smyd1b_tv1 orthologs from other vertebrates revealed several highly conserved residues (Phe223, His224 and Gln226) and two potential phosphorylation sites (Thr221 and Ser225) within the 13 aa insertion. To determine whether these residues are involved in the increased sarcomeric localization of Smyd1b_tv1, we mutated these residues into alanine. Substitution of Phe223 or Ser225 with alanine significantly reduced the sarcomeric localization of Smyd1b_tv1. In contrast, other substitutions had no effect. Moreover, replacing Ser225 with

  8. Association of CYP1A1, CYP1B1 and CYP17 gene polymorphisms and organochlorine pesticides with benign prostatic hyperplasia.

    PubMed

    Kumar, Vivek; Banerjee, Basu Dev; Datta, Sudip Kumar; Yadav, Chandra Shekhar; Singh, Satyender; Ahmed, Rafat Sultana; Gupta, Sanjay

    2014-08-01

    It is well established that steroidal hormones (testosterone and estrogen) increase benign prostatic hyperplasia (BPH) risk. Cytochrome P450 (CYP) enzymes especially CYP1A1, CYP1B1 and CYP17 metabolize these hormones. Apart from that, several endocrine disrupting organochlorine pesticides (OCPs) are reported to mimic the activity of these steroidal hormones. Therefore, functional polymorphisms in these genes and exposure to such pesticides may increase BPH risk further. Our study included 100 newly diagnosed BPH subjects and 100 age-matched healthy male controls. CYP1A1, CYP1B1 and CYP17 polymorphisms were studied using PCR-RFLP and allele-specific PCR method. OCP levels in blood were analyzed by gas chromatography (GC). Levels of p,p'-DDE and endosulfan α were found to be significantly higher amongst BPH subjects as compared to controls (p-values=0.001 and 0.03 respectively) and CYP17 polymorphism was observed to be significantly associated with BPH subjects as compared to controls (p-values=0.03), indicating that these factors may be important risk factors for BPH. However, further studies are required before unequivocal conclusion.

  9. Tomato carotenoid cleavage dioxygenases 1A and 1B: Relaxed double bond specificity leads to a plenitude of dialdehydes, mono-apocarotenoids and isoprenoid volatiles

    PubMed Central

    Ilg, Andrea; Bruno, Mark; Beyer, Peter; Al-Babili, Salim

    2014-01-01

    The biosynthetic processes leading to many of the isoprenoid volatiles released by tomato fruits are still unknown, though previous reports suggested a clear correlation with the carotenoids contained within the fruit. In this study, we investigated the activity of the tomato (Solanum lycopersicum) carotenoid cleavage dioxygenase (SlCCD1B), which is highly expressed in fruits, and of its homolog SlCCD1A. Using in vitro assays performed with purified recombinant enzymes and by analyzing products formed by the two enzymes in carotene-accumulating Escherichia coli strains, we demonstrate that SlCCD1A and, to a larger extent, SlCCD1B, have a very relaxed specificity for both substrate and cleavage site, mediating the oxidative cleavage of cis- and all-trans-carotenoids as well as of different apocarotenoids at many more double bonds than previously reported. This activity gives rise to a plenitude of volatiles, mono-apocarotenoids and dialdehyde products, including cis-pseudoionone, neral, geranial, and farnesylacetone. Our results provide a direct evidence for a carotenoid origin of these compounds and point to CCD1s as the enzymes catalyzing the formation of the vast majority of tomato isoprenoid volatiles, many of which are aroma constituents. PMID:25057464

  10. CYP1B1, CYP1A1, MPO, and GSTP1 polymorphisms and lung cancer risk in never-smoking Korean women.

    PubMed

    Yoon, Kyong-Ah; Kim, Jin Hee; Gil, Hyea-Jin; Hwang, Hyukkee; Hwangbo, Bin; Lee, Jin Soo

    2008-04-01

    Polymorphisms in metabolic genes encoding phase I and phase II enzymes are thought to modulate the risk of lung cancer via changes in enzymatic activity. Recently, the effect of these metabolic enzymes and their interaction with environmental factors has been studied in both smokers and also never-smokers, since never-smokers are a good model in which to study genetic susceptibility at low-dose carcinogen exposure. Here, we investigated the association of CYP1A1 Ile462Val, CYP1B1 Leu432Val, GSTP1 Ile105Val, MPO G-463A polymorphisms and lung cancer risk in never-smoking Korean women. In this case-control study of 213 lung cancer patients and 213 age-matched healthy controls, we found that carrying one variant allele of the CYP1A1 Ile462Val polymorphism was associated with a significantly decreased risk of lung adenocarcinoma (adjusted odds ratio (OR)=0.63; 95% confidence interval (CI), 0.41-0.99). Furthermore, the combination of risk genotypes of CYP1B1 Leu432Val with CYP1A1 Ile462Val was associated with the risk of lung adenocarcinoma (adjusted OR=2.16; 95% CI, 1.02-4.57) as well as overall lung cancer (adjusted OR=2.23; 95% CI 1.01-4.89). The polymorphisms of GSTP1 Ile105Val and MPO G-463A showed no significant association with lung cancer. Theses results suggest that the CYP1A1 Ile462Val polymorphism is associated with a reduced risk of lung adenocarcinoma in never-smoking Korean women, whereas specific combinations of variant genotypes for metabolic enzymes increase lung cancer risk considerably.

  11. Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations.

    PubMed

    Dotto, Renata P; Giuffrida, Fernando M A; Franco, Luciana; Mathez, Andreia L G; Weinert, Leticia S; Silveiro, Sandra P; Sa, Joao R; Reis, Andre F; Dias-da-Silva, Magnus R

    2016-06-01

    Thirty-two patients with diabetes negative for point mutations in GCK and HNF1A underwent further molecular screening of GCK, HNF1A, HNF4A, and HNF1B by MLPA analysis. We described the first Brazilian case of MODY5 due to a heterozygous whole-gene deletion in HNF1B, who developed rapidly progressive renal failure and death.

  12. Ab initio quantum study of the photodynamics and absorption spectrum for the coupled 1(1)A2 and 1(1)B1 states of SO2.

    PubMed

    Lévêque, Camille; Komainda, Adrian; Taïeb, Richard; Köppel, Horst

    2013-01-28

    The nonadiabatic photoinduced dynamics occurring in the coupled 1(1)A(2) and 1(1)B(1) excited states of SO(2) is investigated using ab initio quantum dynamical methods. To this end, large scale calculations of the potential energy surfaces have been carried out at the multireference configuration interaction level. All vibrational degrees of freedom of the molecule are considered in the potential energy surface calculations and the quantum dynamical treatment. To deal with the symmetry-allowed conical intersection which occurs between the potential energy surfaces, we use the diabatic picture in the framework of regularized diabatic states. Wave-packet propagation on the coupled surfaces was performed and allowed to reproduce with good accuracy the complex absorption band observed experimentally in the 29,000-42,000 cm(-1) range. This provides a basis for a subsequent theoretical treatment of the high order harmonic spectra of SO(2).

  13. Cytochrome P450 1A, 1B, and 1C mRNA induction patterns in three-spined stickleback exposed to a transient and a persistent inducer

    PubMed Central

    Gao, Kai; Brandt, Ingvar; Goldstone, Jared V.; Jönsson, Maria E.

    2013-01-01

    Cytochrome P450 1 (CYP1) mRNA induction patterns in three-spined stickleback (Gasterosteous aculeatus) were explored for use in environmental monitoring of aryl hydrocarbon receptor (AHR) agonists. The cDNAs of stickleback CYP1A, CYP1B1, CYP1C1, and CYP1C2 were cloned and their basal and induced expression patterns were determined in brain, gill, liver and kidney. Also, their induction time courses were compared after waterborne exposure to a transient (indigo) or a persistent (3,3′,4,4′,5-pentacholorbiphenyl PCB 126) AHR agonist. The cloned stickleback CYP1s exhibited a high amino acid sequence identity compared with their zebrafish orthologs and their constitutive tissue distribution patterns largely agree with those reported in other species. PCB 126 (100 nM) induced different CYP1 expression patterns in the four tissues, suggesting tissue-specific regulation. Both indigo (1 nM) and PCB 126 (10 nM) induced a strong CYP1 expression in gills. However, while PCB 126 gave rise to a high and persistent induction in gills and liver, induction by indigo was transient in both organs. The number of putative dioxin response elements found in each CYP1 gene promoter roughly reflected the induction levels of the genes. The high responsiveness of CYP1A, CYP1B1, and CYP1C1 observed in several organs suggests that three-spined stickleback is suitable for monitoring of pollution with AHR agonists. PMID:21354474

  14. KEY COMPARISON: Force key comparison CCM.F-K1.a and CCM.F-K1.b: 5 kN and 10 kN

    NASA Astrophysics Data System (ADS)

    Pusa, Aimo

    2009-01-01

    This report describes the key comparisons named CCM.F-K1.a and CCM.F-K1.b, for force with loads of 5 kN and 10 kN. The Draft A Report, reporting the measurement results of the key comparisons, has been accepted at the force expert group meeting in Pretoria on 23 March 2004. This became Part 1 of the preliminary Draft B Report. Then, there have been several discussions to find the best way for the determination of the reference value for force values 5 kN and 10 kN in the key comparisons CCM.F-K1.a and CCM.F-K1.b. Following the meeting held in Queretaro, Mexico, by CENAM, from 3 to 5 December 2007, the reference values have been calculated for each single transducer (see chapter 2), and as one reference value for 5 kN and a second reference value for 10 kN (see chapter 3). To get a better consistency a linear model for the drift of transducers has been applied. The results have been evaluated according to the paper from M G Cox, 'The evaluation of key comparison data' (2002 Metrologia 39 589-595). Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (MRA).

  15. Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats.

    PubMed

    Avila-Rojas, Sabino Hazael; Velázquez-Lagunas, Isabel; Salinas-Abarca, Ana Belen; Barragán-Iglesias, Paulino; Pineda-Farias, Jorge Baruch; Granados-Soto, Vinicio

    2015-10-05

    Serotonin (5-HT) participates in pain modulation by interacting with different 5-HT receptors. The role of 5-HT5A receptor in neuropathic pain has not previously studied. The purpose of this study was to investigate: A) the role of 5-HT5A receptors in rats subjected to spinal nerve injury; B) the expression of 5-HT5A receptors in dorsal spinal cord and dorsal root ganglia (DRG). Neuropathic pain was induced by L5/L6 spinal nerve ligation. Tactile allodynia in neuropathic rats was assessed with von Frey filaments. Western blot methodology was used to determine 5-HT5A receptor protein expression. Intrathecal administration (on day 14th) of 5-HT (10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) reversed nerve injury-induced tactile allodynia. Intrathecal non-selective (methiothepin, 0.1-0.8 nmol) and selective (SB-699551, 1-10 nmol) 5-HT5A receptor antagonists reduced, by ~60% and ~25%, respectively, the antiallodynic effect of 5-HT (100 nmol) or 5-CT (0.3 nmol). Moreover, both selective 5-HT1A and 5-HT1B/1D receptor antagonists, WAY-100635 (0.3-1 nmol) and GR-127935 (0.3-1 nmol), respectively, partially diminished the antiallodynic effect of 5-HT or 5-CT by about 30%. Injection of antagonists, by themselves, did not affect allodynia. 5-HT5A receptors were expressed in the ipsilateral dorsal lumbar spinal cord and DRG and L5/L6 spinal nerve ligation did not modify 5-HT5A receptor protein expression in those sites. Results suggest that 5-HT5A receptors reduce pain processing in the spinal cord and that 5-HT and 5-CT reduce neuropathic pain through activation of 5-HT5A and 5-HT1A/1B/1D receptors. These receptors could be an important part of the descending pain inhibitory system.

  16. Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals.

    PubMed

    Shang, Zhenwei; Lv, Hongchao; Zhang, Mingming; Duan, Lian; Wang, Situo; Li, Jin; Liu, Guiyou; Ruijie, Zhang; Jiang, Yongshuai

    2015-12-15

    Alzheimer's disease (AD) is an acquired disorder of cognitive and behavioral impairment. It is considered to be caused by variety of factors, such as age, environment and genetic factors. In order to identify the genetic affect factors of AD, we carried out a bioinformatic approach which combined genome-wide haplotype-based association study with gene prioritization. The raw SNP genotypes data was downloaded from GEO database (GSE33528). It contains 615 AD patients and 560 controls of Caribbean Hispanic individuals. Firstly, we identified the linkage disequilibrium (LD) haplotype blocks and performed genome-wide haplotype association study to screen significant haplotypes that were associated with AD. Then we mapped these significant haplotypes to genes and obtained candidate genes set for AD. At last, we prioritized AD candidate genes based on their similarity with 36 known AD genes, so as to identify AD related genes. The results showed that 141 haplotypes on 134 LD blocks were significantly associated with AD (P<1E-4), and these significant haplotypes were mapped to 132 AD candidate genes. After prioritizing these candidate genes, we found seven AD related genes: APOE, APOC1, TNFRSF1A, LRP1B, CDH1, TG and CASP7. Among these genes, APOE and APOC1 are known AD risk genes. For the other five genes TNFRSF1A, CDH1, CASP7, LRP1B and TG, this is the first genetic association study which showed the significant association between these five genes and AD susceptibility in Caribbean Hispanic individuals. We believe that our findings can provide a new perspective to understand the genetic affect factors of AD.

  17. Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 Are Associated with Early Age Acute Leukemia.

    PubMed

    Lopes, Bruno Almeida; Emerenciano, Mariana; Gonçalves, Bruno Alves Aguiar; Vieira, Tállita Meciany; Rossini, Ana; Pombo-de-Oliveira, Maria S

    2015-01-01

    Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000-2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29-0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17-4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08-0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08-0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.

  18. Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 Are Associated with Early Age Acute Leukemia

    PubMed Central

    Lopes, Bruno Almeida; Emerenciano, Mariana; Gonçalves, Bruno Alves Aguiar; Vieira, Tállita Meciany; Rossini, Ana; Pombo-de-Oliveira, Maria S.

    2015-01-01

    Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000–2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29–0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17–4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08–0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08–0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns. PMID:25992585

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

    PubMed

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

    2010-12-20

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

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

    PubMed Central

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

    2010-01-01

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

  1. Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes

    PubMed Central

    Balaguer, Patrick; Ekstrand, Bo; Daujat-Chavanieu, Martine; Gerbal-Chaloin, Sabine

    2016-01-01

    Skatole (3-methylindole) is a product of bacterial fermentation of tryptophan in the intestine. A significant amount of skatole can also be inhaled during cigarette smoking. Skatole is a pulmonary toxin that induces the expression of aryl hydrocarbon receptor (AhR) regulated genes, such as cytochrome P450 1A1 (CYP1A1), in human bronchial cells. The liver has a high metabolic capacity for skatole and is the first organ encountered by the absorbed skatole; however, the effect of skatole in the liver is unknown. Therefore, we investigated the impact of skatole on hepatic AhR activity and AhR-regulated gene expression. Using reporter gene assays, we showed that skatole activates AhR and that this is accompanied by an increase of CYP1A1, CYP1A2 and CYP1B1 expression in HepG2-C3 and primary human hepatocytes. Specific AhR antagonists and siRNA-mediated AhR silencing demonstrated that skatole-induced CYP1A1 expression is dependent on AhR activation. The effect of skatole was reduced by blocking intrinsic cytochrome P450 activity and indole-3-carbinole, a known skatole metabolite, was a more potent inducer than skatole. Finally, skatole could reduce TCDD-induced CYP1A1 expression, suggesting that skatole is a partial AhR agonist. In conclusion, our findings suggest that skatole and its metabolites affect liver homeostasis by modulating the AhR pathway. PMID:27138278

  2. Electrophoretic protein analysis for the identification of doubled haploid 1A-1R, 1B-1R wheat-rye double translocation lines and for the assessment of their genetic stability.

    PubMed

    Vahl, U; Müller, G; Böhme, T

    1993-06-01

    Eighteen available doubled haploid wheat lines with a cytologically proven 1A-1R, 1B-1R double translocation, which where derived via anther culture from four crosses of the 1A-1R wheat-rye translocation cv "Amigo" with several 1B-1R wheat-rye translocation forms, were subjected to electrophoretic seed protein analysis. Besides, the five parents used in the crosses and some other wheat cultivars and doubled haploid lines (19 with a 1B-1R single translocation, 10 with a 1A-1R translocation and 7 without any 1R translocation) were also included in the investigation. It was found that the gliadin patterns visualized after SDS polyacrylamide gel electrophoresis of alcohol-soluble seed protein extracts can differentiate not only 1B-1R and 1A-1R translocation forms from wheats without any 1R-translocation chromosome, but also 1B-1R and 1A-1R wheats from each other. Moreover, 1A-1R, 1B-1R double translocation lines can be distinguished as well due to characteristic differences revealed between 1A-1R and 1B-1R translocation forms. Thus, all of tested dh1- and dh2-grains of the double translocation lines showed the expected doublet: the 1A-1R translocation ("Amigo")-typical rye band and the 1B-1R translocation ("Kawkas")-typical rye band. Consequently, gliadin patterns estimated after SDS electrophoresis may be used as markers for the fast detection of the desired 1A-1R, 1B-1R double translocation forms among 1A-1R single translocation lines, 1B-1R single translocation lines and lines without any 1R-translocation in the progenies of appropriate crosses. Furthermore, by means of gliadin tests on the dh2-generation the excellent stability of the double translocation 1A-1R, 1B-1R during more than one propagation phase has been proven. Estimations of high-molecular weight (HMW) glutenin subunits coded by 1A and 1B chromosomes are compatible with the double translocation constitution. A few deviating results can be explained by crossing-over events. Seed protein analysis

  3. Association of CYP1A1 and CYP1B1 polymorphisms with bone mineral density variations in postmenopausal Mexican-Mestizo women.

    PubMed

    Chávez, Bertha; Vilchis, Felipe; Rojano-Mejía, David; Coral Vázquez, Ramón Mauricio; Aguirre-García, María Del Carmen; Canto, Patricia

    2017-03-16

    Herein, we investigated potential associations between polymorphisms of genes related to estrogen metabolism and bone mineral density (BMD) in postmenopausal women. This was a cross-sectional study, in which two hundred and ninety postmenopausal Mexican-Mestizo women were studied. The BMD of the lumbar spine (LS), total hip (TH), and femoral neck (FN) was measured. The distribution of the genetic polymorphisms, including rs1799814 and rs1048943 at CYP1A1 as well as rs1056836 at CYP1B1, were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single-stranded conformational polymorphism (SSCP), and DNA sequencing. Deviations from Hardy-Weinberg equilibrium (HWE) were tested, and linkage disequilibrium (LD) was calculated by direct correlation (r(2)). Moreover, haplotype analysis was performed. All polymorphisms were in HWE. The genotype and allele distributions of the three single nucleotide polymorphisms (SNPs) studied showed no significant differences. However, statistical significance was reached when constructing haplotypes. The CG haplotype in CYP1A1 was associated with variations in LS and FN BMD after adjustment for covariates (p = 0.021 and 0.045, respectively), but the association with TH BMD was not significant. These results suggested that the CG haplotype in CYP1A1 may play an important role in the mechanism of osteoporosis and may be useful as a genetic marker.

  4. Open reading frames 1a and 1b of the porcine reproductive and respiratory syndrome virus (PRRSV) collaboratively initiate viral minus-strand RNA synthesis.

    PubMed

    Tang, Yan-Dong; Fang, Qiong-Qiong; Liu, Ji-Ting; Wang, Tong-Yun; Wang, Yu; Tao, Ye; Liu, Yong-Gang; Cai, Xue-Hui

    2016-09-02

    The porcine reproductive and respiratory syndrome virus (PRRSV) causes a persistent threat to the swine industry, especially when highly pathogenic PRRSV (HP-PRRSV) emerges. Previous studies have indicated that PRRSV RNA synthesis was correlated with HP-PRRSV virulence. PRRSV RNA synthesis includes genomic RNA and sub-genomic mRNA, and these processes require minus-strand RNA as a template. However, the mechanisms involved in PRRSV minus-strand RNA synthesis are not fully understood. A mini-genome system can be used to assess viral replication mechanisms and to evaluate the effects of potential antiviral drugs on viral replicase activities. In this study, we developed a mini-genome system that uses firefly luciferase as a reporter. Based on this system, we found that PRRSV RNA-dependent RNA polymerase nsp9 alone failed to activate virus minus-strand RNA synthesis. We also demonstrated that combinations of open reading frames 1a (ORF1a) and ORF1b are necessary for viral minus-strand RNA synthesis.

  5. Differential Induction of CYP1A1 and CYP1B1 by Benzo[a]pyrene in Oral Squamous Cell Carcinoma Cell Lines and by Tobacco Smoking in Oral Mucosa

    PubMed Central

    Chi, Angela C.; Appleton, Kathryn; Henriod, Joel B.; Krayer, Joe W.; Marlow, Nicole M.; Bandyopadhyay, Dipankar; Sigmon, Ryan C.; Kurtz, David T.

    2009-01-01

    Polyaromatic hydrocarbons, including benzo[a]pyrene (BP), are major tobacco carcinogens. Their carcinogenic effects require metabolic activation by cytochrome p450 (CYP) enzymes. Relative CYP isoform expression is related to tissue-specific tobacco-related squamous cell carcinoma (SCC) susceptibility. There have been conflicting reports regarding relative CYP1A1 and CYP1B1 oral expression, and information regarding CYP1B1 expression in oral tissues is limited. OBJECTIVE To quantify BP- and tobacco-induced CYP1A1 and CYP1B1 expression in oral SCC cells and oral mucosa. STUDY DESIGN Real-time qPCR was performed to measure 1) BP-induced CYP1A1 and CYP1B1 mRNA expression in seven oral/other head and neck SCC cell lines 2) CYP1A1 and CYP1B1 mRNA expression in gingiva from 22 smokers and 24 nonsmokers. RESULTS SCC lines exhibited either similar induction of both isoforms or preferential CYP1A1 induction (CYP1A1-to-CYP1B1 ratios 0.8-4.3). In contrast, gingival tissues from smokers exhibited preferential CYP1B1 induction. Marked interindividual variation in CYP1A1 and CYP1B1 expression was observed among smokers. CONCLUSIONS In vitro conditions may not account for factors that modulate expression in vivo. Interindividual variation in inducible CYP1A1 and CYP1B1 expression may account in part for variation in tobacco-related oral SCC risk. PMID:19576839

  6. Distribution of natural resistance to NS3 protease inhibitors in hepatitis C genotype 1a separated into clades 1 and 2 and in genotype 1b of HIV-infected patients.

    PubMed

    Bagaglio, S; Uberti-Foppa, C; Messina, E; Merli, M; Hasson, H; Andolina, A; Galli, A; Lazzarin, A; Morsica, G

    2016-04-01

    Naturally occurring resistance-associated variants (RAVs) within the protease domain of hepatitis C virus (HCV) genotype (G) 1a separated into clades 1 and 2, and G1b were investigated in 59 HIV/HCV coinfected patients. RAVs were detected in 10/23 G1a/clade 1 and 1/19 G1b (p 0.0059). A similar frequency of RAVs was found when comparing G1a/clade 2 and G1b (p 0.1672). A cross-resistance to the macrocyclic compounds simeprevir and paritaprevir was detected in two G1a/clade 2 and 1 G1b sequences and none of G1a/clade 1 sequences. The simultaneous characterization of subtype and natural RAVs by population analysis of the NS3 domain by may add important information for anti-HCV treatment strategies including protease inhibitors.

  7. Promoter Variation and Expression Levels of Inflammatory Genes IL1A, IL1B, IL6 and TNF in Blood of Spinocerebellar Ataxia Type 3 (SCA3) Patients.

    PubMed

    Raposo, Mafalda; Bettencourt, Conceição; Ramos, Amanda; Kazachkova, Nadiya; Vasconcelos, João; Kay, Teresa; Bruges-Armas, Jácome; Lima, Manuela

    2017-03-01

    Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset. Using blood from 86 SCA3 patients and 106 controls, this work aimed to analyse promoter variation of four cytokines (IL1A, IL1B, IL6 and TNF) and to investigate the association between variants detected and their transcript levels, evaluated by quantitative PCR. Moreover, the effect of APOE isoforms, known to modulate cytokines, was investigated. Correlations between cytokine variants and onset were tested; the cumulative modifier effects of cytokines and APOE were analysed. Patients carrying the IL6*C allele had a significant earlier onset (4 years in average) than patients carrying the G allele, in agreement with lower mRNA levels produced by IL6*C carriers. The presence of APOE*ɛ2 allele seems to anticipate onset in average 10 years in patients carrying the IL6*C allele; a larger number of patients will be needed to confirm this result. These results highlight the pertinence of conducting further research on the role of cytokines as SCA3 modulators, pointing to the presence of shared mechanisms involving IL6 and APOE.

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

    PubMed

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

    2014-06-01

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

  9. Evaluation of the Serotonergic Genes htr1A, htr1B, htr2A, and slc6A4 in Aggressive Behavior of Golden Retriever Dogs

    PubMed Central

    Vos-Loohuis, M.; Schilder, M. B. H.; van Oost, B. A.; Hazewinkel, H. A. W.; Wade, C. M.; Karlsson, E. K.; Lindblad-Toh, K.; Liinamo, A. E.; Leegwater, P. A. J.

    2007-01-01

    Aggressive behavior displays a high heritability in our study group of Golden Retriever dogs. Alterations in brain serotonin metabolism have been described in aggressive dogs before. Here, we evaluate whether four genes of the canine serotonergic system, coding for the serotonin receptors 1A, 1B, and 2A, and the serotonin transporter, could play a major role in aggression in Golden Retrievers. We performed mutation screens, linkage analysis, an association study, and a quantitative genetic analysis. There was no systematic difference between the coding DNA sequence of the candidate genes in aggressive and non-aggressive Golden Retrievers. An affecteds-only parametric linkage analysis revealed no strong major locus effect on human-directed aggression related to the candidate genes. An analysis of 41 single nucleotide polymorphisms (SNPs) in the 1 Mb regions flanking the genes in 49 unrelated human-directed aggressive and 49 unrelated non-aggressive dogs did not show association of SNP alleles, genotypes, or haplotypes with aggression at the candidate loci. We completed our analyses with a study of the effect of variation in the candidate genes on a collection of aggression-related phenotypic measures. The effects of the candidate gene haplotypes were estimated using the Restricted Maximum Likelihood method, with the haplotypes included as fixed effects in a linear animal model. We observed no effect of the candidate gene haplotypes on a range of aggression-related phenotypes, thus extending our conclusions to several types of aggressive behavior. We conclude that it is unlikely that these genes play a major role in the variation in aggression in the Golden Retrievers that we studied. Smaller phenotypic effects of these loci could not be ruled out with our sample size. Electronic supplementary material The online version of this article (doi:10.1007/s10519-007-9179-7) contains supplementary material, which is available to authorized users. PMID:18066658

  10. Cytochrome P450 1A1 and 1B1 in human blood lymphocytes are not suitable as biomarkers of exposure to dioxin-like compounds: polymorphisms and interindividual variation in expression and inducibility.

    PubMed

    van Duursen, Majorie B M; Sanderson, J Thomas; van den Berg, Martin

    2005-05-01

    Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) are phase I enzymes, the expression of which can be affected by many environmental compounds, including dioxins and dioxin-like compounds. Because CYP1A1 and CYP1B1 expression can easily be determined in peripheral blood lymphocytes, it is often suggested as biomarker of exposure to these compounds. In this study we investigated the interindividual differences in constitutive and induced CYP1A1-catalyzed ethoxyresorufin-O-deethylase (EROD) activity and CYP1A1 and CYP1B1 gene expression in human blood lymphocytes in a group of ten non-smoking females. Freshly isolated lymphocytes were cultured in medium containing the mitogen PHA and were exposed to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the less potent dioxin-like polychlorinated biphenyl 126 (PCB126). In addition, we determined the occurrence of the CYP1A1 MspI and CYP1B1 Leu432Val polymorphisms. All individuals showed a concentration-dependent increase of EROD activity by TCDD, which was significantly correlated with an increase in CYP1A1, but not CYP1B1 expression. The maximum induced EROD activity by TCDD was very different among the individuals, but the EC50 values were about the same. PCB126 also caused a concentration-dependent increase of EROD activity, but was a factor 100-1000 less potent than TCDD among the individuals. The allele frequencies for CYP1A1 MspI and CYP1B1 Leu432Val reflected a normal Caucasian population and in this study the polymorphisms had no apparent effect on the expression and activity of these enzymes. Our study shows a large interindividual variability in constitutive and induced EROD activity, and CYP1A1 and CYP1B1 expression in human lymphocytes. In addition, dioxin concentrations at which effects were observed in our in vitro study are about 10-fold higher than the human blood levels found in vivo, indicating that EROD activity and CYP1A1 and CYP1B1 expression in human lymphocytes might not be

  11. The vasopressin-induced excitation of hypoglossal and facial motoneurons in young rats is mediated by V1a but not V1b receptors, and is independent of intracellular calcium signalling.

    PubMed

    Reymond-Marron, I; Tribollet, E; Raggenbass, M

    2006-09-01

    As a hormone, vasopressin binds to three distinct receptors: V1a and V1b receptors, which induce phospholipase-Cbeta (PLCbeta) activation and Ca2+ mobilization; and V2 receptors, which are coupled to adenylyl cyclase. V1a and V1b receptors are also present in neurons. In particular, hypoglossal (XII) and facial (VII) motoneurons are excited following vasopressin-V1a receptor binding. The aim of the present study was double: (i) to determine whether V1b receptors contribute to the excitatory effect of vasopressin in XII and VII motoneurons; and (ii) to establish whether the action of vasopressin on motoneurons is mediated by Ca2+ signalling. Patch-clamp recordings were performed in brainstem slices of young rats. Vasopressin depolarized the membrane or generated an inward current. By contrast, [1-deamino-4-cyclohexylalanine] arginine vasopressin (d[Cha4]AVP), a V1b agonist, had no effect. The action of vasopressin was suppressed by Phaa-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2, a V1a antagonist, but not by SSR149415, a V1b antagonist. Thus, the vasopressin-induced excitation of brainstem motoneurons was exclusively mediated by V1a receptors. Light microscopic autoradiography failed to detect V1b binding sites in the facial nucleus. In motoneurons loaded with GTP-gamma-S, a non-hydrolysable analogue of GTP, the effect of vasopressin was suppressed, indicating that neuronal V1a receptors are G-protein-coupled. Intracellular Ca2+ chelation suppressed a Ca2+-activated potassium current, but did not affect the vasopressin-evoked current. H7 and GF109203, inhibitors of protein kinase C, were without effect on the vasopressin-induced excitation. U73122 and D609, PLCbeta inhibitors, were also without effect. Thus, excitation of brainstem motoneurons by V1a receptor activation is probably mediated by a second messenger distinct from that associated with peripheral V1a receptors.

  12. CYP1A1 and CYP1B1 gene expression and DNA adduct formation in normal human mammary epithelial cells exposed to benzo[a]pyrene in the absence or presence of chlorophyllin.

    PubMed

    John, Kaarthik; Divi, Rao L; Keshava, Channa; Orozco, Christine C; Schockley, Marie E; Richardson, Diana L; Poirier, Miriam C; Nath, Joginder; Weston, Ainsley

    2010-06-28

    Benzo[a]pyrene (BP) is a potent pro-carcinogen and ubiquitous environmental pollutant. Here, we examined the induction and modulation of CYP1A1 and CYP1B1 and 10-(deoxyguanosin-N(2)-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG) adduct formation in DNA from 20 primary normal human mammary epithelial cell (NHMEC) strains exposed to BP (4muM) in the absence or presence of chlorophyllin (5muM). Real-time polymerase chain reaction (RT-PCR) analysis revealed strong induction of both CYP1A1 and CYP1B1 by BP, with high levels of inter-individual variability. Variable BPdG formation was found in all strains by r7, t8-dihydroxy-t-9, 10 epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA chemiluminescence assay (CIA). Chlorophyllin mitigated BP-induced CYP1A1 and CYP1B1 gene expression in all 20 strains when administered with BP. Chlorophyllin, administered prior to BP-exposure, mitigated CYP1A1 expression in 18/20 NHMEC strains (p<0.005) and CYP1B1 expression in 17/20 NHMEC strains (p<0.005). Maximum percent reductions of CYP1A1 and CYP1B1 gene expression and BPdG adduct formation were observed when cells were pre-dosed with chlorophyllin followed by administration of the carcinogen with chlorophyllin (p<0.005 for CYP1A1 and CYP1B1 expression and p<0.0005 for BPdG adducts). Therefore, chlorophyllin is likely to be a good chemoprotective agent for a large proportion of the human population.

  13. Role of mouse hepatitis virus (MHV) receptor murine CEACAM1 in the resistance of mice to MHV infection: studies of mice with chimeric mCEACAM1a and mCEACAM1b.

    PubMed

    Hirai, Asuka; Ohtsuka, Nobuhisa; Ikeda, Toshio; Taniguchi, Rie; Blau, Dianna; Nakagaki, Keiko; Miura, Hideka S; Ami, Yasushi; Yamada, Yasuko K; Itohara, Shigeyoshi; Holmes, Kathryn V; Taguchi, Fumihiro

    2010-07-01

    Although most inbred mouse strains are highly susceptible to mouse hepatitis virus (MHV) infection, the inbred SJL line of mice is highly resistant to its infection. The principal receptor for MHV is murine CEACAM1 (mCEACAM1). Susceptible strains of mice are homozygous for the 1a allele of mCeacam1, while SJL mice are homozygous for the 1b allele. mCEACAM1a (1a) has a 10- to 100-fold-higher receptor activity than does mCEACAM1b (1b). To explore the hypothesis that MHV susceptibility is due to the different MHV receptor activities of 1a and 1b, we established a chimeric C57BL/6 mouse (cB61ba) in which a part of the N-terminal immunoglobulin (Ig)-like domain of the mCeacam1a (1a) gene, which is responsible for MHV receptor function, is replaced by the corresponding region of mCeacam1b (1b). We compared the MHV susceptibility of these chimeric mice to that of SJL and B6 mice. B6 mice that are homozygous for 1a are highly susceptible to MHV-A59 infection, with a 50% lethal dose (LD(50)) of 10(2.5) PFU, while chimeric cB61ba mice and SJL mice homozygous for 1ba and 1b, respectively, survived following inoculation with 10(5) PFU. Unexpectedly, cB61ba mice were more resistant to MHV-A59 infection than SJL mice as measured by virus replication in target organs, including liver and brain. No infectious virus or viral RNA was detected in the organs of cB61ba mice, while viral RNA and infectious virus were detected in target organs of SJL mice. Furthermore, SJL mice produced antiviral antibodies after MHV-A59 inoculation with 10(5) PFU, but cB61ba mice did not. Thus, cB61ba mice are apparently completely resistant to MHV-A59 infection, while SJL mice permit low levels of MHV-A59 virus replication during self-limited, asymptomatic infection. When expressed on cultured BHK cells, the mCEACAM1b and mCEACAM1ba proteins had similar levels of MHV-A59 receptor activity. These results strongly support the hypothesis that although alleles of mCEACAM1 are the principal determinants of

  14. CYP1A1 (Ile462Val), CYP1B1 (Ala119Ser and Val432Leu), GSTM1 (null), and GSTT1 (null) polymorphisms and bladder cancer risk in a Turkish population.

    PubMed

    Berber, Ufuk; Yilmaz, Ismail; Yilmaz, Omer; Haholu, Aptullah; Kucukodaci, Zafer; Ates, Ferhat; Demirel, Dilaver

    2013-01-01

    We aimed to investigate bladder cancer risk with reference to polymorphic variants of cytochrome p450 (CYP) 1A1, CYP1B1, glutathione S-transferase (GST) M1, and GSTT1 genes in a case control study. Polymorphisms were examined in 114 bladder cancer patients and 114 age and sex-matched cancer-free subjects. Genotypes were determined using allele specific PCR for CYP1A1 and CYP1B1 genes, and by multiplex PCR and melting curve analysis for GSTM1 and GSTT1 genes. Our results revealed a statistically significant increased bladder cancer risk for GSTT1 null genotype carriers with an odds ratio of 3.06 (95% confidence interval=1.39-6.74, p=0.006). Differences of CYP1A1, CYP1B1 and GSTM1 genotype frequencies were not statistically significant between patients and controls. However, the specific combination of GSTM1 null, GSTT1 null, and CYP1B1 codon 119 risk allele carriers and specific combination of GSTM1 present, GSTT1 null, and CYP1B1 432 risk allele carriers exhibited increased cancer risk in the combined analysis. We did not observe any association between different genotype groups and prognostic tumor characteristics of bladder cancer. Our results indicate that inherited absence of GSTT1 gene may be associated with bladder cancer susceptibility, and specific combinations of GSTM1, GSTT1 and CYP1B1 gene polymorphisms may modify bladder cancer risk in the Turkish population, without any association being observed for CYP1A1 gene polymorphism and bladder cancer risk.

  15. Social instigation and aggression in postpartum female rats: role of 5-Ht1A and 5-Ht1B receptors in the dorsal raphé nucleus and prefrontal cortex

    PubMed Central

    da Veiga, Caroline Perinazzo; Miczek, Klaus A.; Lucion, Aldo Bolten

    2013-01-01

    Rationale 5-HT1A and 5-HT1B receptor agonists effectively reduce aggressive behavior in males that has been escalated by social instigation. Important sites of action for these drugs are the receptors in dorsal raphé nuclei (DRN) and the ventral–orbital prefrontal cortex (VO PFC). DRN and VO PFC areas are particularly relevant in the inhibitory control of escalated aggressive and impulsive behavior. Objectives The objectives of this study are to assess the anti-aggressive effects of 5-HT1A (8-OH-DPAT) and 5-HT1B (CP-93,129) receptor agonists microinjected into DRN and VO PFC, respectively, and to study the aggressive behavior in postpartum female Wistar rats using the social instigation protocol to increase aggression. Methods and Results 8-OH-DPAT (0.56 µg) in the DRN increased aggressive behavior in postpartum female rats. By contrast, CP-93,129 (1.0 µg) microinjected into VO PFC decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming and the latter increasing these acts. When 8-OH-DPAT was microinjected into DRN and CP-93,129 was microinjected into VO PFC in female rats at the same time, maternal aggression decreased. Specific participation of 5-HT1B receptors was verified by reversal of the anti-aggressive effects using the selective antagonist SB-224,289 (1.0 µg). Conclusions The decrease in maternal aggressive behavior after microinjections of 5-HT1B receptor agonists into the VO PFC and DRN of female postpartum rats that were instigated socially supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner, due to activation of 5-HT1B receptors at the soma and terminals. PMID:21107539

  16. Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment

    PubMed Central

    Bagaglio, Sabrina; Andolina, Andrea; Merli, Marco; Uberti-Foppa, Caterina; Morsica, Giulia

    2016-01-01

    Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs. PMID:27023593

  17. Effects of hydroxyl group numbers on the B-ring of 5,7-dihydroxyflavones on the differential inhibition of human CYP 1A and CYP1B1 enzymes.

    PubMed

    Kim, Hyun-Jung; Lee, Sang Bum; Park, Song-Kyu; Kim, Hwan Mook; Park, Young In; Dong, Mi-Sook

    2005-10-01

    Flavonoids are polyphenols composed of two aromatic rings (A, B) and a heterocyclic ring (C). In order to determine the effects of the number of hydroxyl groups in the B-ring of the flavonoids on human cytochrome P450 (CYP) 1 family enzymes, we evaluated the inhibition of CYP1A-dependent 7-ethoxyresorufin omicron-deethylation activity by chrysin, apigenin and luteolin, using bacterial membranes that co-express human CYP1A1, CYP1A2, or CYP1B1 with human NADPH-cytochrome P450 reductase. Chrysin, which possesses no hydroxyl groups in its B-ring, exhibited the most pronounced inhibitory effects on CYP1A2-dependent EROD activity, followed by apigenin and luteolin. On the contrary, CYP1A1-mediated EROD activity was most potently inhibited by luteolin, which is characterized by two hydroxyl groups in its B-ring, followed by apigenin and chrysin. However, all of the 5,7-dihydroxyflavones were determined to similarly inhibit CYP1B1 activity. Chrysin, apigenin, and luteolin exhibited a mixed-type mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 microM, respectively. These findings suggested that the number of hydroxyl groups in the B-ring of 5,7-dihydroxyflavone might have some influence on the degree to which CYP1A enzymes were inhibited, but not on the degree to which CYP1B1 enzymes were inhibited.

  18. CYP1A1 and CYP1B1 expressions in medulloblastoma cells are AhR-independent and have no direct link with resveratrol-induced differentiation and apoptosis.

    PubMed

    Wu, Mo-Li; Li, Hong; Wu, Da-Chang; Wang, Xiao-Wei; Chen, Xiao-Yan; Kong, Qing-You; Ma, Jing-Xin; Gao, Ying; Liu, Jia

    Resveratrol induces apoptosis and regulates CYP1A1 and CYP1B1 expression in human medulloblastoma cells. To elucidate the potential correlation of their expressions with the anti-medulloblastoma effects of resveratrol, human medulloblastoma cells, UW228-3, were treated with CYP1A1 selective inhibitor (alpha-naphthoflavone, alpha-NF), selective CYP1A1/1A2 inducer (beta-naphthoflavone, beta-NF) and their combination with resveratrol, respectively. The influences of those treatments on the expressions of CYP1A1, 1A2 and 1B1 as well as the cell growth, differentiation and death were analyzed. It was found that neither alpha-NF nor beta-NF had any effect on cell growth. alpha-NF inhibited resveratrol-induced CYP1A1 expression without interfering cell differentiation and apoptosis. beta-NF could up-regulate resveratrol-induced CYP1A1 expression but not enhance the anti-cancer effects of resveratrol. CYP1A2 was undetectable in the cells irrespective to the treatments. Aryl hydrocarbon receptor (AhR) was absent in UW228-3 cells under normal culture and treated with resveratrol but induced by both alpha- and beta-NF. Immunohistochemical examination performed on 11 pairs of human medulloblastoma and noncancerous cerebellar tissues revealed that AhR was undetectable in either of them, whereas CYP1A1 was expressed in cerebellum but down-regulated or diminished in their malignant counterparts. Our data suggest for the first time that CYP1A1 and 1B1 expressions in human medulloblastoma cells are AhR-independent and have no direct links with resveratrol-induced differentiation and apoptosis. Appearance of CYP1A1 expression may reflect a more maturated status and a better prognosis of medulloblastomas.

  19. Estrogen Receptor α Increases Basal and Cigarette Smoke Extract-Induced Expression of CYP1A1 and CYP1B1, but not GSTP1, in Normal Human Bronchial Epithelial Cells

    PubMed Central

    Han, W; Pentecost, BT; Pietropaolo, RL; Fasco, MJ; Spivack, SD

    2005-01-01

    Gender-specific estrogen receptor α (ERα) expression may plausibly influence lung carcinogenesis in females. Initial genome-wide microarray studies confirmed that carcinogen metabolism genes (CYP1A1, CYP1B1) were those most responsive to cigarette smoke extract (CSE) in normal bronchial epithelial (NHBE) cells. These two genes encoding phase I bioactivating enzymes and the GSTP1 gene encoding a phase II deactivating enzyme were then tested for induction by ERα. NHBE cells (native ERα−) were transfected with wild-type ERα-adenoviral constructs, and then exposed to CSE, 17β-estradiol (E2), and/or the ERα inhibitor, ICI 182,780. The expression levels of CYP1A1, CYP1B1 and GSTP1 were then determined by RNA-specific quantitative RT-PCR and immunoassay. ERα increased the basal expression of CYP1B1 4.04-fold (p<0.01) at the mRNA level and 6.5-fold at the protein level. ERα also increased the CSE-induced mRNA expression of CYP1B1 2.26-fold (p<0.01), but not the protein expression. ERα did not alter the CYP1A1 mRNA levels, but did increase protein expression 2.0-fold (p<0.01) on CSE exposure, and 6.2-fold (p<0.01) upon E2 exposure. These effects could be inhibited by ICI 182,780. ERα did not alter the expression of GSTP1. ChIP assay confirmed ERα binding to CYP1B1 promoter near the transcription start site. These results suggest that ERα regulates the CYP1B1 expression at a transcriptional level, and CYP1A1 expression at a translational level. These data raise the possibility that inter-gender differences in expression of ERα that are known to exist in human lung may contribute to inter-individual expression differences in CYP1A1 and CYP1B1, and to differences in carcinogen metabolism and mutation. PMID:16010691

  20. The Human Adenovirus Type 5 E4orf6/E1B55K E3 Ubiquitin Ligase Complex Can Mimic E1A Effects on E2F

    PubMed Central

    Dallaire, Frédéric; Schreiner, Sabrina; Blair, G. Eric; Dobner, Thomas; Branton, Philip E.

    2015-01-01

    ABSTRACT The human adenovirus E4orf6/E1B55K E3 ubiquitin ligase is well known to promote viral replication by degrading an increasing number of cellular proteins that inhibit the efficient production of viral progeny. We report here a new function of the adenovirus 5 (Ad5) viral ligase complex that, although at lower levels, mimics effects of E1A products on E2F transcription factors. When expressed in the absence of E1A, the E4orf6 protein in complex with E1B55K binds E2F, disrupts E2F/retinoblastoma protein (Rb) complexes, and induces hyperphosphorylation of Rb, leading to induction of viral and cellular DNA synthesis as well as stimulation of early and late viral gene expression and production of viral progeny of E1/E3-defective adenovirus vectors. These new and previously undescribed functions of the E4orf6/E1B55K E3 ubiquitin ligase could play an important role in promoting the replication of wild-type viruses. IMPORTANCE During the course of work on the adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins, we found, very surprisingly, that expression of these species was sufficient to permit low levels of replication of an adenovirus vector lacking E1A, the central regulator of infection. E1A products uncouple E2F transcription factors from Rb repression complexes, thus stimulating viral gene expression and cell and viral DNA synthesis. We found that the E4orf6/E1B55K ligase mimics these functions. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication. PMID:27303679

  1. Photoperiod-dependent regulation of cell growth by PpCCA1a and PpCCA1b genes encoding single-myb clock proteins in the moss Physcomitrella patens.

    PubMed

    Okada, Ryo; Satbhai, Santosh B; Aoki, Setsuyuki

    2009-10-01

    The PpCCA1a and PpCCA1b genes of the moss Physcomitrella patens are functional homologs of the Arabidopsis thaliana circadian clock genes CCA1/LHY. We made use of disruptant lines for PpCCA1a and/or PpCCA1b to elucidate the physiological significance of these genes in the growth of moss protonemal tissue under alternating day/night cycles. Protonemal cells of the double disruptant line, carrying neither of the two genes, grew faster than those of the wild-type plant (WT) in long days (LD), whereas no difference in the growth rate was detected between them in short days (SD). The double disruptant line also showed day length-dependent phenotypic changes in the PpCCA1b promoter activity: the diurnal profile of bioluminescence from the P(CCA1b)::LUC+ reporter strain was more significantly affected in LD than in SD. These observations are the first demonstration of a physiological function of the circadian clock in non-angiosperm land plants, and are consistent with recent findings that the clock controls hypocotyl elongation of A. thaliana in a photoperiod-dependent manner.

  2. Enhanced expression of glutamine synthetase (GS1a) confers altered fibre and wood chemistry in field grown hybrid poplar (Populus tremula X alba) (717-1B4).

    PubMed

    Coleman, Heather D; Cánovas, Francisco M; Man, Huimin; Kirby, Edward G; Mansfield, Shawn D

    2012-09-01

    Hybrid poplar (Populus tremula X P. alba) genetically engineered to express the pine cytosolic glutamine synthetase gene (GS1a) has been previously shown to display desirable field performance characteristics, including enhancements in growth and nitrogen use efficiency. Analysis of wood samples from a 3-year-old field trial of three independently transformed GS1a transgenic hybrid poplar lines revealed that, when compared with wild-type controls, ectopic expression of GS1a resulted in alterations in wood properties and wood chemistry. Included were significant enhancements in wood fibre length, wood density, microfibre angle, per cent syringyl lignin and elevated concentrations of wood sugars, specifically glucose, galactose, mannose and xylose. Total extractive content and acid-insoluble lignin were significantly reduced in wood of GS1a transgenics when compared with wild-type trees. Together, these cell wall characteristics resulted in improved wood pulping attributes, including improved lignin solubilization with no concurrent decrease in yield. Trees with increased GS1a expression have improved characteristics for pulp and paper production and hold potential as a feedstock for biofuels production.

  3. Evaluation of 309 molecules as inducers of CYP3A4, CYP2B6, CYP1A2, OATP1B1, OCT1, MDR1, MRP2, MRP3 and BCRP in cryopreserved human hepatocytes in sandwich culture.

    PubMed

    Badolo, Lassina; Jensen, Bente; Säll, Carolina; Norinder, Ulf; Kallunki, Pekka; Montanari, Dino

    2015-02-01

    1. Regulation of hepatic metabolism or transport may lead to increase in drug clearance and compromise efficacy or safety. In this study, cryopreserved human hepatocytes were used to assess the effect of 309 compounds on the activity and mRNA expression (using qPCR techniques) of CYP1A2, CYP2B6 and CYP3A4, as well as mRNA expression of six hepatic transport proteins: OATP1B1 (SCLO1B1), OCT1 (SLC22A1), MDR1 (ABCB1), MRP2 (ABCC2), MRP3 (ABCC3) and BCRP (ABCG2). 2. The results showed that 6% of compounds induced CYP1A2 activity (1.5-fold increase); 30% induced CYP2B6 while 23% induced CYP3A4. qPCR data identified 16, 33 or 32% inducers of CYP1A2, CYP2B6 or CYP3A4, respectively. MRP2 was induced by 27 compounds followed by MDR1 (16)>BCRP (9)>OCT1 (8)>OATP1B1 (5)>MRP3 (2). 3. CYP3A4 appeared to be down-regulated (≥2-fold decrease in mRNA expression) by 53 compounds, 10 for CYP2B6, 6 for OCT1, 4 for BCRP, 2 for CYP1A2 and OATP1B1 and 1 for MDR1 and MRP2. 4. Structure-activity relationship analysis showed that CYP2B6 and CYP3A4 inducers are bulky lipophilic molecules with a higher number of heavy atoms and a lower number of hydrogen bond donors. Finally, a strategy for testing CYP inducers in drug discovery is proposed.

  4. Chlorophyllin significantly reduces benzo[a]pyrene [BP]-DNA adduct formation and alters Cytochrome P450 1A1 and 1B1 expression and EROD activity in normal human mammary epithelial cells (NHMECs)

    PubMed Central

    Keshava, Channa; Divi, Rao L.; Einem, Tracey L.; Richardson, Diana L.; Leonard, Sarah L.; Keshava, Nagalakshmi; Poirier, Miriam C.; Weston, Ainsley

    2008-01-01

    We hypothesized that chlorophyllin (CHLN) would reduce BP-DNA adduct levels. Using NHMECs exposed to 4 μM BP for 24 hr in the presence or absence of 5 μM CHLN, we measured BP-DNA adducts by chemiluminescence immunoassay (CIA). The protocol included the following experimental groups: BP alone, BP given simultaneously with CHLN (BP+CHLN) for 24 hr, CHLN given for 24 hr followed by BP for 24 hr (preCHLN, postBP), and CHLN given for 48 hr with BP added for the last 24 hr (preCHLN, postBP+CHLN). Incubation with CHLN decreased BPdG levels in all groups, with 87 % inhibition in the preCHLN, postBP+CHLN group. To examine metabolic mechanisms, we monitored expression by Affymetrix microarray (U133A), and found BP-induced up-regulation of CYP1A1 and CYP1B1 expression, as well as up-regulation of groups of interferon-inducible, inflammation and signal transduction genes. Incubation of cells with CHLN and BP in any combination decreased expression of many of these genes. Using real time PCR (RT-PCR) the maximal inhibition of BP-induced gene expression, >85% for CYP1A1 and >70% for CYP1B1, was observed in the preCHLN, postBP+CHLN group. To explore the relationship between transcription and enzyme activity, the ethoxyresorufin-O-deethylase (EROD) assay was used to measure the combined CYP1A1 and CYP1B1 activities. BP exposure caused the EROD levels to double, compared to the unexposed controls. The CHLN-exposed groups all showed EROD levels similar to the unexposed controls. Therefore, the addition of CHLN to BP-exposed cells reduced BPdG formation and CYP1A1 and CYP1B1 expression, but EROD activity was not significantly reduced. PMID:19152381

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

    PubMed Central

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

    2007-01-01

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

  6. Differences in 4-hydroxyestradiol levels in leukocytes are related to CYP1A1(∗)2C, CYP1B1(∗)3 and COMT Val158Met allelic variants.

    PubMed

    Martínez-Ramírez, O C; Pérez-Morales, R; Petrosyan, P; Castro-Hernández, C; Gonsebatt, M E; Rubio, J

    2015-10-01

    Exposure to estrogen and its metabolites, including catechol estrogens (CEs) and catechol estrogen quinones (CE-Qs) is closely related to breast cancer. Polymorphisms of the genes involved in the catechol estrogens metabolism pathway (CEMP) have been shown to affect the production of CEs and CE-Qs. In this study, we measured the induction of CYP1A1, CYP1B1, COMT, and GSTP1 by 17β-estradiol (17β-E2) in leukocytes with CYP1A1(∗)2C, CYP1B1(∗)3, COMT Val158Met and GSTP1 Ile105Val polymorphisms by semi quantitative RT-PCR and compared the values to those of leukocytes with wild type alleles; we also compared the differences in formation of 4- hydroxyestradiol (4-OHE2) and DNA-adducts. The data show that in the leukocytes with mutant alleles treatment with 17β-E2 up-regulates CYP1A1 and CYP1B1 and down-regulates COMT mRNA levels, resulting in major increments in 4-OHE2 levels compared to leukocytes with wild-type alleles. Therefore, we propose induction levels of gene expression and intracellular 4-OHE2 concentrations associated with allelic variants in response to exposure of 17β-E2 as a noninvasive biomarker that can help determine the risk of developing non-hereditary breast cancer in women.

  7. Inactivation of the Oxytocin and the Vasopressin (Avp) 1b Receptor Genes, But Not the Avp 1a Receptor Gene, Differentially Impairs the Bruce Effect in Laboratory Mice (Mus musculus)

    PubMed Central

    Wersinger, Scott R.; Temple, Jennifer L.; Caldwell, Heather K.; Young, W. Scott

    2008-01-01

    The Bruce effect is a pheromonally mediated process whereby exposure to chemosensory cues from an unfamiliar male terminates pregnancy in a recently mated female. Pharmacological and genetic evidence implicates both oxytocin (Oxt) and vasopressin (Avp) in the regulation of social memory in males, but less work has been done in females. We tested the extent to which the Avp receptors (Avprs) 1a and 1b and Oxt are essential for the Bruce effect, a phenomenon that relies on olfactory memory. Adult female mice were paired with stimulus males and monitored for the presence of sperm plugs. Wild-type, heterozygous, and homozygous knockout (KO) females for either the Avpr1a, Avpr1b, or Oxt genes were randomly assigned to one of the following treatment groups: 1) alone (mate removed, no second exposure to another animal); 2) paired continuously (mate kept with female for 10–14 d); 3) familiar male (mate removed, reintroduced 24 h later); or 4) unfamiliar male (mate removed, BalbC male introduced 24 h later). Regardless of genotype, 90–100% of females in the alone or paired continuously groups became pregnant. The Oxt KO females terminated their pregnancies regardless of whether their original mate or an unfamiliar male was reintroduced. The Avpr1b KO mice failed to terminate pregnancy in the presence of an unfamiliar male. The Avpr1a KO mice exhibited a normal Bruce effect. These data demonstrate that both Oxt and the Avpr1b are critical for the normal expression of the Bruce effect but have different effects on the interpretation of social cues. PMID:17947352

  8. The 5-HT1-like receptors mediating inhibition of sympathetic vasopressor outflow in the pithed rat: operational correlation with the 5-HT1A, 5-HT1B and 5-HT1D subtypes

    PubMed Central

    Villalón, Carlos M; Centurión, David; Rabelo, Gonzalo; de Vries, Peter; Saxena, Pramod R; Sánchez-López, Araceli

    1998-01-01

    It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT1-like receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors.Intravenous (i.v.) continuous infusions of 5-HT and the 5-HT1 receptor agonists, 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP 93,129 (5-HT1B) and sumatriptan (5-HT1B/1D), resulted in a dose-dependent inhibition of sympathetically-induced vasopressor responses.The sympatho-inhibitory responses induced by 5-HT, 8-OH-DPAT, indorenate, CP 93,129 or sumatriptan were analysed before and after i.v. treatment with blocking doses of the putative 5-HT receptor antagonists, WAY 100635 (5-HT1A), cyanopindolol (5-HT1A/1B) or GR 127935 (5-HT1B/1D). Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished.In additional experiments, the inhibition induced by 5-HT was not modified after 5-HT7 receptor blocking doses of mesulergine.The above results suggest that the 5-HT1-like receptors, which inhibit the sympathetic vasopressor outflow in pithed rats, display the pharmacological profile of the 5-HT1A, 5-HT1B and 5-HT1D, but not that of 5-HT7, receptors. PMID:9692787

  9. TES Level 1B

    Atmospheric Science Data Center

    2014-12-08

    TES Level 1B data files contain radiometric calibrated spectral radiances and their ... and some engineering data are also provided. A Level 1B data file contains data from a single TES orbit for one focal ... as the Aura orbit number at the time of the South Pole apex crossing. version id represents the version identification number, ...

  10. Prenatal 3,3',4,4',5-pentachlorobiphenyl exposure modulates induction of rat hepatic CYP 1A1, 1B1, and AhR by 7,12-dimethylbenz[a]anthracene

    SciTech Connect

    Wakui, Shin . E-mail: wakui@azabu-u.ac.jp; Yokoo, Kiyofumi; Takahashi, Hiroyuki; Muto, Tomoko; Suzuki, Yoshihiko; Kanai, Yoshikatsu; Hano, Hiroshi; Furusato, Masakuni; Endou, Hitoshi

    2006-02-01

    We previously reported the finding that prenatal exposure to a relatively low dose of PCB126 increases the rate of DMBA-induced rat mammary carcinoma, while a high dose decreased it. One of the most important factors determining the sensitivity to mammary carcinogenesis is the metabolic stage at administration of the carcinogenic agent. DMBA is a procarcinogen that recruits the host metabolism to yield its ultimate carcinogenic form, and CYP1A1 and CYP1B1 (CYP1) conduct this metabolism. We investigated the hepatic expression of CYP1 and AhR following oral administration of DMBA (100 mg/kg b.w.) (i.g.) to 50-day-old female Sprague-Dawley rats whose dams had been treated (i.g.) with 2.5 ng, 250 ng, 7.5 {mu}g of PCB126/kg or the vehicle on days 13 to 19 post-conception. Real-time quantitative RT-PCR analysis revealed that the prenatal exposure to a relatively low dose of PCB126 (the 250 ng group) prolonged the higher expression of CYP1A1, CYP1B1, and AhR mRNA, while prenatal exposure to a high dose of PCB126 (the 7.5 {mu}g group) prolonged the higher expression of CYP1A1 and AhR mRNA. Western blotting and immunohistochemical analyses were consistent with mRNAs changes. Because DMBA oxidation produces a highly mutagenic metabolite and is finally catalyzed by CYP1B1, a relatively low PCB126 dose might produce the biological character to potentially increase the risk of DMBA-induced mammary carcinoma.

  11. Induction of CYP1A1 and CYP1B1 by benzo(k)fluoranthene and benzo(a)pyrene in T-47D human breast cancer cells: Roles of PAH interactions and PAH metabolites

    SciTech Connect

    Spink, David C. Wu, Susan J.; Spink, Barbara C.; Hussain, Mirza M.; Vakharia, Dilip D.; Pentecost, Brian T.; Kaminsky, Laurence S.

    2008-02-01

    The interactions of polycyclic aromatic hydrocarbons (PAH) and cytochromes P450 (CYP) are complex; PAHs are enzyme inducers, substrates, and inhibitors. In T-47D breast cancer cells, exposure to 0.1 to 1 {mu}M benzo(k)fluoranthene (BKF) induced CYP1A1/1B1-catalyzed 17{beta}-estradiol (E{sub 2}) metabolism, whereas BKF levels greater than 1 {mu}M inhibited E{sub 2} metabolism. Time course studies showed that induction of CYP1-catalyzed E{sub 2} metabolism persisted after the disappearance of BKF or co-exposed benzo(a)pyrene, suggesting that BKF metabolites retaining Ah receptor agonist activity were responsible for prolonged CYP1 induction. BKF metabolites were shown, through the use of ethoxyresorufin O-deethylase and CYP1A1-promoter-luciferase reporter assays to induce CYP1A1/1B1 in T-47D cells. Metabolites formed by oxidation at the C-2/C-3 region of BKF had potencies for CYP1 induction exceeding those of BKF, whereas C-8/C-9 oxidative metabolites were somewhat less potent than BKF. The activities of expressed human CYP1A1 and 1B1 with BKF as substrate were investigated by use of HPLC with fluorescence detection, and by GC/MS. The results showed that both enzymes efficiently catalyzed the formation of 3-, 8-, and 9-OHBKF from BKF. These studies indicate that the inductive effects of PAH metabolites as potent CYP1 inducers are likely to be additional important factors in PAH-CYP interactions that affect metabolism and bioactivation of other PAHs, ultimately modulating PAH toxicity and carcinogenicity.

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

    PubMed

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

    2007-01-01

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

  13. Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging

    PubMed Central

    Ridge, Perry G.; Maxwell, Taylor J.; Corcoran, Christopher D.; Norton, Maria C.; Tschanz, JoAnn T.; O’Brien, Elizabeth; Kerber, Richard A.; Cawthon, Richard M.; Munger, Ronald G.; Kauwe, John S. K.

    2012-01-01

    Background Alzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. Methodology/Principal Findings We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. Conclusions/Significance Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary. PMID:23028804

  14. Development of a ten-signature classifier using a support vector machine integrated approach to subdivide the M1 stage into M1a and M1b stages of nasopharyngeal carcinoma with synchronous metastases to better predict patients' survival

    PubMed Central

    Zhang, Meng-Xia; Wang, Tong-Min; Sun, Rui; Luo, Dong-Hua; Huang, Pei-Yu; Chen, Qiu-Yan; Hua, Yi-Jun; Tang, Lin-Quan; Guo, Ling; Mo, Hao-Yuan; Qian, Chao-Nan; Mai, Hai-Qiang; Hong, Ming-Huang; Cai, Hong-Min; Chen, Ming-Yuan

    2016-01-01

    The aim of this study was to develop a prognostic classifier and subdivided the M1 stage for nasopharyngeal carcinoma patients with synchronous metastases (mNPC). A retrospective cohort of 347 mNPC patients was recruited between January 2000 and December 2010. Thirty hematological markers and 11 clinical characteristics were collected, and the association of these factors with overall survival (OS) was evaluated. Advanced machine learning schemes of a support vector machine (SVM) were used to select a subset of highly informative factors and to construct a prognostic model (mNPC-SVM). The mNPC-SVM classifier identified ten informative variables, including three clinical indexes and seven hematological markers. The median survival time for low-risk patients (M1a) as identified by the mNPC-SVM classifier was 38.0 months, and survival time was dramatically reduced to 13.8 months for high-risk patients (M1b) (P < 0.001). Multivariate adjustment using prognostic factors revealed that the mNPC-SVM classifier remained a powerful predictor of OS (M1a vs. M1b, hazard ratio, 3.45; 95% CI, 2.59 to 4.60, P < 0.001). Moreover, combination treatment of systemic chemotherapy and loco-regional radiotherapy was associated with significantly better survival outcomes than chemotherapy alone (the 5-year OS, 47.0% vs. 10.0%, P < 0.001) in the M1a subgroup but not in the M1b subgroup (12.0% vs. 3.0%, P = 0.101). These findings were validated by a separate cohort. In conclusion, the newly developed mNPC-SVM classifier led to more precise risk definitions that offer a promising subdivision of the M1 stage and individualized selection for future therapeutic regimens in mNPC patients. PMID:26636646

  15. Development of a ten-signature classifier using a support vector machine integrated approach to subdivide the M1 stage into M1a and M1b stages of nasopharyngeal carcinoma with synchronous metastases to better predict patients' survival.

    PubMed

    Jiang, Rou; You, Rui; Pei, Xiao-Qing; Zou, Xiong; Zhang, Meng-Xia; Wang, Tong-Min; Sun, Rui; Luo, Dong-Hua; Huang, Pei-Yu; Chen, Qiu-Yan; Hua, Yi-Jun; Tang, Lin-Quan; Guo, Ling; Mo, Hao-Yuan; Qian, Chao-Nan; Mai, Hai-Qiang; Hong, Ming-Huang; Cai, Hong-Min; Chen, Ming-Yuan

    2016-01-19

    The aim of this study was to develop a prognostic classifier and subdivided the M1 stage for nasopharyngeal carcinoma patients with synchronous metastases (mNPC). A retrospective cohort of 347 mNPC patients was recruited between January 2000 and December 2010. Thirty hematological markers and 11 clinical characteristics were collected, and the association of these factors with overall survival (OS) was evaluated. Advanced machine learning schemes of a support vector machine (SVM) were used to select a subset of highly informative factors and to construct a prognostic model (mNPC-SVM). The mNPC-SVM classifier identified ten informative variables, including three clinical indexes and seven hematological markers. The median survival time for low-risk patients (M1a) as identified by the mNPC-SVM classifier was 38.0 months, and survival time was dramatically reduced to 13.8 months for high-risk patients (M1b) (P < 0.001). Multivariate adjustment using prognostic factors revealed that the mNPC-SVM classifier remained a powerful predictor of OS (M1a vs. M1b, hazard ratio, 3.45; 95% CI, 2.59 to 4.60, P < 0.001). Moreover, combination treatment of systemic chemotherapy and loco-regional radiotherapy was associated with significantly better survival outcomes than chemotherapy alone (the 5-year OS, 47.0% vs. 10.0%, P < 0.001) in the M1a subgroup but not in the M1b subgroup (12.0% vs. 3.0%, P = 0.101). These findings were validated by a separate cohort. In conclusion, the newly developed mNPC-SVM classifier led to more precise risk definitions that offer a promising subdivision of the M1 stage and individualized selection for future therapeutic regimens in mNPC patients.

  16. Cystathione gamma lyase/Hydrogen Sulphide Pathway Up Regulation Enhances the Responsiveness of α1A and α1B-Adrenoreceptors in the Kidney of Rats with Left Ventricular Hypertrophy

    PubMed Central

    Ahmad, Ashfaq; Sattar, Munavvar A.; Azam, Maleeha; Abdulla, Mohammed H.; Khan, Safia A.; Hashmi, Fayyaz; Abdullah, Nor A.; Johns, Edward J.

    2016-01-01

    The purpose of the present study was to investigate the interaction between H2S and NO (nitric oxide) in the kidney and to evaluate its impact on the functional contribution of α1A and α1B-adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy (LVH). In rats the LVH induction was by isoprenaline administration and caffeine in the drinking water together with intraperitoneal administration of H2S. The responsiveness of α1A and α1B to exogenous noradrenaline, phenylephrine and methoxaminein the absence and presence of 5-methylurapidil (5-MeU) and chloroethylclonidine (CEC) was studied. Cystathione gamma lyase (CSE), cystathione β synthase (CBS), 3-mercaptopyruvate sulphar transferase (3-MST) and endothelial nitric oxide synthase (eNOS) were quantified. There was significant up regulation of CSE and eNOS in the LVH-H2S compared to the LVH group (P<0.05). Baseline renal cortical blood perfusion (RCBP) was increased (P<0.05) in the LVH-H2S compared to the LVH group. The responsiveness of α1A-adrenergic receptors to adrenergic agonists was increased (P<0.05) after administration of low dose 5-Methylurapidil in the LVH-H2S group while α1B-adrenergic receptors responsiveness to adrenergic agonists were increased (P<0.05) by both low and high dose chloroethylclonidine in the LVH-H2S group. Treatment of LVH with H2S resulted in up-regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways in the kidney. These up regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways enhanced the responsiveness of α1A and α1B-adrenoreceptors subtypes to adrenergic agonists in LVH-H2S. These findings indicate an important role for H2S in modulating deranged signalling in the renal vasculature resulting from LVH development. PMID:27191852

  17. Cytogenetic damage in Turkish coke oven workers exposed to polycyclic aromatic hydrocarbons: Association with CYP1A1, CYP1B1, EPHX1, GSTM1, GSTT1, and GSTP1 gene polymorphisms.

    PubMed

    Ada, Ahmet Oguz; Demiroglu, Canan; Yilmazer, Meltem; Suzen, Halit Sinan; Demirbag, Ali Eba; Efe, Sibel; Alemdar, Yilmaz; Iscan, Mumtaz; Burgaz, Sema

    2013-09-01

    The aim of this study was to determine the frequencies of chromosomal aberrations (CA) and cytochalasin-blocked micronuclei (CBMN) in peripheral blood lymphocytes from Turkish coke oven workers and the influence of CYP1A1, CYP1B1, EPHX1, GSTM1, GSTT1, and GSTP1 gene polymorphisms on these biomarkers. Cytogenetic analysis showed that occupational exposure significantly increased the CA and CBMN frequencies. Gene polymorphisms, on the other hand, did not affect CA or CBMN in either exposed or control subjects. However, due to the limited sample size, our findings need to be verified in future studies with a larger sample.

  18. Chlorophyllin significantly reduces benzo[a]pyrene-DNA adduct formation and alters cytochrome P450 1A1 and 1B1 expression and EROD activity in normal human mammary epithelial cells.

    PubMed

    Keshava, Channa; Divi, Rao L; Einem, Tracey L; Richardson, Diana L; Leonard, Sarah L; Keshava, Nagalakshmi; Poirier, Miriam C; Weston, Ainsley

    2009-03-01

    We hypothesized that chlorophyllin (CHLN) would reduce benzo[a]pyrene-DNA (BP-DNA) adduct levels. Using normal human mammary epithelial cells (NHMECs) exposed to 4 microM BP for 24 hr in the presence or absence of 5 microM CHLN, we measured BP-DNA adducts by chemiluminescence immunoassay (CIA). The protocol included the following experimental groups: BP alone, BP given simultaneously with CHLN (BP+CHLN) for 24 hr, CHLN given for 24 hr followed by BP for 24 hr (preCHLN, postBP), and CHLN given for 48 hr with BP added for the last 24 hr (preCHLN, postBP+CHLN). Incubation with CHLN decreased BPdG levels in all groups, with 87% inhibition in the preCHLN, postBP+CHLN group. To examine metabolic mechanisms, we monitored expression by Affymetrix microarray (U133A), and found BP-induced up-regulation of CYP1A1 and CYP1B1 expression, as well as up-regulation of groups of interferon-inducible, inflammation and signal transduction genes. Incubation of cells with CHLN and BP in any combination decreased expression of many of these genes. Using reverse transcription real time PCR (RT-PCR) the maximal inhibition of BP-induced gene expression, >85% for CYP1A1 and >70% for CYP1B1, was observed in the preCHLN, postBP+CHLN group. To explore the relationship between transcription and enzyme activity, the ethoxyresorufin-O-deethylase (EROD) assay was used to measure the combined CYP1A1 and CYP1B1 activities. BP exposure caused the EROD levels to double, when compared with the unexposed controls. The CHLN-exposed groups all showed EROD levels similar to the unexposed controls. Therefore, the addition of CHLN to BP-exposed cells reduced BPdG formation and CYP1A1 and CYP1B1 expression, but EROD activity was not significantly reduced.

  19. Comparative immunohistochemical localisation of GABA(B1a), GABA(B1b) and GABA(B2) subunits in rat brain, spinal cord and dorsal root ganglion.

    PubMed

    Charles, K J; Evans, M L; Robbins, M J; Calver, A R; Leslie, R A; Pangalos, M N

    2001-01-01

    GABA(B) receptors are G-protein-coupled receptors mediating the slow onset and prolonged synaptic actions of GABA in the CNS. The recent cloning of two genes, GABA(B1) and GABA(B2), has revealed a novel requirement for GABA(B) receptor signalling. Studies have demonstrated that the two receptor subunits associate as a GABA(B1)/GABA(B2) heterodimer to form a functional GABA(B) receptor. In this study we have developed polyclonal antisera specific to two splice variants of the GABA(B1) subunit, GABA(B1a) and GABA(B1b), as well as an antiserum to the GABA(B2) subunit. Using affinity-purified antibodies derived from these antisera we have mapped out the distribution profile of each subunit in rat brain, spinal cord and dorsal root ganglion. In brain the highest areas of GABA(B1a), GABA(B1b) and GABA(B2) subunit expression were found in neocortex, hippocampus, thalamus, cerebellum and habenula. In spinal cord, GABA(B1) and GABA(B2) subunits were expressed in the superficial layers of the dorsal horn, as well as in motor neurones in the deeper layers of the ventral horn. GABA(B) receptor subunit immunoreactivity in dorsal root ganglion suggested that expression of GABA(B1b) was restricted to the large diameter neurones, in contrast to GABA(B1a) and GABA(B2) subunits which were expressed in both large and small diameter neurones. Although expression levels of GABA(B1) and GABA(B2) subunits varied we found no areas in which GABA(B1) was expressed in the absence of GABA(B2). This suggests that most, if not all, GABA(B1) immunoreactivity may represent functional GABA(B) receptors. Although our data are in general agreement with functional studies, some discrepancies in GABA(B1) subunit expression occurred with respect to other immunohistochemical studies. Overall our data suggest that GABA(B) receptors are widely expressed throughout the brain and spinal cord, and that GABA(B1a) and GABA(B1b) subunits can associate with GABA(B2) to form both pre- and post-synaptic receptors.

  20. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes.

    PubMed

    Stratakis, C A; Tichomirowa, M A; Boikos, S; Azevedo, M F; Lodish, M; Martari, M; Verma, S; Daly, A F; Raygada, M; Keil, M F; Papademetriou, J; Drori-Herishanu, L; Horvath, A; Tsang, K M; Nesterova, M; Franklin, S; Vanbellinghen, J-F; Bours, V; Salvatori, R; Beckers, A

    2010-11-01

    The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.

  1. Hepatitis C virus NS5A replication complex inhibitors. Part 6: Discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotypes 1a and 1b replicons.

    PubMed

    Belema, Makonen; Nguyen, Van N; Romine, Jeffrey L; St Laurent, Denis R; Lopez, Omar D; Goodrich, Jason T; Nower, Peter T; O'Boyle, Donald R; Lemm, Julie A; Fridell, Robert A; Gao, Min; Fang, Hua; Krause, Rudolph G; Wang, Ying-Kai; Oliver, A Jayne; Good, Andrew C; Knipe, Jay O; Meanwell, Nicholas A; Snyder, Lawrence B

    2014-03-13

    A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.

  2. Rapid detection of HCV genotyping 1a, 1b, 2a, 3a, 3b and 6a in a single reaction using two-melting temperature codes by a real-time PCR-based assay.

    PubMed

    Athar, Muhammad Ammar; Xu, Ye; Xie, Xiaoting; Xu, Zhenxing; Ahmad, Vakil; Hayder, Zulfiqar; Hussain, Syed Sajid; Liao, Yiqun; Li, Qingge

    2015-09-15

    The genotype of the hepatitis C virus (HCV) is an important indicator for antiviral therapeutic response. We hereby described development of a rapid HCV genotyping approach that enabled the identification of the six most common HCV subtypes of Asia, i.e., 1a, 1b, 2a, 3a, 3b, and 6a, in a single reaction. Using two dual-labeled, self-quenched probes that target the core region of the HCV genome, the exact subtype could be accurately identified by two-melting temperature codes determined from the two respective probes in a real-time PCR assay. Analytical sensitivity studies using armored RNA samples representing each of the six HCV subtypes showed that 5 copies/reaction of HCV RNA could be detected. The assay was evaluated using 244 HCV-positive serum samples and the results were compared with sequencing analysis. Of the 224 samples, subtype 3a (127, 52.3%) was the dominant, followed by 1b (51, 20.9%), 3b (47, 19.3%), 2a (8, 3.3%), 6a (4, 1.6%) and the least was subtype 1a (1, 0.4%). Moreover, 6 (2.5%) mixed infection samples were also detected. These results were fully concordant with sequencing analysis. We concluded that this real-time PCR-based assay could provide a rapid and reliable tool for routine HCV genotyping in most Asian countries.

  3. How to be an ant on figs

    NASA Astrophysics Data System (ADS)

    Bain, Anthony; Harrison, Rhett D.; Schatz, Bertrand

    2014-05-01

    Mutualistic interactions are open to exploitation by one or other of the partners and a diversity of other organisms, and hence are best understood as being embedded in a complex network of biotic interactions. Figs participate in an obligate mutualism in that figs are dependent on agaonid fig wasps for pollination and the wasps are dependent on fig ovules for brood sites. Ants are common insect predators and abundant in tropical forests. Ants have been recorded on approximately 11% of fig species, including all six subgenera, and often affect the fig-fig pollinator interaction through their predation of either pollinating and parasitic wasps. On monoecious figs, ants are often associated with hemipterans, whereas in dioecious figs ants predominantly prey on fig wasps. A few fig species are true myrmecophytes, with domatia or food rewards for ants, and in at least one species this is linked to predation of parasitic fig wasps. Ants also play a role in dispersal of fig seeds and may be particularly important for hemi-epiphytic species, which require high quality establishment microsites in the canopy. The intersection between the fig-fig pollinator and ant-plant systems promises to provide fertile ground for understanding mutualistic interactions within the context of complex interaction networks.

  4. Modeling and molecular dynamics simulations of the V33 variant of the integrin subunit β3: Structural comparison with the L33 (HPA-1a) and P33 (HPA-1b) variants.

    PubMed

    Jallu, Vincent; Poulain, Pierre; Fuchs, Patrick F J; Kaplan, Cecile; de Brevern, Alexandre G

    2014-10-01

    The human platelet alloantigen (HPA)-1 system, the first cause of alloimmune thrombocytopenia in Caucasians, results from leucine-to-proline substitution (alleles 1a and 1b) of residue 33 in β3 subunit of the integrin αIIbβ3. A third variant with a valine (V33) has been described. Although leucine and valine share similar physicochemical properties, sera containing alloantibodies to the HPA-1a antigen variably reacted with V33-β3, suggesting structural alterations of β3. To analyze the effect of the L33V transition, molecular dynamics simulations were performed on a 3D structural model of the V33 form of the whole β3 extracellular domain (690 residues). Dynamics of the PSI (carrying residue 33), I-EGF-1, and I-EGF-2 domains of β3 were compared to previously obtained dynamics of HPA-1a structure and HPA-1b structural model using classical and innovative developments (a structural alphabet). Clustering approach and local structure analysis showed that L33-β3 and V33-β3 mostly share common structures co-existing in different dynamic equilibria. The L33V substitution mainly displaces the equilibrium between common structures. These observations can explain the variable reactivity of anti-HPA-1a alloantibodies suggesting that molecular dynamic plays a key role in the binding of these alloantibodies. Unlike the L33P substitution, the L33V transition would not affect the structure flexibility of the β3 knee, and consequently the functions of αIIbβ3.

  5. Genomic localization of the human genes TAF1A, TAF1B and TAF1C, encoding TAF(I)48, TAF(I)63 and TAF(I)110 subunits of class I general transcription initiation factor SL1.

    PubMed

    Di Pietro, C; Rapisarda, A; Amico, V; Bonaiuto, C; Viola, A; Scalia, M; Motta, S; Amato, A; Engel, H; Messina, A; Sichel, G; Grzeschik, K; Purrello, M

    2000-01-01

    Human SL1 is a general transcription initiation factor (GTF) essential for RNA polymerase I to start rRNA synthesis at class I promoters. It is comprised of the TATA box-binding protein (TBP) and three TBP-associated factors (TAF(I)48, TAF(I)63 and TAF(I)110). We have determined that the human genes TAF1A, TAF1B and TAF1C, encoding these three TAF(I) polypeptides, are localized at lq42, 2p25 and 16q24, respectively. All three genes are present as single copies in the human genome and map to different chromosomes, as shown by somatic cell hybrid panel and radiation hybrid panel analysis and FISH. Two of these genes, TAF1C and TAF1B, are transcribed into multiple RNAs, as determined through Northern analysis of mRNA from various human organs and cell lines. If translated into different polypeptides, this could result in production of variant isoforms of SL1 with different activation potentials.

  6. Induction of Cyp1a1 and Cyp1b1 and formation of DNA adducts in C57BL/6, Balb/c, and F1 mice following in utero exposure to 3-methylcholanthrene

    SciTech Connect

    Xu Mian; Nelson, Garret B.; Moore, Joseph E.; McCoy, Thomas P.; Dai, Jian; Manderville, Richard A.; Ross, Jeffrey A.; Miller, Mark Steven . E-mail: msmiller@wfubmc.edu

    2005-11-15

    Fetal mice are more sensitive to chemical carcinogens than are adults. Previous studies from our laboratory demonstrated differences in the mutational spectrum induced in the Ki-ras gene from lung tumors isolated from [D2 x B6D2F1]F2 mice and Balb/c mice treated in utero with 3-methylcholanthrene (MC). We thus determined if differences in metabolism, adduct formation, or adduct repair influence strain-specific responses to transplacental MC exposure in C57BL/6 (B6), Balb/c (BC), and reciprocal F1 crosses between these two strains of mice. The induction of Cyp1a1 and Cyp1b1 in fetal lung and liver tissue was determined by quantitative fluorescent real-time PCR. MC treatment caused maximal induction of Cyp1a1 and Cyp1b1 RNA 2-8 h after injection in both organs. RNA levels for both genes then declined in both fetal organs, but a small biphasic, secondary increase in Cyp1a1 was observed specifically in the fetal lung 24-48 h after MC exposure in all four strains. Cyp1a1 induction by MC at 4 h was 2-5 times greater in fetal liver (7000- to 16,000-fold) than fetal lung (2000- to 6000-fold). Cyp1b1 induction in both fetal lung and liver was similar and much lower than that observed for Cyp1a1, with induction ratios of 8- to 18-fold in fetal lung and 10- to 20-fold in fetal liver. The overall kinetics and patterns of induction were thus very similar across the four strains of mice. The only significant strain-specific effect appeared to be the relatively poor induction of Cyp1b1 in the parental strain of B6 mice, especially in fetal lung tissue. We also measured the levels of MC adducts and their disappearance from lung tissue by the P{sup 32} post-labeling assay on gestation days 18 and 19 and postnatal days 1, 4, 11, and 18. Few differences were seen between the different strains of mice; the parental strain of B6 mice had nominally higher levels of DNA adducts 2 (gestation day 19) and 4 (postnatal day 1) days after injection, although this was not statistically

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

    SciTech Connect

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

    2013-02-01

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

  8. The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

    PubMed

    Korte, S Mechiel; Prins, Jolanda; Van den Bergh, Filip S; Oosting, Ronald S; Dupree, Rudy; Korte-Bouws, Gerdien A H; Westphal, Koen G C; Olivier, Berend; Denys, Damiaan A; Garland, Alexis; Güntürkün, Onur

    2017-01-05

    The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.

  9. Polymorphisms of heat shock protein 70 genes (HSPA1A, HSPA1B and HSPA1L) and susceptibility of noise-induced hearing loss in a Chinese population: A case-control study

    PubMed Central

    Li, Yanhong; Yu, Shanfa; Gu, Guizhen; Chen, Guoshun; Zheng, Yuxin; Jiao, Jie; Zhou, Wenhui; Wu, Hui; Zhang, Zengrui; Zhang, Huanling; He, Lihua; Yang, Qiuyue; Xu, Xiangrong

    2017-01-01

    Noise-induced hearing loss (NIHL) is the second-most frequent form of sensorineural hearing loss. When exposed to the same noise, some workers develop NIHL while others do not, suggesting that NIHL may be associated with genetic factors. To explore the relationship between single nucleotide polymorphisms (SNPs) in heat shock protein 70 (HSP70) genes (HSPA1A, HSPA1B and HSPA1L) and susceptibility to NIHL in Han Chinese workers exposed to noise, a case-control association study was carried out with 286 hearing loss cases and 286 matched with gender, age, type of work, and exposure time, drawn from a population of 3790 noise-exposed workers. Four SNPs were selected and genotyped. Subsequently, the effects of the alleles and genotypes of the three HSP70 genes (HSPA1A, HSPA1B and HSPA1L) on NIHL were analyzed by using a conditional logistic regression. A generalized multiple dimensionality reduction (GMDR) was applied to further detect an interaction between the four SNPs. Compared with the combined genotypes CC/TC, carriers of the TT genotype of rs2763979 appeared to show greater susceptibility to NIHL (P = 0.042, adjusted OR = 1.731, 95% CI 1.021–2.935). A significant interaction between rs2763979 and CNE was found (P = 0.029), and a significant association was found between TT of s2763979 and NIHL (P = 0.024, adjusted OR = 5.694, 95%CI 1.256-25.817) in the 96 dB (A)≤CNE<101 dB (A) group. The results suggest that the rs2763979 locus of the HSP70 genes may be associated with susceptibility to NIHL in Chinese individuals, and other HSP70 genes may also be susceptibility genes for NIHL, but the results must be further replicated in additional independent sample sets. PMID:28182740

  10. Polymorphisms of heat shock protein 70 genes (HSPA1A, HSPA1B and HSPA1L) and susceptibility of noise-induced hearing loss in a Chinese population: A case-control study.

    PubMed

    Li, Yanhong; Yu, Shanfa; Gu, Guizhen; Chen, Guoshun; Zheng, Yuxin; Jiao, Jie; Zhou, Wenhui; Wu, Hui; Zhang, Zengrui; Zhang, Huanling; He, Lihua; Yang, Qiuyue; Xu, Xiangrong

    2017-01-01

    Noise-induced hearing loss (NIHL) is the second-most frequent form of sensorineural hearing loss. When exposed to the same noise, some workers develop NIHL while others do not, suggesting that NIHL may be associated with genetic factors. To explore the relationship between single nucleotide polymorphisms (SNPs) in heat shock protein 70 (HSP70) genes (HSPA1A, HSPA1B and HSPA1L) and susceptibility to NIHL in Han Chinese workers exposed to noise, a case-control association study was carried out with 286 hearing loss cases and 286 matched with gender, age, type of work, and exposure time, drawn from a population of 3790 noise-exposed workers. Four SNPs were selected and genotyped. Subsequently, the effects of the alleles and genotypes of the three HSP70 genes (HSPA1A, HSPA1B and HSPA1L) on NIHL were analyzed by using a conditional logistic regression. A generalized multiple dimensionality reduction (GMDR) was applied to further detect an interaction between the four SNPs. Compared with the combined genotypes CC/TC, carriers of the TT genotype of rs2763979 appeared to show greater susceptibility to NIHL (P = 0.042, adjusted OR = 1.731, 95% CI 1.021-2.935). A significant interaction between rs2763979 and CNE was found (P = 0.029), and a significant association was found between TT of s2763979 and NIHL (P = 0.024, adjusted OR = 5.694, 95%CI 1.256-25.817) in the 96 dB (A)≤CNE<101 dB (A) group. The results suggest that the rs2763979 locus of the HSP70 genes may be associated with susceptibility to NIHL in Chinese individuals, and other HSP70 genes may also be susceptibility genes for NIHL, but the results must be further replicated in additional independent sample sets.

  11. 5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus.

    PubMed

    Freitas, Renato Leonardo; Ferreira, Célio Marcos dos Reis; Urbina, Maria Angélica Castiblanco; Mariño, Andrés Uribe; Carvalho, Andressa Daiane; Butera, Giuseppe; de Oliveira, Ana Maria; Coimbra, Norberto Cysne

    2009-05-01

    Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 microg/0.2 microL) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception.

  12. Triton 2 (1B)

    NASA Technical Reports Server (NTRS)

    Clark, Michelle L.; Meiss, A. G.; Neher, Jason R.; Rudolph, Richard H.

    1994-01-01

    The goal of this project was to perform a detailed design analysis on a conceptually designed preliminary flight trainer. The Triton 2 (1B) must meet the current regulations in FAR Part 23. The detailed design process included the tasks of sizing load carrying members, pulleys, bolts, rivets, and fuselage skin for the safety cage, empennage, and control systems. In addition to the regulations in FAR Part 23, the detail design had to meet established minimums for environmental operating conditions and material corrosion resistance.

  13. Morphological Structure and Transcriptome Comparison of the Cytoplasmic Male Sterility Line in Brassica napus (SaNa-1A) Derived from Somatic Hybridization and Its Maintainer Line SaNa-1B

    PubMed Central

    Du, Kun; Liu, Qier; Wu, Xinyue; Jiang, Jinjin; Wu, Jian; Fang, Yujie; Li, Aimin; Wang, Youping

    2016-01-01

    SaNa-1A is a novel cytoplasmic male sterility (CMS) line in Brassica napus derived from progenies of somatic hybrids between B.napus and Sinapis alba, and SaNa-1B is the corresponding maintainer line. In this study, phenotypic differences of floral organs between CMS and the maintainer lines were observed. By microscope observation in different anther developmental stages of two lines, we found the anther development in SaNa-1A was abnormal since the tetrad stage, and microspore development was ceased during the uninucleate stage. Transcriptomic sequencing for floral buds of sterile and fertile plants were conducted to elucidate gene expression and regulation caused by the alien chromosome and cytoplasm from S. alba. Clean tags obtained were assembled into 195,568 unigenes, and 7811 unigenes distributed in the metabolic and protein synthesis pathways were identified with significant expression differences between two libraries. We also observed that genes participating in carbon metabolism, tricarboxylic acid cycle, oxidative phosphorylation, oxidation–reduction system, pentatricopeptide repeat, and anther development were downregulated in the sterile line. Some of them are candidates for researches on the sterility mechanism in the CMS material, fertility restoration, and improvement of economic traits in the maintainer line. Further research on the tags with expressional specificity in the fertile line would be helpful to explore desirable agronomic traits from wild species of rapeseed. PMID:27656189

  14. High Resolution Spectroscopy of A^1B1u ← X^1A_g 8^1_04^1_0 Band of Naphthalene Referenced to AN Optical Frequency Comb

    NASA Astrophysics Data System (ADS)

    Nakashima, Kazuki; Nishiyama, Akiko; Misono, Masatoshi

    2016-06-01

    In the excited vibronic states of naphthalene, there exist various interesting interactions such as intramolecular vibrational energy redistribution (IVR), intersystem crossing (ISC), and internal conversion (IC). More than thirty yeas ago, Beck et al. showed that IVR became remarkable when the excess energy exceeded about 2000 cm-1^, ^a. In the present study, we observe Doppler-free two-photon absorption spectra of A^1B1u ← X^1A_g 8^1_04^1_0 band of naphthalene around 34281 cm-1. The excess energy is 2261 cm-1, which is just above the threshold of IVR. Thus we expect this band is suitable to analyze the dynamics in the excited vibronic states. In our experiment, the spectral resolution is about 100 kHz, and rovibronic lines are well-resolved. To decide the transition frequencies, frequency shifts, and spectral linewidths with high accuracy and precision, we employed the comb-referenced Doppler-free two-photon absorption spectroscopic system^b. We proceed to assign the rovibronic lines in ^qQ transition, and to determine molecular constants in the excited vibronic state. ^a S. M. Beck, J. B. Hopkins, D. E. Powers, and R. E. Smalley, J. Chem. Phys. 74, 43(1981). ^b A. Nishiyama, K. Nakashima, A. Matsuba, and M. Misono, J. Mol. Spectrosc. 318, 40 (2015).

  15. Ecology of a fig ant-plant

    NASA Astrophysics Data System (ADS)

    Harrison, Rhett D.

    2014-05-01

    Mutualistic interactions are embedded in networks of interactions that affect the benefits accruing to the mutualistic partners. Figs and their pollinating wasps are engaged in an obligate mutualism in which the fig is dependent on the fig pollinator for pollination services and the pollinator is dependent on fig ovules for brood sites. This mutualism is exploited by non-pollinating fig wasps that utilise the same ovules, but do not provide a pollination service. Most non-pollinating wasps oviposit from outside the inflorescence (syconium), where they are vulnerable to ant predation. Ficus schwarzii is exposed to high densities of non-pollinating wasps, but Philidris sp. ants patrolling the syconia prevent them from ovipositing. Philidris rarely catch wasps, but the fig encourages the patrolling by providing a reward through extra-floral nectaries on the surface of syconia. Moreover, the reward is apparently only produced during the phase when parasitoids are ovipositing. An ant-exclusion experiment demonstrated that, in the absence of ants, syconia were heavily attacked and many aborted as a consequence. Philidris was normally rare on the figs during the receptive phase or at the time of day when wasp offspring are emerging, so predation on pollinators was limited. However, Myrmicaria sp. ants, which only occurred on three trees, preyed substantially on pollinating as well as non-pollinating wasps. F. schwarzii occurs in small clusters of trees and has an exceptionally rapid crop turnover. These factors appear to promote high densities of non-pollinating wasps and, as a consequence, may have led to both a high incidence of ants on trees and increased selective pressure on fig traits that increase the payoffs of the fig-ant interaction for the fig. The fig receives no direct benefit from the reward it provides, but protects pollinating wasps that will disperse its pollen.

  16. A combination of alleles 2 of interleukin (IL)-1A(-889) and IL-1B(+3954) is associated with lower gingival bleeding tendency in plaque-induced gingivitis in young adults of Arabic heritage.

    PubMed

    Müller, H P; Barrieshi-Nusair, K M

    2007-09-01

    The aim of this study was to investigate the possible association of a distinct combination of polymorphisms in the interleukin (IL)-1 gene cluster on gingival bleeding tendency in young adult Arabs with plaque-induced gingivitis. Fifty otherwise healthy, nonsmoking volunteers, 19-28 years of age, participated. Clinical examinations included periodontal probing depth, bleeding on probing, and plaque index. Probing was done with a pressure-controlled probe at about 1.27 MPa. Examinations were repeated after 2 and 4 weeks. Polymorphisms in the IL-1 gene cluster were assessed using a reverse hybridization assay. A subject carrying alleles 2 at IL-1A ( -889 ) and IL-1B ( +3954 ) was designated genotype-positive. Twenty-six subjects were genotype-positive (52%). A repeated measures two-level (occasion, subject) model of the proportion of sites bleeding on probing, which was adjusted for gender, average plaque index, probing depth, and calculus, revealed a significantly lower proportion of bleeding sites in genotype-positive subjects (estimate -0.050, standard error 0.025, p < 0.05). Biserial correlations of bleeding proportions were high (0.71-0.78), confirming the steady-state plaque environment. It was concluded that inflammatory responses to dental plaque were considerably dampened in genotype-positive, nonsmoking young adults of Arabic heritage.

  17. Determination of loperamide in mdr1a/1b knock-out mouse brain tissue using matrix-assisted laser desorption/ionization mass spectrometry and comparison with quantitative electrospray-triple quadrupole mass spectrometry analysis.

    PubMed

    Shin, Young G; Dong, Teresa; Chou, Bilin; Menghrajani, Kapil

    2011-11-01

    Recently matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) imaging has been used to analyze small molecule pharmaceutical compounds directly on tissue sections to determine spatial distribution within target tissue and organs. The data presented to date usually indicate relative amounts of drug within the tissue. The determination of absolute amounts is still done using tissue homogenization followed by traditional liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, the quantitative determination of loperamide, an antidiarrheal agent and a P-glycoprotein substrate, in mdr1a/1b (-/-) mouse brain tissue sections using MALDI MS on a quadrupole time-of-flight mass spectrometry is described. 5 mg/mL α-cyano-4-hydroxycinnamic acid in 50% acetonitrile with 0.1% trifluoroacetic acid and 0.5 μM reserpine was used as the MALDI matrix. The calibration curve constructed by the peak intensities of standard samples from MALDI MS was linear from 0.025 to 0.5 μM with r² = 0.9989. The accuracy of calibration curve standards was 78.3-105.9% and the percent deviation was less than 25%. Comparison between direct MALDI tissue analysis and conventional tissue analysis using homogenization followed by electrospray LC-MS/MS was also explored.

  18. Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

    PubMed

    Kim, Joung Min; Jeong, Seong Wook; Yang, Jihoon; Lee, Seong Heon; Kim, Woon Mo; Jeong, Seongtae; Bae, Hong Beom; Yoon, Myung Ha; Choi, Jeong Il

    2015-07-23

    Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation.

  19. Franck-Condon factors perturbed by damped harmonic oscillators: Solvent enhanced X {sup 1}A{sub g} ↔ A{sup 1}B{sub 1u} absorption and fluorescence spectra of perylene

    SciTech Connect

    Wang, Chen-Wen; Zhu, Chaoyuan Lin, Sheng-Hsien; Yang, Ling; Yu, Jian-Guo

    2014-08-28

    Damped harmonic oscillators are utilized to calculate Franck-Condon factors within displaced harmonic oscillator approximation. This is practically done by scaling unperturbed Hessian matrix that represents local modes of force constants for molecule in gaseous phase, and then by diagonalizing perturbed Hessian matrix it results in direct modification of Huang–Rhys factors which represent normal modes of solute molecule perturbed by solvent environment. Scaling parameters are empirically introduced for simulating absorption and fluorescence spectra of an isolated solute molecule in solution. The present method is especially useful for simulating vibronic spectra of polycyclic aromatic hydrocarbon molecules in which hydrogen atom vibrations in solution can be scaled equally, namely the same scaling factor being applied to all hydrogen atoms in polycyclic aromatic hydrocarbons. The present method is demonstrated in simulating solvent enhanced X {sup 1}A{sub g} ↔ A{sup 1}B{sub 1u} absorption and fluorescence spectra of perylene (medium-sized polycyclic aromatic hydrocarbon) in benzene solution. It is found that one of six active normal modes v{sub 10} is actually responsible to the solvent enhancement of spectra observed in experiment. Simulations from all functionals (TD) B3LYP, (TD) B3LYP35, (TD) B3LYP50, and (TD) B3LYP100 draw the same conclusion. Hence, the present method is able to adequately reproduce experimental absorption and fluorescence spectra in both gas and solution phases.

  20. Ants use odour cues to exploit fig-fig wasp interactions

    NASA Astrophysics Data System (ADS)

    Schatz, Bertrand; Hossaert-McKey, Martine

    2010-01-01

    Fig wasps may constitute a relatively abundant food source for ants associated with the fig-fig wasp nursery pollination mutualism. We found previously that a Mediterranean ant species detects fig wasps by chemical signals. In this paper we want to test the generality of this finding by studying two tropical ants, Oecophylla smaragdina and Crematogaster sp., preying on fig wasps on the dioecious Ficus fistulosa in Brunei (Borneo). Behavioural tests in a Y-tube olfactometer showed that these two ants were attracted both to odours emitted by receptive figs and to those emitted by fig wasps (male and female of the pollinator, and a non-pollinating fig wasp) used here as a kairomone. Naïve workers were not attracted to fig wasps, suggesting that olfactory learning may play a role in prey detection. We also found that O. smaragdina was much more likely to be present on figs of male trees (where fig wasps are more abundant), and that the abundance of this ant species varied strongly with developmental phase of figs on individual trees. Moreover, its aggressiveness was also strongly influenced by the nature of the object presented in our behavioural tests, the site of the test and the developmental phase of the fig tested. Investigation on the chemical and behavioural ecology of the different interacting species provides important insights into the intricate relationships supported by the fig-fig wasp mutualism.

  1. Larger fig wasps are more careful about which figs to enter--with good reason.

    PubMed

    Liu, Cong; Yang, Da-Rong; Compton, Stephen G; Peng, Yan-Qiong

    2013-01-01

    Floral longevity reflects a balance between gains in pollinator visitation and the costs of flower maintenance. Because rewards to pollinators change over time, older flowers may be less attractive, reducing the value of extended longevity. Un-pollinated figs, the inflorescences of Ficus species, can remain receptive for long periods, but figs that are older when entered by their host-specific fig wasp pollinators produce fewer seeds and fig wasp offspring. Our field experiments with Ficushispida, a dioecious fig tree, examined how the length of time that receptive figs have remained un-pollinated influences the behaviour and reproductive success of its short-lived fig wasp pollinator, Ceratosolensolmsi marchali. The results were consistent in three different seasons, and on male and female trees, although receptivity was greatly extended during colder months. Pollinators took longer to find the ostioles of older figs, and longer to penetrate them. They also became increasingly unwilling to enter figs as they aged, and increasing numbers of the wasps became trapped in the ostiolar bracts. Larger individuals were particularly unwilling to enter older figs, resulting in older figs being pollinated by smaller wasps. On female trees, where figs produce only seeds, seed production declined rapidly with fig age. On male trees, the numbers and size of fig wasp offspring declined, and a higher proportion were male. Older male figs are harder to enter, especially for larger individuals, and offer poorer quality oviposition opportunities. This study opens an interesting new perspective on the coevolution of figs and their pollinators, especially factors influencing pollinator body size and emphasises the subtleties of interactions between mutualists.

  2. Only pollinator fig wasps have males that collaborate to release their females from figs of an Asian fig tree.

    PubMed

    Suleman, Nazia; Raja, Shazia; Compton, Stephen G

    2012-06-23

    Male insects rarely collaborate with each other, but pollinator fig wasps (Hymenoptera: Agaonidae) are said to be an exception. Immature fig wasps feed on galled ovules located inside figs, the inflorescences of Ficus species (Moraceae). After mating, adult pollinator males chew communal exit-holes that allow mated females (which are often also their siblings) to escape. Figs also support non-pollinating fig wasps (NPFWs), some of which produce exit-holes independently. We determined whether collaboration between pollinator males (Kradibia tentacularis from Ficus montana) was necessary for the release of their females, and used the relationship between male numbers and likelihood of success to measure the extent of cooperation during exit-hole production. These attributes were then compared with those of an NPFW (Sycoscapter sp.) from the same host plant. Pollinators were more abundant than NPFW, but their more female-biased sex ratio meant male pollinator densities were only slightly higher. Individual males of both species could produce an exit-hole. Single males of the NPFW were just as successful as single male pollinators, but only male pollinators cooperated effectively, becoming more successful as their numbers increased. The lack of cooperation among NPFW may be linked to their earlier period of intense inter-male aggression.

  3. Ancient fig wasps indicate at least 34 Myr of stasis in their mutualism with fig trees

    PubMed Central

    Compton, Stephen G.; Ball, Alexander D.; Collinson, Margaret E.; Hayes, Peta; Rasnitsyn, Alexandr P.; Ross, Andrew J.

    2010-01-01

    Fig wasps and fig trees are mutually dependent, with each of the 800 or so species of fig trees (Ficus, Moraceae) typically pollinated by a single species of fig wasp (Hymenoptera: Agaonidae). Molecular evidence suggests that the relationship existed over 65 Ma, during the Cretaceous. Here, we record the discovery of the oldest known fossil fig wasps, from England, dated at 34 Ma. They possess pollen pockets that contain fossil Ficus pollen. The length of their ovipositors indicates that their host trees had a dioecious breeding system. Confocal microscopy and scanning electron microscopy reveal that the fossil female fig wasps, and more recent species from Miocene Dominican amber, display the same suite of anatomical characters associated with fig entry and pollen-carrying as modern species. The pollen is also typical of modern Ficus. No innovations in the relationship are discernible for the last tens of millions of years. PMID:20554563

  4. Ancient fig wasps indicate at least 34 Myr of stasis in their mutualism with fig trees.

    PubMed

    Compton, Stephen G; Ball, Alexander D; Collinson, Margaret E; Hayes, Peta; Rasnitsyn, Alexandr P; Ross, Andrew J

    2010-12-23

    Fig wasps and fig trees are mutually dependent, with each of the 800 or so species of fig trees (Ficus, Moraceae) typically pollinated by a single species of fig wasp (Hymenoptera: Agaonidae). Molecular evidence suggests that the relationship existed over 65 Ma, during the Cretaceous. Here, we record the discovery of the oldest known fossil fig wasps, from England, dated at 34 Ma. They possess pollen pockets that contain fossil Ficus pollen. The length of their ovipositors indicates that their host trees had a dioecious breeding system. Confocal microscopy and scanning electron microscopy reveal that the fossil female fig wasps, and more recent species from Miocene Dominican amber, display the same suite of anatomical characters associated with fig entry and pollen-carrying as modern species. The pollen is also typical of modern Ficus. No innovations in the relationship are discernible for the last tens of millions of years.

  5. Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory.

    PubMed

    Meneses, Alfredo

    2007-11-22

    In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.

  6. Strong HCV NS3/4a, NS4b, NS5a, NS5b-specific cellular immune responses induced in Rhesus macaques by a novel HCV genotype 1a/1b consensus DNA vaccine.

    PubMed

    Latimer, Brian; Toporovski, Roberta; Yan, Jian; Pankhong, Panyupa; Morrow, Matthew P; Khan, Amir S; Sardesai, Niranjan Y; Welles, Seth L; Jacobson, Jeffrey M; Weiner, David B; Kutzler, Michele A

    2014-01-01

    Chronic HCV is a surreptitious disease currently affecting approximately 3% of the world's population that can lead to liver failure and cancer decades following initial infection. However, there are currently no vaccines available for the prevention of chronic HCV. From patients who acutely resolve HCV infection, it is apparent that a strong and broad cytotoxic T lymphocyte (CTL) response is important in HCV clearance. DNA vaccines are naked plasmid DNA molecules that encode pathogen antigens to induce a pathogen-specific immune response. They are inexpensive to produce and have an excellent safety profile in animals and humans. Additionally, DNA vaccines are able to induce strong CTL responses, making them well-suited for an HCV vaccine. We aimed to maximize vaccine recipients' opportunity to induce a broad T cell response with a novel antigenic sequence, multi-antigen vaccine strategy. We have generated DNA plasmids encoding consensus sequences of HCV genotypes 1a and 1b non-structural proteins NS3/4a, NS4b, NS5a, and NS5b. Rhesus macaques were used to study the immunogenicity of these constructs. Four animals were immunized 3 times, 6 weeks apart, at a dose of 1.0mg per antigen construct, as an intramuscular injection followed by in vivo electroporation, which greatly increases DNA uptake by local cells. Immune responses were measured 2 weeks post-immunization regimen (PIR) in immunized rhesus macaques and showed a broad response to multiple HCV nonstructural antigens, with up to 4680 spot-forming units per million peripheral blood mononuclear cells (PBMCs) as measured by Interferon-γ ELISpot. In addition, multiparametric flow cytometry detected HCV-specific CD4+ and CD8+ T cell responses by intracellular cytokine staining and detected HCV-specific CD107a+/GrzB+ CD8+ T cells indicating an antigen specific cytolytic response 2 weeks PIR compared with baseline measurements. At the final study time point, 6 weeks PIR, HCV-specific CD45RA- memory-like T cells

  7. The occurrence of fig wasps in the fruits of female gynodioecious fig trees

    NASA Astrophysics Data System (ADS)

    Wu, Tao; Dunn, Derek W.; Hu, Hao-Yuan; Niu, Li-Ming; Xiao, Jin-Hua; Pan, Xian-Li; Feng, Gui; Fu, Yue-Guan; Huang, Da-Wei

    2013-01-01

    Fig trees are pollinated by wasp mutualists, whose larvae consume some of the plant's ovaries. Many fig species (350+) are gynodioecious, whereby pollinators generally develop in the figs of 'male' trees and seeds generally in the 'females.' Pollinators usually cannot reproduce in 'female' figs at all because their ovipositors cannot penetrate the long flower styles to gall the ovaries. Many non-pollinating fig wasp (NPFW) species also only reproduce in figs. These wasps can be either phytophagous gallers or parasites of other wasps. The lack of pollinators in female figs may thus constrain or benefit different NPFWs through host absence or relaxed competition. To determine the rates of wasp occurrence and abundance we surveyed 11 dioecious fig species on Hainan Island, China, and performed subsequent experiments with Ficus tinctoria subsp. gibbosa to identify the trophic relationships between NPFWs that enable development in female syconia. We found NPFWs naturally occurring in the females of Ficus auriculata, Ficus hainanensis and F. tinctoria subsp. gibbosa. Because pollinators occurred only in male syconia, when NPFWs also occurred in female syconia, overall there were more wasps in male than in female figs. Species occurrence concurred with experimental data, which showed that at least one phytophagous galler NPFW is essential to enable multiple wasp species to coexist within a female fig. Individuals of galler NPFW species present in both male and female figs of the same fig species were more abundant in females than in males, consistent with relaxed competition due to the absence of pollinator. However, these wasps replaced pollinators on a fewer than one-to-one basis, inferring that other unknown mechanisms prevent the widespread exploitation by wasps of female figs. Because some NPFW species may use the holes chewed by pollinator males to escape from their natal fig, we suggest that dispersal factors could be involved.

  8. GD1b-specific antibodies may bind to complex of GQ1b and GM1, causing ataxia.

    PubMed

    Yuki, Nobuhiro; Fukami, Yuki; Yanaka, Chiaki; Koike, Saiko; Hirata, Koichi

    2014-08-01

    Monospecific IgG antibodies to GD1b ganglioside (GD1b-specific antibodies) have been found in patients with acute ataxic neuropathy and Guillain-Barré syndrome, but the association of the GD1b-specific antibodies with specific neurological conditions has yet to be established. We tested sera from more than 10,000 patients with various neurological disorders, and found six sera, which contained IgG antibodies to GD1b, but not to LM1, GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, GT1b and GQ1b. All six patients who carried GD1b-specific antibodies presented with acute onset of ataxia and monophasic course of the illness, of whom five demonstrated cerebellar-like ataxia. Four patients had antecedent symptoms of upper respiratory tract infection. The six patients demonstrated areflexia, and four complained of distal numbness. All the six patients who had the GD1b-specific antibodies carried IgG antibodies to complex of GQ1b/GM1 and GT1a/GM1. GD1b-specific antibodies were significantly absorbed by GQ1b/GM1 and GT1a/GM1 and anti-GQ1b/GM1 and -GT1a/GM1 antibodies were absorbed by GD1b. In conclusion, the GD1b-specific antibodies, which recognizes GQ1b/GM1 or GT1a/GM1 complex, are associated with acute ataxia.

  9. Critical review of host specificity and its coevolutionary implications in the fig/fig-wasp mutualism

    PubMed Central

    Machado, Carlos A.; Robbins, Nancy; Gilbert, M. Thomas P.; Herre, Edward Allen

    2005-01-01

    Figs (Ficus spp., Moraceae) and their pollinating wasps (Agaonidae, Chalcidoidea) constitute perhaps the most tightly integrated pollination mutualism that is known. Figs are characterized by extraordinarily high global and local species diversity. It has been proposed that the diversification of this mutualism has occurred through strict-sense coadaptation and cospeciation between pairs of fig and wasp species that are associated in highly specific one-to-one relationships. However, existing studies cast doubt on the generality of this proposition. Here, we review our current knowledge of the evolutionary history of the fig/fig-wasp mutualism. We critically examine the idea that codivergence between figs and their pollinators has been dominated by strict-sense cospeciation. We present phylogenetic and population genetic data from neotropical fig and fig wasp species that suggest that a more accurate model for diversification in this mutualism is that of groups of genetically well defined wasp species coevolving with genetically less well defined (frequently hybridizing) groups of figs. Last, we use our results to assess previously proposed hypotheses on models of speciation in this mutualism. PMID:15851680

  10. Asymmetric interaction and indeterminate fitness correlation between cooperative partners in the fig-fig wasp mutualism.

    PubMed

    Wang, Rui-Wu; Sun, Bao-Fa; Zheng, Qi; Shi, Lei; Zhu, Lixing

    2011-10-07

    Empirical observations have shown that cooperative partners can compete for common resources, but what factors determine whether partners cooperate or compete remain unclear. Using the reciprocal fig-fig wasp mutualism, we show that nonlinear amplification of interference competition between fig wasps-which limits the fig wasps' ability to use a common resource (i.e. female flowers)-keeps the common resource unsaturated, making cooperation locally stable. When interference competition was manually prevented, the fitness correlation between figs and fig wasps went from positive to negative. This indicates that genetic relatedness or reciprocal exchange between cooperative players, which could create spatial heterogeneity or self-restraint, was not sufficient to maintain stable cooperation. Moreover, our analysis of field-collected data shows that the fitness correlation between cooperative partners varies stochastically, and that the mainly positive fitness correlation observed during the warm season shifts to a negative correlation during the cold season owing to an increase in the initial oviposition efficiency of each fig wasp. This implies that the discriminative sanction of less-cooperative wasps (i.e. by decreasing the egg deposition efficiency per fig wasp) but reward to cooperative wasps by fig, a control of the initial value, will facilitate a stable mutualism. Our finding that asymmetric interaction leading to an indeterminate fitness interaction between symbiont (i.e. cooperative actors) and host (i.e. recipient) has the potential to explain why conflict has been empirically observed in both well-documented intraspecific and interspecific cooperation systems.

  11. Asymmetric or diffusive co-evolution generates meta-populations in fig-fig wasp mutualisms.

    PubMed

    Wang, RuiWu; Yang, Yan; Wiggins, Natasha L

    2014-06-01

    Co-evolutionary theory assumes co-adapted characteristics are a positive response to counter those of another species, whereby co-evolved species reach an evolutionarily stable interaction through bilateral adaptation. However, evidence from the fig-fig wasp mutualistic system implies very different co-evolutionary selection mechanisms, due to the inherent conflict among interacted partners. Fig plants appear to have discriminatively enforced fig wasps to evolve "adaptation characteristics" that provide greater benefit to the fig, and fig wasps appear to have diversified their evolutionary strategies in response to discriminative enforcement by figs and competition among different fig wasp species. In what appears to be an asymmetric interaction, the prosperity of cooperative pollinating wasps should inevitably lead to population increases of parasitic individuals, thus resulting in localized extinctions of pollinating wasps. In response, the sanctioning of parasitic wasps by the fig should lead to a reduction in the parasitic wasp population. The meta-populations created by such asymmetric interactions may result in each population of coevolved species chaotically oscillated, temporally or evolutionarily.

  12. Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population.

    PubMed

    Kapelski, Pawel; Skibinska, Maria; Maciukiewicz, Malgorzata; Wilkosc, Monika; Frydecka, Dorota; Groszewska, Agata; Narozna, Beata; Dmitrzak-Weglarz, Monika; Czerski, Piotr; Pawlak, Joanna; Rajewska-Rager, Aleksandra; Leszczynska-Rodziewicz, Anna; Slopien, Agnieszka; Zaremba, Dorota; Twarowska-Hauser, Joanna

    2015-12-01

    Schizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed.

  13. Climate warming and the potential extinction of fig wasps, the obligate pollinators of figs

    PubMed Central

    Jevanandam, Nanthinee; Goh, Alexander G. R.; Corlett, Richard T.

    2013-01-01

    Figs (Ficus) have a reciprocally obligate mutualism with tiny, short-lived (1–2 days) fig wasps (Agaonidae). The small size and short life of these pollinators is expected to make them more vulnerable to climate change than their larger and longer-lived hosts. We experimentally tested the thermal tolerances of four species of adult female fig wasp from equatorial Singapore. The results suggest that an increase of 3°C or more above the current temperatures experienced across much of the equatorial tropics would markedly decrease the active adult lifespan of all four species. Fig plants are the centre of an intricate web of specialist and generalist animals. Unless fig wasps can acclimate or adapt to warmer temperatures in time, these responses may disrupt the mutualism, potentially affecting multiple trophic levels. PMID:23515979

  14. Climate warming and the potential extinction of fig wasps, the obligate pollinators of figs.

    PubMed

    Jevanandam, Nanthinee; Goh, Alexander G R; Corlett, Richard T

    2013-06-23

    Figs (Ficus) have a reciprocally obligate mutualism with tiny, short-lived (1-2 days) fig wasps (Agaonidae). The small size and short life of these pollinators is expected to make them more vulnerable to climate change than their larger and longer-lived hosts. We experimentally tested the thermal tolerances of four species of adult female fig wasp from equatorial Singapore. The results suggest that an increase of 3°C or more above the current temperatures experienced across much of the equatorial tropics would markedly decrease the active adult lifespan of all four species. Fig plants are the centre of an intricate web of specialist and generalist animals. Unless fig wasps can acclimate or adapt to warmer temperatures in time, these responses may disrupt the mutualism, potentially affecting multiple trophic levels.

  15. Strv1-b Flight Experiment

    NASA Technical Reports Server (NTRS)

    1992-01-01

    The Space Technology Research Vehicle (STRV-1b) is discussed. The STRV-1b is a small (100 watt) satellite flown by the British Defense Research Agency (DRA). The mission goal is to fly new and emerging space technologies at a more reasonable cost in a short-term timeframe. The STRV-1b's orbit can be described as a geosynchronous transfer orbit (GTO) with a perigee of 200 km, an apogee of 36,000 km (geosynchronous earth orbit (GEO)), and a period of 10.5 hours. The Phillips Laboratory plans to use the STRV-1b to test up to 20 advanced experimental photovoltaic cells. The discussion is presented in vugraph form.

  16. Interferon Beta-1b Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS, a disease in which ... interferon beta-1b injection at around the same time of day each time you inject it. Follow ...

  17. Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells.

    PubMed

    Zou, Jianlong; Hu, Bo; Arpag, Sezgi; Yan, Qing; Hamilton, Audra; Zeng, Yuan-Shan; Vanoye, Carlos G; Li, Jun

    2015-04-29

    Loss of function of FIG4 leads to Charcot-Marie-Tooth disease Type 4J, Yunis-Varon syndrome, or an epilepsy syndrome. FIG4 is a phosphatase with its catalytic specificity toward 5'-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2). However, the loss of FIG4 decreases PI3,5P2 levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2 synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (Fig4(-/-)) recapitulate the pathology in humans with FIG4 deficiency. Using a flow cytometry technique that rapidly quantifies lysosome sizes, we detected an impaired lysosomal fission, but normal fusion, in Fig4(-/-) cells. The fission defect was associated with a robust increase of intralysosomal Ca(2+) in Fig4(-/-) cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca(2+) efflux of lysosomes because the endogenous ligand of lysosomal Ca(2+) channel TRPML1 is PI3,5P2 that is deficient in Fig4(-/-) cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML-SA1. This treatment reduced the intralysosomal Ca(2+) level and rescued abnormal lysosomal storage in Fig4(-/-) culture cells and ex vivo DRGs. Furthermore, we found that the suppressed Ca(2+) efflux in Fig4(-/-) culture cells and Fig4(-/-) mouse brains profoundly downregulated the expression/activity of dynamin-1, a GTPase known to scissor organelle membranes during fission. This downregulation made dynamin-1 unavailable for lysosomal fission. Together, our study revealed a novel mechanism explaining abnormal lysosomal storage in FIG4 deficiency. Synthetic ligands of the TRPML1 may become a potential therapy against diseases with FIG4 deficiency.

  18. Validation of a P-Glycoprotein (P-gp) Humanized Mouse Model by Integrating Selective Absolute Quantification of Human MDR1, Mouse Mdr1a and Mdr1b Protein Expressions with In Vivo Functional Analysis for Blood-Brain Barrier Transport

    PubMed Central

    Sadiq, Muhammad Waqas; Uchida, Yasuo; Hoshi, Yutaro; Tachikawa, Masanori; Terasaki, Tetsuya; Hammarlund-Udenaes, Margareta

    2015-01-01

    It is essential to establish a useful validation method for newly generated humanized mouse models. The novel approach of combining our established species-specific protein quantification method combined with in vivo functional studies is evaluated to validate a humanized mouse model of P-gp/MDR1 efflux transporter. The P-gp substrates digoxin, verapamil and docetaxel were administered to male FVB Mdr1a/1b(+/+) (FVB WT), FVB Mdr1a/1b(-/-) (Mdr1a/1b(-/-)), C57BL/6 Mdr1a/1b(+/+) (C57BL/6 WT) and humanized C57BL (hMDR1) mice. Brain-to-plasma total concentration ratios (Kp) were measured. Quantitative targeted absolute proteomic (QTAP) analysis was used to selectively quantify the protein expression levels of hMDR1, Mdr1a and Mdr1b in the isolated brain capillaries. The protein expressions of other transporters, receptors and claudin-5 were also quantified. The Kp for digoxin, verapamil, and docetaxel were 20, 30 and 4 times higher in the Mdr1a/1b(-/-) mice than in the FVB WT controls, as expected. The Kp for digoxin, verapamil and docetaxel were 2, 16 and 2-times higher in the hMDR1 compared to the C57BL/6 WT mice. The hMDR1 mice had 63- and 9.1-fold lower expressions of the hMDR1 and Mdr1a proteins than the corresponding expression of Mdr1a in C57BL/6 WT mice, respectively. The protein expression levels of other molecules were almost consistent between C57BL/6 WT and hMDR1 mice. The P-gp function at the BBB in the hMDR1 mice was smaller than that in WT mice due to lower protein expression levels of hMDR1 and Mdr1a. The combination of QTAP and in vivo functional analyses was successfully applied to validate the humanized animal model and evaluates its suitability for further studies. PMID:25932627

  19. Validation of a P-Glycoprotein (P-gp) Humanized Mouse Model by Integrating Selective Absolute Quantification of Human MDR1, Mouse Mdr1a and Mdr1b Protein Expressions with In Vivo Functional Analysis for Blood-Brain Barrier Transport.

    PubMed

    Sadiq, Muhammad Waqas; Uchida, Yasuo; Hoshi, Yutaro; Tachikawa, Masanori; Terasaki, Tetsuya; Hammarlund-Udenaes, Margareta

    2015-01-01

    It is essential to establish a useful validation method for newly generated humanized mouse models. The novel approach of combining our established species-specific protein quantification method combined with in vivo functional studies is evaluated to validate a humanized mouse model of P-gp/MDR1 efflux transporter. The P-gp substrates digoxin, verapamil and docetaxel were administered to male FVB Mdr1a/1b(+/+) (FVB WT), FVB Mdr1a/1b(-/-) (Mdr1a/1b(-/-)), C57BL/6 Mdr1a/1b(+/+) (C57BL/6 WT) and humanized C57BL (hMDR1) mice. Brain-to-plasma total concentration ratios (Kp) were measured. Quantitative targeted absolute proteomic (QTAP) analysis was used to selectively quantify the protein expression levels of hMDR1, Mdr1a and Mdr1b in the isolated brain capillaries. The protein expressions of other transporters, receptors and claudin-5 were also quantified. The Kp for digoxin, verapamil, and docetaxel were 20, 30 and 4 times higher in the Mdr1a/1b(-/-) mice than in the FVB WT controls, as expected. The Kp for digoxin, verapamil and docetaxel were 2, 16 and 2-times higher in the hMDR1 compared to the C57BL/6 WT mice. The hMDR1 mice had 63- and 9.1-fold lower expressions of the hMDR1 and Mdr1a proteins than the corresponding expression of Mdr1a in C57BL/6 WT mice, respectively. The protein expression levels of other molecules were almost consistent between C57BL/6 WT and hMDR1 mice. The P-gp function at the BBB in the hMDR1 mice was smaller than that in WT mice due to lower protein expression levels of hMDR1 and Mdr1a. The combination of QTAP and in vivo functional analyses was successfully applied to validate the humanized animal model and evaluates its suitability for further studies.

  20. Diffusive coevolution and mutualism maintenance mechanisms in a fig-fig wasp system.

    PubMed

    Wang, Rui-Wu; Sun, Bao-Fa; Zheng, Qi

    2010-05-01

    In reciprocal mutualism systems, the exploitation events by exploiters might disrupt the reciprocal mutualism, wherein one exploiter species might even exclude other coexisting exploiter species over an evolutionary time frame. What remains unclear is how such a community is maintained. Niche partitioning, or spatial heterogeneity among the mutualists and exploiters, is generally believed to enable stability within a mutualistic system. However, our examination of a reciprocal mutualism between a fig species (Ficus racemosa) and its pollinator wasp (Ceratosolen fusciceps) shows that spatial niche partitioning does not sufficiently prevent exploiters from overexploiting the common resource (i.e., the female flowers), because of the considerable niche overlap between the mutualists and exploiters. In response to an exploiter, our experiment shows that the fig can (1) abort syconia-containing flowers that have been galled by the exploiter, Apocryptophagus testacea, which oviposits before the pollinators do; and (2) retain syconia-containing flowers galled by Apocryptophagus mayri, which oviposit later than pollinators. However, as a result of (2), there is decreased development of adult non-pollinators or pollinator species in syconia that have not been sufficiently pollinated, but not aborted. Such discriminative abortion of figs or reduction in offspring development of exploiters while rewarding cooperative individuals with higher offspring development by the fig will increase the fitness of cooperative pollinating wasps, but decrease the fitness of exploiters. The fig-fig wasp interactions are diffusively coevolved, a case in which fig wasps diversify their genotype, phenotype, or behavior as a result of competition between wasps, while figs diverge their strategies to facilitate the evolution of cooperative fig waps or lessen the detrimental behavior by associated fig wasps. In habitats or syconia that suffer overexploitation, discriminative abortion of figs or

  1. An Extreme Case of Plant–Insect Codiversification: Figs and Fig-Pollinating Wasps

    PubMed Central

    Cruaud, Astrid; Rønsted, Nina; Chantarasuwan, Bhanumas; Chou, Lien Siang; Clement, Wendy L.; Couloux, Arnaud; Cousins, Benjamin; Genson, Gwenaëlle; Harrison, Rhett D.; Hanson, Paul E.; Hossaert-Mckey, Martine; Jabbour-Zahab, Roula; Jousselin, Emmanuelle; Kerdelhué, Carole; Kjellberg, Finn; Lopez-Vaamonde, Carlos; Peebles, John; Peng, Yan-Qiong; Pereira, Rodrigo Augusto Santinelo; Schramm, Tselil; Ubaidillah, Rosichon; van Noort, Simon; Weiblen, George D.; Yang, Da-Rong; Yodpinyanee, Anak; Libeskind-Hadas, Ran; Cook, James M.; Rasplus, Jean-Yves; Savolainen, Vincent

    2012-01-01

    It is thought that speciation in phytophagous insects is often due to colonization of novel host plants, because radiations of plant and insect lineages are typically asynchronous. Recent phylogenetic comparisons have supported this model of diversification for both insect herbivores and specialized pollinators. An exceptional case where contemporaneous plant–insect diversification might be expected is the obligate mutualism between fig trees (Ficus species, Moraceae) and their pollinating wasps (Agaonidae, Hymenoptera). The ubiquity and ecological significance of this mutualism in tropical and subtropical ecosystems has long intrigued biologists, but the systematic challenge posed by >750 interacting species pairs has hindered progress toward understanding its evolutionary history. In particular, taxon sampling and analytical tools have been insufficient for large-scale cophylogenetic analyses. Here, we sampled nearly 200 interacting pairs of fig and wasp species from across the globe. Two supermatrices were assembled: on an average, wasps had sequences from 77% of 6 genes (5.6 kb), figs had sequences from 60% of 5 genes (5.5 kb), and overall 850 new DNA sequences were generated for this study. We also developed a new analytical tool, Jane 2, for event-based phylogenetic reconciliation analysis of very large data sets. Separate Bayesian phylogenetic analyses for figs and fig wasps under relaxed molecular clock assumptions indicate Cretaceous diversification of crown groups and contemporaneous divergence for nearly half of all fig and pollinator lineages. Event-based cophylogenetic analyses further support the codiversification hypothesis. Biogeographic analyses indicate that the present-day distribution of fig and pollinator lineages is consistent with a Eurasian origin and subsequent dispersal, rather than with Gondwanan vicariance. Overall, our findings indicate that the fig-pollinator mutualism represents an extreme case among plant–insect interactions of

  2. An extreme case of plant-insect codiversification: figs and fig-pollinating wasps.

    PubMed

    Cruaud, Astrid; Rønsted, Nina; Chantarasuwan, Bhanumas; Chou, Lien Siang; Clement, Wendy L; Couloux, Arnaud; Cousins, Benjamin; Genson, Gwenaëlle; Harrison, Rhett D; Hanson, Paul E; Hossaert-McKey, Martine; Jabbour-Zahab, Roula; Jousselin, Emmanuelle; Kerdelhué, Carole; Kjellberg, Finn; Lopez-Vaamonde, Carlos; Peebles, John; Peng, Yan-Qiong; Pereira, Rodrigo Augusto Santinelo; Schramm, Tselil; Ubaidillah, Rosichon; van Noort, Simon; Weiblen, George D; Yang, Da-Rong; Yodpinyanee, Anak; Libeskind-Hadas, Ran; Cook, James M; Rasplus, Jean-Yves; Savolainen, Vincent

    2012-12-01

    It is thought that speciation in phytophagous insects is often due to colonization of novel host plants, because radiations of plant and insect lineages are typically asynchronous. Recent phylogenetic comparisons have supported this model of diversification for both insect herbivores and specialized pollinators. An exceptional case where contemporaneous plant-insect diversification might be expected is the obligate mutualism between fig trees (Ficus species, Moraceae) and their pollinating wasps (Agaonidae, Hymenoptera). The ubiquity and ecological significance of this mutualism in tropical and subtropical ecosystems has long intrigued biologists, but the systematic challenge posed by >750 interacting species pairs has hindered progress toward understanding its evolutionary history. In particular, taxon sampling and analytical tools have been insufficient for large-scale cophylogenetic analyses. Here, we sampled nearly 200 interacting pairs of fig and wasp species from across the globe. Two supermatrices were assembled: on an average, wasps had sequences from 77% of 6 genes (5.6 kb), figs had sequences from 60% of 5 genes (5.5 kb), and overall 850 new DNA sequences were generated for this study. We also developed a new analytical tool, Jane 2, for event-based phylogenetic reconciliation analysis of very large data sets. Separate Bayesian phylogenetic analyses for figs and fig wasps under relaxed molecular clock assumptions indicate Cretaceous diversification of crown groups and contemporaneous divergence for nearly half of all fig and pollinator lineages. Event-based cophylogenetic analyses further support the codiversification hypothesis. Biogeographic analyses indicate that the present-day distribution of fig and pollinator lineages is consistent with a Eurasian origin and subsequent dispersal, rather than with Gondwanan vicariance. Overall, our findings indicate that the fig-pollinator mutualism represents an extreme case among plant-insect interactions of

  3. Prevalence and genetic diversity of fig mosaic virus isolates infecting fig tree in Iran.

    PubMed

    Danesh-Amuz, S; Rakhshandehroo, F; Rezaee, S

    2014-01-01

    Commercial and outdoor fig orchards in four Iranian provinces were surveyed for the incidence of fig mosaic virus (FMV), fig leaf mottle associated virus 2 (FLMaV-2) and fig mild mottle associated virus (FMMaV) from March 2011 to October 2012. A total of 350 asymptomatic and symptomatic fig samples were collected and tested by dot-immunobinding assay (DIBA) for the fig mosaic disease (FMD) using a polyclonal antiserum. According to DIBA results, FMD was present in 73% of the collected symptomatic samples from all visited regions. Samples with positive reactions in DIBA were then analyzed by RT-PCR using with specific primers. PCR results showed that about 14.8% of the FMD-positive samples from three inspected provinces are infected with at least one virus. FMV was the most widely spread virus (14%) followed by FLMaV-2 (1.5%), whereas FMMaV was not found. Phylogenetic analysis of the glycoprotein nucleotide and amino acid sequences of known FMV isolates showed two independent groups with high bootstrap values, with all Iranian isolates distinctly clustered in group I, subgroup IA beside those reported in Turkey. Nucleotide diversity was high within but low between different selected geographic regions and except for Europe, nucleotide distance within geographic regions was low. Statistical analyses indicated a correlation between the genetic structure of the FMV isolates and the geographical origin of isolation. Our analyses suggested that the FMV population is in a state of increase following a bottleneck or founder event in Iran.

  4. A trophic cascade induced by predatory ants in a fig-fig wasp mutualism.

    PubMed

    Wang, Bo; Geng, Xiang-Zong; Ma, Li-Bin; Cook, James M; Wang, Rui-Wu

    2014-09-01

    A trophic cascade occurs when predators directly decrease the densities, or change the behaviour, of herbivores and thus indirectly increase plant productivity. The predator-herbivore-plant context is well known, but some predators attack species beneficial to plants (e.g. pollinators) and/or enemies of herbivores (e.g. parasites), and their role in the dynamics of mutualisms remains largely unexplored. We surveyed the predatory ant species and studied predation by the dominant ant species, the weaver ant Oecophylla smaragdina, associated with the fig tree Ficus racemosa in southwest China. We then tested the effects of weaver ants on the oviposition behaviour of pollinating and non-pollinating fig wasps in an ant-exclusion experiment. The effects of weaver ants on fig wasp community structure and fig seed production were then compared between trees with and without O. smaragdina. Oecophylla smaragdina captured more non-pollinating wasps (Platyneura mayri) than pollinators as the insects arrived to lay eggs. When ants were excluded, more non-pollinators laid eggs into figs and fewer pollinators entered figs. Furthermore, trees with O. smaragdina produced more pollinator offspring and fewer non-pollinator offspring, shifting the community structure significantly. In addition, F. racemosa produced significantly more seeds on trees inhabited by weaver ants. Oecophylla smaragdina predation reverses the dominance of the two commonest wasp species at the egg-laying stage and favours the pollinators. This behavioural pattern is mirrored by wasp offspring production, with pollinators' offspring dominating figs produced by trees inhabited by weaver ants, and offspring of the non-pollinator P. mayri most abundant in figs on trees inhabited by other ants. Overall, our results suggest that predation by weaver ants limits the success of the non-pollinating P. mayri and therefore indirectly benefits the mutualism by increasing the reproductive success of both the

  5. 21 CFR 145.131 - Artificially sweetened canned figs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Artificially sweetened canned figs. 145.131... § 145.131 Artificially sweetened canned figs. (a) Artificially sweetened canned figs is the food which conforms to the definition and standard of identity prescribed for canned figs by § 145.130, except that...

  6. [Anaphylactic reaction to Ficus benjamina (weeping fig)].

    PubMed

    Werfel, S; Ruëff, F; Przybilla, B

    2001-10-01

    Ficus benjamina (weeping fig) is a widespread indoor ornamental plant. Allergens of Ficus benjamina are a well-known cause of IgE-mediated respiratory diseases. We treated a 32-year-old female who for 10 years had suffered from perennial rhinoconjunctivitis. When dusting her 2 meter high Ficus benjamina, she developed an anaphylactic reaction which resolved without sequelae. Skin prick testing revealed a strong immediate type reaction to a Ficus extract, the serum concentration of specific IgE-antibodies to Ficus was > 100 kU/I (CAP class 6). In view of these strong test reactions and the conclusive history, no challenge tests with Ficus allergens were performed. After removal of the Ficus plants which she had owned for 17 years and after thorough cleaning of her dwelling, the patient's symptoms of perennial rhinoconjunctivitis stopped. The patient also was sensitized to, but not allergic to natural rubber latex, which occurs frequently in Ficus allergy and probably is due to cross reactivity to allergens from both sources. As Ficus benjamina is an important source of indoor allergens, it should not be used in dwellings or work places.

  7. Host sanctions and pollinator cheating in the fig tree–fig wasp mutualism

    PubMed Central

    Jandér, K. Charlotte; Herre, Edward Allen

    2010-01-01

    Theory predicts that mutualisms should be vulnerable to invasion by cheaters, yet mutualistic interactions are both ancient and diverse. What prevents one partner from reaping the benefits of the interaction without paying the costs? Using field experiments and observations, we examined factors affecting mutualism stability in six fig tree–fig wasp species pairs. We experimentally compared the fitness of wasps that did or did not perform their most basic mutualistic service, pollination. We found host sanctions that reduced the fitness of non-pollinating wasps in all derived, actively pollinated fig species (where wasps expend time and energy pollinating), but not in the basal, passively pollinated fig species (where wasps do not). We further screened natural populations of pollinators for wasp individuals that did not carry pollen (‘cheaters’). Pollen-free wasps occurred only in actively pollinating wasp species, and their prevalence was negatively correlated with the sanction strength of their host species. Combined with previous studies, our findings suggest that (i) mutualisms can show coevolutionary dynamics analogous to those of ‘arms races’ in overtly antagonistic interactions; (ii) sanctions are critical for long-term mutualism stability when providing benefits to a host is costly, and (iii) there are general principles that help maintain cooperation both within and among species. PMID:20071379

  8. Host sanctions and pollinator cheating in the fig tree-fig wasp mutualism.

    PubMed

    Jandér, K Charlotte; Herre, Edward Allen

    2010-05-22

    Theory predicts that mutualisms should be vulnerable to invasion by cheaters, yet mutualistic interactions are both ancient and diverse. What prevents one partner from reaping the benefits of the interaction without paying the costs? Using field experiments and observations, we examined factors affecting mutualism stability in six fig tree-fig wasp species pairs. We experimentally compared the fitness of wasps that did or did not perform their most basic mutualistic service, pollination. We found host sanctions that reduced the fitness of non-pollinating wasps in all derived, actively pollinated fig species (where wasps expend time and energy pollinating), but not in the basal, passively pollinated fig species (where wasps do not). We further screened natural populations of pollinators for wasp individuals that did not carry pollen ('cheaters'). Pollen-free wasps occurred only in actively pollinating wasp species, and their prevalence was negatively correlated with the sanction strength of their host species. Combined with previous studies, our findings suggest that (i) mutualisms can show coevolutionary dynamics analogous to those of 'arms races' in overtly antagonistic interactions; (ii) sanctions are critical for long-term mutualism stability when providing benefits to a host is costly, and (iii) there are general principles that help maintain cooperation both within and among species.

  9. Spatial heterogeneity and host repression in fig-fig wasp mutualism.

    PubMed

    Wang, RuiWu; Wen, XiaoLan; Chen, Chun; Shi, Lei; Compton, Stephen G

    2015-05-01

    It is generally believed that physical heterogeneity in common resource or evolutionary restraint can sufficiently prevent direct conflict between host and symbionts in mutualism systems. Our data on fig/fig wasp reciprocal mutualism (Ficus racemosa), however, show that structural barriers of female flowers or genetic constraints of pollinators previously hypothesized exist, but cannot sufficiently maintain the mutualism stability. The results show that a positive relationship between seed and wasp production could be maintained in warm season, which might be because of density dependence restraint among foundresses and their low oviposition and pollination efficiency, keeping common resource (female flowers) utilization unsaturated. Whilst, a negative correlation between wasp offspring and viable seed production was also observed in cold season, which might be that the increased oviposition and pollination efficiency maximized the common resource utilization. The fitness trade-off between fig and pollinator wasps is greatly affected by environmental or ecological variations. The local stability might result from temporal low exploitation efficiency of pollinators together with interference competition among pollinators. We suggest that host repression through the active regulation of bract closure, which can create interference competition among the foundresses and prevent extra more foundresses sequential entry in fruit cavities, would help the figs avoiding the cost of over-exploitation. This essentially takes the same role as sanctioning of cheating or competitive behaviors.

  10. Nematodes Associated with Fig Wasps, Pegoscapus spp. (Agaonidae), and Syconia of Native Floridian Figs (Ficus spp.)

    PubMed Central

    Giblin-Davis, Robin M.; Center, Barbara J.; Nadel, Hannah; Frank, J. Howard; Ramírez B., William

    1995-01-01

    Syconia in successive developmental phases from Ficus laevigata Vahl (F. citrifolia Miller sensu DeWolf 1960) (Moraceae) and successive life stages of its fig wasp pollinator, Pegoscapus sp. (P. assuetus (Grandi) sensu Wiebes 1983) (Agaonidae) were dissected to elucidate their association with two undescribed species of nematodes. Parasitodiplogazter sp. (Diplogasteridae) are transported by female Pegoscapus sp. into the cavity of a phase B syconium as third-stage juveniles (J3), where they molt to the J4 stage and greatly increase in size in the hemocoel of the fig wasp after it begins to pollinate and oviposit in female florets. The J4 exit the wasp cadaver in a phase B or early phase C syconium, and molt to adults that mate and lay eggs. New J3 infect the next generation of female or male wasps as they emerge from their galls in phase D figs. Mated entomogenous females of Schistonchus sp. (Aphelenchoididae) are transported in the hemocoel of female wasps to the fig cavity of a phase B syconium. Female Schistonchus sp. exit the wasp and parasitize immature male florets causing an exudate, the development of hypertrophied epidermal cells of the anther filaments and anthers, and aberrations of the anther filament, anthers, and pollen. At least one generation of Schistonchus sp. occurs in the male florets. Entomogenous females appear at about the time that fig wasps molt to adults in their galls in late phase C syconia. Another Schistonchus sp. was recovered from females of P. mexicanus (Ashmead) (P. jimenezi (Grandi) sensu Wiebes 1983) and from the syconia of F. aurea Nuttall and appears to have a life cycle similar to that described for the Schistonchus sp. from F. laevigata. PMID:19277255

  11. Biomechanics of substrate boring by fig wasps.

    PubMed

    Kundanati, Lakshminath; Gundiah, Namrata

    2014-06-01

    Female insects of diverse orders bore into substrates to deposit their eggs. Such insects must overcome several biomechanical challenges to successfully oviposit, which include the selection of suitable substrates through which the ovipositor can penetrate without itself fracturing. In many cases, the insect may also need to steer and manipulate the ovipositor within the substrate to deliver eggs at desired locations before rapidly retracting her ovipositor to avoid predation. In the case of female parasitoid ichneumonid wasps, this process is repeated multiple times during her lifetime, thus testing the ability of the ovipositioning apparatus to endure fracture and fatigue. What specific adaptations does the ovipositioning apparatus of a female ichneumonoid wasp possess to withstand these challenges? We addressed this question using a model system composed of parasitoid and pollinator fig wasps. First, we show that parasitoid ovipositor tips have teeth-like structures, preferentially enriched with zinc, unlike the smooth morphology of pollinator ovipositors. We describe sensillae present on the parasitoid ovipositor tip that are likely to aid in the detection of chemical species and mechanical deformations and sample microenvironments within the substrate. Second, using atomic force microscopy, we show that parasitoid tip regions have a higher modulus compared with regions proximal to the abdomen in parasitoid and pollinator ovipositors. Finally, we use videography to film wasps during substrate boring and analyse buckling of the ovipositor to estimate the forces required for substrate boring. Together, these results allow us to describe the biomechanical principles underlying substrate boring in parasitoid ichneumonid wasps. Such studies may be useful for the biomimetic design of surgical tools and in the use of novel mechanisms to bore through hard substrates.

  12. Ecology of parasite Sycophilomorpha sp. on Ficus altissima and its effect on the fig-fig wasp mutualism.

    PubMed

    Peng, Y Q; Zhao, J B; Harrison, R D; Yang, D R

    2010-11-01

    Figs and their pollinating wasps are a classic example of an obligate mutualism. In addition, figs are parasitized by a suite of non-mutualistic wasps whose basic ecology is largely undescribed. Sycophilomorpha (subfamily Epichrysomallinae) fig wasps are ovule gallers and the genus contains only 1 described species. An undescribed Sycophilomorpha species parasitized Ficus altissima at Xishuangbana, Southwestern China. The wasp was observed ovipositing on the tiny immature figs that were still concealed beneath the involucral bracts. A Sycophilomorpha wasp oviposited on more than 1 fig and spent long time-periods to lay large clutches on a single fig. The wasps naturally occurred on all 7 sampled trees, but the occurrence of wasps was significantly different among trees, crops and months. These wasps were able to prevent unpollinated figs from being aborted, and their offspring were able to develop in the figs that otherwise had no pollinator wasps or seeds. The Sycophilomorpha wasp had a detrimental effect on the fig-fig wasp mutualism. Figs in which Sycophilomorpha wasps were present, produced significantly fewer seeds, pollinators and cheaters. However, the abundance of Sycophilomorpha in a fig was only significantly negatively correlated with pollinator production and not seed or cheater production. Our study illustrates a previously unknown fig wasp niche and expands our understanding of factors that can affect the fig-fig wasp interaction.

  13. Quinazoline derivatives as selective CYP1B1 inhibitors.

    PubMed

    Mohd Siddique, Mohd Usman; McCann, Glen J P; Sonawane, Vinay R; Horley, Neill; Gatchie, Linda; Joshi, Prashant; Bharate, Sandip B; Jayaprakash, Venkatesan; Sinha, Barij N; Chaudhuri, Bhabatosh

    2017-04-21

    CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid 'O' atom with 'N' atom led to the prediction that a 'quinazoline' scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells.

  14. Molecular phylogenies of figs and fig-pollinating wasps in the Ryukyu and Bonin (Ogasawara) islands, Japan.

    PubMed

    Azuma, Hiroshi; Harrison, Rhett D; Nakamura, Keiko; Su, Zhi-Hui

    2010-01-01

    The interaction between figs (Ficus, Moraceae) and fig-pollinating wasps (Chalcidoidea, Agaonidae) is one of the most specific mutualisms, and thus is a model system for studying coevolution and cospeciation. In this study we focused on figs and their associated fig-wasps found in the Ryukyu and Bonin (Ogasawara) Islands, Japan, because it has been suggested that breakdown in the specificity may occur in islands or at edge of a species' distribution. We collected 136 samples of 15 native fig species and 95 samples of 13 associated fig-wasps from all major islands in the Ryukyu Islands, including two fig species and one fig-wasp species endemic to the Bonin Islands. We performed molecular phylogenetic analyses using plastid DNA and nuclear ITS sequences for the figs and nuclear 28S rRNA and mitochondrial COI genes for the fig-wasps to investigate the interspecific phylogenies and intraspecific variation within the mutualism. Our phylogenetic analyses using multiple samples per species show the single clade of each fig (except the Bonin endemic species) and fig-pollinating wasp species. Fig species belonging to the same subgenera formed well-supported clades in both plastid and ITS trees, except for the subgenus Urostigma. Likewise, fig wasps emerging from host fig species belonging to the same subgenera formed mostly well supported clades in both 28S and COI trees. Host specificity between the figs and fig-wasps functions strictly in these islands. There was very little sequence variation within species, and that no major geographic structure was found. The two Bonin endemic species (F. boninsimae and F. nishimurae) or their common ancestor and the associated fig-wasps (Blastophaga sp.) are apparently derived from F. erecta and its associated fig-wasps (B. nipponica), respectively, and probably migrated from the Ryukyu Islands.

  15. Female figs as traps: Their impact on the dynamics of an experimental fig tree-pollinator-parasitoid community

    NASA Astrophysics Data System (ADS)

    Suleman, Nazia; Sait, Steve; Compton, Stephen G.

    2015-01-01

    Interactions between fig trees (Ficus) and their pollinating fig wasps (Agaonidae) result in both a highly species-specific nursery mutualism and mutual exploitation. Around half of the 800 or so fig tree species are functionally dioecious. Figs on male plants produce pollen and fig wasp offspring, whereas figs on female plants produce only seeds. Figs on female plants are traps for pollinators. The fig wasps enter the female figs to oviposit, but lose their wings on entry and are then prevented from oviposition by the long styles that characterise the flowers in female figs. Continuation of the mutualism depends on the pollinators' failure to distinguish between male and female figs before entry. Female plants may also have a negative impact on the parasitoid fig wasps that feed on pollinators, if they are also attracted to female figs. We used glasshouse populations of figs (with and without female plants), pollinators and parasitoids to infer the impact of female figs on fig wasp dynamics. Cyclic population fluctuations were present in both species. Female plants appeared to dampen the amplitudes of pollinator population cycles, and parasitoid populations may become less tightly coupled with host populations, but the presence of female figs did not reduce parasitism rates, nor parasitoid and pollinator densities, and only parasitoid sex ratios were affected. Our glasshouse experimental design was likely to favour the impact of female figs on the wasp populations, which suggests that female plants in the field are unlikely to have a major negative impact on their pollinators, despite being a major mortality factor.

  16. [Oviposition timing and community structure of Ficus curtipes fig wasps].

    PubMed

    Zhang, Feng-Ping; Yang, Da-Rong

    2009-08-01

    Through the behavioral observation of Ficus curtipes fig wasps and the counting of various kinds of flowerets in F. curtipes figs, the oviposition timing and community structure of 12 F. curtipes fig wasp species were studied. Besides the agaonid wasp Eupristina sp., the two non-agaonid wasps Diaziella yangi and Lipothymus sp. could enter into F. curtipes figs and oviposit. The other nine non-agaonid fig wasps ( Walkerella sp., Micranisa sp., Sycophilomorpha sp., Philotrypesis sp., Sycosapter sp., Sycobia sp., Ficomila sp., Ormyrus sp. and Sycophila sp.) oviposited outside the figs. In the fig wasp community, Eupristina sp. was the dominant species, accounting for 62.11% of the total, D. yangi and Lipothymus sp. accounted for 27.19% and 4.71%, respectively, while the other nine non-agaonid fig wasp species only occupied 5.99%. The non-agaonid fig wasps produced their progeny through the reproduction strategies of oviposition timing and diet allocation of female flowerets, so as to sustain the fig-wasp mutualism. The individuals of non-agaonid fig wasp progeny had significant negative correlation with those of agaonid fig wasp progeny, but no correlation with F. curtipes seed production.

  17. Characterization of Three Novel SXT/R391 Integrating Conjugative Elements ICEMfuInd1a and ICEMfuInd1b, and ICEMprChn1 Identified in the Genomes of Marinomonas fungiae JCM 18476T and Marinomonas profundimaris Strain D104

    PubMed Central

    Badhai, Jhasketan; Das, Subrata K.

    2016-01-01

    The genus Marinomonas comprises Gram negative bacteria which are widespread in the marine environment and there is no report on the genomic analysis of SXT/R391 ICEs derived from this group of bacteria. This study describes the genomic features of three new SXT/R391 integrating conjugating elements (ICEs) identified in the genome of Marinomonas fungiae JCM 18476T (ICEMfuInd1a and ICEMfuInd1b) and in Marinomonas profundimaris strain D104 (ICEMprChn1). Structural organizations of the three ICEs were similar to the typical SXT/R391 family of ICEs and showed high degree of conservation in the core genes. Sequence analysis revealed ICEMfuInd1b and ICEMprChn1 were inserted into the genome at 5′-end of an typical host prfC gene, while ICEMfuInd1a was inserted at 5′-end of an atypical hipA-like gene. Despite their coexistence, the ICEMfuInd1a and ICEMfuInd1b were not present in a tandem fashion in the genome of M. fungiae. Phylogenetic analyses revealed the three ICEs either evolved independently or high degrees of recombination events had masked their evolution from a common SXT ancestor. Further, we found that the typical entry exclusion mechanism mediated by the TraG/EeX protein pair was likely defective in preventing the conjugative transfer of a second copy of the same S (SXT) group ICE into the M. fungiae genome due to mutations. Our analysis showed the presence of 16, 25, and 27 variable genes in the hotspots of ICEMfuInd1a, ICEMfuInd1b, and ICEMprChn1, respectively, many of which were not reported earlier for SXT/R391 ICEs. Sequence analysis predicted these hotspot regions were shaped by acquisition of genes through homologous recombination between the SXT and R391 related ICEs or mobile genetic elements present in disparate marine bacteria. Multidrug resistance genes which are hallmark feature of SXT/R391 ICEs were not present in either of the two ICEs from M. fungiae but were present within a transposon cassette in the HS-1 of the ICEMprChn1 from M

  18. Floral ratios in the figs of Ficus montana span the range from actively to passively pollinated fig trees

    NASA Astrophysics Data System (ADS)

    Suleman, Nazia; Quinnell, Rupert J.; Compton, Stephen G.

    2014-05-01

    Fig trees (Ficus spp., Moraceae) and their associated obligate pollinator fig wasps (Agaonidae) are partners in what is often a pair-wise species-specific association. Their interaction centres on the unique enclosed inflorescence of Ficus species - the fig. Among dioecious fig tree species, only pollinated ovules in figs on female trees develop into seeds. On male trees, galled ovules support development of the fig wasp offspring that will transport their pollen, but no seeds develop. Some fig wasp species actively collect and disperse pollen, whereas others are typical insect pollinators in that pollen is transferred passively. Active pollination is associated with improved larval survivorship in pollinated figs. Because active pollination is much more efficient, their host figs need to contain far fewer male flowers and across numerous Ficus species anther-ovule ratios are a good predictor of pollination mode. We examined variation in inflorescence size and floral ratios among male figs of the Asian Ficus montana and its consequences for the amounts of pollen that would be available for each pollinator to collect. Inflorescence size (total flower number) was highly variable, and female pollinator offspring production was higher in figs with more female flowers. Pollinator offspring numbers and anther-ovule ratios were also highly variable, and encompassed the range typical of both actively and passively pollinated fig tree species. In combination, this variation resulted in large differences in the extent to which pollinators were competing for access to pollen, with potential fitness consequences for both partners in the mutualism.

  19. Aflatoxins in Turkish dried figs intended for export to the European Union.

    PubMed

    Senyuva, H Z; Gilbert, J; Ulken, U

    2007-04-01

    Dried figs for export from Turkey from crop years 2003 through 2006 were tested for aflatoxin B1 and total aflatoxins. For export to the European Union, consignments of 0.5 to 10 tonnes of dried figs were sampled according to European Commission regulations, and high-pressure liquid chromatography (HPLC) was used to determine concentrations of aflatoxins Bl, B2, G1, and G2. For each consignment of dried figs, a 30-kg sample (comprising 100 subsamples) was divided into three 10-kg subsamples, which were separately blended and analyzed with HPLC. This monitoring effort was conducted for figs from 2003, 2004, 2005, and up to June 2006, for a total of 10,396 30-kg samples (28,489 analyses). The incidence of contamination with aflatoxin B1 at higher than 2 ng/g was on average 0.6, 2.0, 4.0, and 2.4% for 2003, 2004, 2005, and up to June 2006, respectively, whereas contamination with total aflatoxins at higher than 4 ng/g was 2.6, 3.0, 5.1, and 2.7%. There was significant variability in contamination between replicate 1-kg samples, indicating small numbers of individual contaminated figs were probably responsible. There were also substantial differences in the relative proportions of aflatoxins B1, B2, G1, and G2 among samples, suggesting different contributing fungal sources.

  20. Effect of moisture content on textural attributes of dried figs

    NASA Astrophysics Data System (ADS)

    Ansari, Sara; Maftoon-Azad, Neda; Farahnaky, Asgar; Hosseini, Ebrahim; Badii, Fojan

    2014-10-01

    Due to their soft texture consumers prefer moist figs, which has motivated fig processors to increase the production of this product. However, as water enhances the browning reaction rate, moisture content optimisation of moist figs is very important. Processed figs must have suitable texture softness with browning kept to a minimum. The purpose of this study was to examine the effect of moisture content on the textural attributes of dried figs. Hardness, compression energy, gradient, gumminess and chewiness of fig samples decreased with moisture content exponentially, whereas the trend of springiness and cohesiveness with change of moisture content was nearly constant. Moreover, in the texture profile analysis plot of rehydrated figs, the presence of negative area is an indication of adhesiveness which was zero in control dried figs. The results of the texture profile analysis tests proved the existence of a critical moisture content of about 18.4%, above which no significant effect of moisture content on textural parameters was found. The glass-rubber transition results from differential scanning calorimeter may explain the different texture profile analysis attributes of dried figs compared with rehydrated figs.

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

    PubMed

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

    2014-08-01

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

  2. FIG4 regulates lysosome membrane homeostasis independent of phosphatase function.

    PubMed

    Bharadwaj, Rajnish; Cunningham, Kathleen M; Zhang, Ke; Lloyd, Thomas E

    2016-02-15

    FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. Since FIG4 and FAB1 are present together in the same biochemical complex, these data are consistent with a model in which FIG4 serves a phosphatase-independent biosynthetic function that is essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, demonstrating that FIG4 functions after endosome-to-lysosome fusion. Furthermore, disruption of the retromer complex, implicated in recycling from the lysosome to Golgi, does not lead to similar phenotypes as Fig4, suggesting that the lysosomal defects are not due to compromised retromer-mediated recycling of endolysosomal membranes. These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS.

  3. FIG4 regulates lysosome membrane homeostasis independent of phosphatase function

    PubMed Central

    Bharadwaj, Rajnish; Cunningham, Kathleen M.; Zhang, Ke; Lloyd, Thomas E.

    2016-01-01

    FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. Since FIG4 and FAB1 are present together in the same biochemical complex, these data are consistent with a model in which FIG4 serves a phosphatase-independent biosynthetic function that is essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, demonstrating that FIG4 functions after endosome-to-lysosome fusion. Furthermore, disruption of the retromer complex, implicated in recycling from the lysosome to Golgi, does not lead to similar phenotypes as Fig4, suggesting that the lysosomal defects are not due to compromised retromer-mediated recycling of endolysosomal membranes. These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS. PMID:26662798

  4. Seasonality of Leaf and Fig Production in Ficus squamosa, a Fig Tree with Seeds Dispersed by Water

    PubMed Central

    Pothasin, Pornwiwan; Compton, Stephen G.; Wangpakapattanawong, Prasit

    2016-01-01

    The phenology of plants reflects selection generated by seasonal climatic factors and interactions with other plants and animals, within constraints imposed by their phylogenetic history. Fig trees (Ficus) need to produce figs year-round to support their short-lived fig wasp pollinators, but this requirement is partially de-coupled in dioecious species, where female trees only develop seeds, not pollinator offspring. This allows female trees to concentrate seed production at more favorable times of the year. Ficus squamosa is a riparian species whose dispersal is mainly by water, rather than animals. Seeds can float and travel in long distances. We recorded the leaf and reproductive phenology of 174 individuals for three years in Chiang Mai, Northern Thailand. New leaves were produced throughout the year. Fig production occurred year-round, but with large seasonal variations that correlated with temperature and rainfall. Female and male trees initiated maximal fig crops at different times, with production in female trees confined mainly to the rainy season and male figs concentrating fig production in the preceding months, but also often bearing figs continually. Ficus squamosa concentrates seed production by female plants at times when water levels are high, favouring dispersal by water, and asynchronous flowering within male trees allow fig wasps to cycle there, providing them with potential benefits by maintaining pollinators for times when female figs become available to pollinate. PMID:27010540

  5. Seasonality of Leaf and Fig Production in Ficus squamosa, a Fig Tree with Seeds Dispersed by Water.

    PubMed

    Pothasin, Pornwiwan; Compton, Stephen G; Wangpakapattanawong, Prasit

    2016-01-01

    The phenology of plants reflects selection generated by seasonal climatic factors and interactions with other plants and animals, within constraints imposed by their phylogenetic history. Fig trees (Ficus) need to produce figs year-round to support their short-lived fig wasp pollinators, but this requirement is partially de-coupled in dioecious species, where female trees only develop seeds, not pollinator offspring. This allows female trees to concentrate seed production at more favorable times of the year. Ficus squamosa is a riparian species whose dispersal is mainly by water, rather than animals. Seeds can float and travel in long distances. We recorded the leaf and reproductive phenology of 174 individuals for three years in Chiang Mai, Northern Thailand. New leaves were produced throughout the year. Fig production occurred year-round, but with large seasonal variations that correlated with temperature and rainfall. Female and male trees initiated maximal fig crops at different times, with production in female trees confined mainly to the rainy season and male figs concentrating fig production in the preceding months, but also often bearing figs continually. Ficus squamosa concentrates seed production by female plants at times when water levels are high, favouring dispersal by water, and asynchronous flowering within male trees allow fig wasps to cycle there, providing them with potential benefits by maintaining pollinators for times when female figs become available to pollinate.

  6. Molecular dating and biogeography of fig-pollinating wasps.

    PubMed

    Lopez-Vaamonde, Carlos; Wikström, Niklas; Kjer, Karl M; Weiblen, George D; Rasplus, Jean Yves; Machado, Carlos A; Cook, James M

    2009-09-01

    Figs and fig-pollinating wasps are obligate mutualists that have coevolved for over 60 million years. But when and where did pollinating fig wasps (Agaonidae) originate? Some studies suggest that agaonids arose in the Late Cretaceous and the current distribution of fig-wasp faunas can be explained by the break-up of the Gondwanan landmass. However, recent molecular-dating studies suggest divergence time estimates that are inconsistent with the Gondwanan vicariance hypothesis and imply that long distance oceanic dispersal could have been an important process for explaining the current distribution of both figs and fig wasps. Here, we use a combination of phylogenetic and biogeographical data to infer the age, the major period of diversification, and the geographic origin of pollinating fig wasps. Age estimates ranged widely depending on the molecular-dating method used and even when using the same method but with slightly different constraints, making it difficult to assess with certainty a Gondwanan origin of agaonids. The reconstruction of ancestral areas suggests that the most recent common ancestor of all extant fig-pollinating wasps was most likely Asian, although a southern Gondwana origin cannot be rejected. Our analysis also suggests that dispersal has played a more important role in the development of the fig-wasp biota than previously assumed.

  7. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  8. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  9. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  10. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2014 CFR

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    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  11. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2014 CFR

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    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  12. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

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    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  13. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2011 CFR

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    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  14. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2011 CFR

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    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Enforcement hotline. 1b.21 Section 1b.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.21 Enforcement hotline. (a)...

  15. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2011 CFR

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    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  16. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2014 CFR

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  17. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2011 CFR

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    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  18. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2014 CFR

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  19. 18 CFR 1b.5 - Formal investigations.

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  20. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2014 CFR

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  1. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

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    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  2. 18 CFR 1b.12 - Transcripts.

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  3. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2013 CFR

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    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Policy. 1b.2 Section 1b.2 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.2 Policy. (a) All policies and programs of... compliance with Executive Order 12114, “Environmental Effects Abroad of Major Federal Actions.”...

  4. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2013 CFR

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  5. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2010 CFR

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  6. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2012 CFR

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  7. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  8. 18 CFR 1b.2 - Scope.

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    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  9. 18 CFR 1b.19 - Submissions.

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    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  10. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2013 CFR

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    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  11. 18 CFR 1b.19 - Submissions.

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  12. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2012 CFR

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  13. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2012 CFR

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  14. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

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    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  15. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  16. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  17. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  18. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  19. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  20. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  1. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  2. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  3. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  4. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Formal investigations. 1b.5 Section 1b.5 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.5 Formal investigations....

  5. Exchange of hosts: can agaonid fig wasps reproduce successfully in the figs of non-host Ficus?

    NASA Astrophysics Data System (ADS)

    Yang, Pei; Li, Zongbo; Peng, Yanqiong; Yang, Darong

    2012-03-01

    In the obligate mutualism between figs ( Ficus) and their specific pollinators (Chalcidoidea, Agaonidae), each species of fig wasp typically reproduces in figs of a single host species. Host specificity is maintained largely because pollinators are attracted to tree-specific volatiles released from their host figs, but whether the wasps can reproduce if they enter figs of non-host species is unclear. We investigated the reproductive success of Ceratosolen emarginatus (associated with Ficus auriculata) and Ceratosolen sp. (associated with F. hainanensis) in atypical hosts by experimentally introducing foundresses into host and non-host figs. F. auriculata figs entered by Ceratosolen sp. were more likely to abort than if entered by C. emarginatus, but abortion of F. hainanensis figs was not affected by pollinator species. Single C. emarginatus foundresses produced more but smaller offspring in F. hainanensis than in their normal host. Conversely Ceratosolen sp. produced fewer but larger offspring in F. auriculata than in their normal host, probably as a result of having longer to develop. Mean style length differences, relative to the lengths of the wasps' ovipositors, may have dictated the number of offspring produced, with oviposition made easier by the shorter styles in F. hainanensis figs. Our results imply that, in addition to morphological constraints and tree-specific volatiles, reduced reproductive success in atypical hosts can be another factor maintaining host specificity, but for other species only behavioural changes are required for host switching to occur.

  6. The early regulation of figs in the United States.

    PubMed

    Young, J H

    1999-01-01

    When the Food and Drugs Act became law in 1906, the commercial fig industry in California had just become established. Domestic figs began to compete with imported figs, especially from Turkey and Greece. Fig culture, both in the Near East and the American West, was beset by many threats, especially insect pests. The Bureau of Chemistry in the U.S. Department of Agriculture (USDA), enforcer of the 1906 law, undertook to protect consumers from spoiled figs from overseas and in interstate commerce. Simultaneously the USDA helped both domestic and Turkish growers to counter infestation. Through the State Department, sanitary controls in Smyrna were enhanced. Scientific experts from Agriculture educated American growers and packers in protective techniques. A high point of both legal actions and educational endeavors came in the late 1920s. In the 1930s, the state of California assumed the role of guiding inspection and helping dispose of substandard figs. World War II brought retrogression in fig quality, requiring a new corrective campaign by the Food and Drug Administration, successor to the Bureau of Chemistry, to prevent spoiled figs from reaching the market. By the 1950s, the need for such legal actions was rare.

  7. Rain-fed fig yield as affected by rainfall distribution

    NASA Astrophysics Data System (ADS)

    Bagheri, Ensieh; Sepaskhah, Ali Reza

    2014-08-01

    Variable annual rainfall and its uneven distribution are the major uncontrolled inputs in rain-fed fig production and possibly the main cause of yield fluctuation in Istahban region of Fars Province, I.R. of Iran. This introduces a considerable risk in rain-fed fig production. The objective of this study was to find relationships between seasonal rainfall distribution and rain-fed fig production in Istahban region to determine the critical rainfall periods for rain-fed fig production and supplementary irrigation water application. Further, economic analysis for rain-fed fig production was considered in this region to control the risk of production. It is concluded that the monthly, seasonal and annual rainfall indices are able to show the effects of rainfall and its distribution on the rain-fed fig yield. Fig yield with frequent occurrence of 80 % is 374 kg ha-1. The internal rates of return for interest rate of 4, 8 and 12 % are 21, 58 and 146 %, respectively, that are economically feasible. It is concluded that the rainfall in spring especially in April and in December has negatively affected fig yield due to its interference with the life cycle of Blastophaga bees for pollination. Further, it is concluded that when the rainfall is limited, supplementary irrigation can be scheduled in March.

  8. Genetic structure and differentiation in cultivated fig (Ficus carica L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    One hundred ninety-four germplasm accessions of fig representing the four fig types, Common, Smyrna, San Pedro, and Caprifig were analyzed for genetic diversity, structure, and differentiation using genetic polymorphism at 17 microsatellite loci. The collection showed considerable polymorphism with ...

  9. One fig to bind them all: host conservatism in a fig wasp community unraveled by cospeciation analyses among pollinating and nonpollinating fig wasps.

    PubMed

    Jousselin, Emmanuelle; van Noort, Simon; Berry, Vincent; Rasplus, Jean-Yves; Rønsted, Nina; Erasmus, J Christoff; Greeff, Jaco M

    2008-07-01

    The study of chalcid wasps that live within syconia of fig trees (Moraceae, Ficus), provides a unique opportunity to investigate the evolution of specialized communities of insects. By conducting cospeciation analyses between figs of section Galoglychia and some of their associated fig wasps, we show that, although host switches and duplication have evidently played a role in the construction of the current associations, the global picture is one of significant cospeciation throughout the evolution of these communities. Contrary to common belief, nonpollinating wasps are at least as constrained as pollinators by their host association in their diversification in this section. By adapting a randomization test in a supertree context, we further confirm that wasp phylogenies are significantly congruent with each other, and build a "wasp community" supertree that retrieves Galoglychia taxonomic subdivisions. Altogether, these results probably reflect wasp host specialization but also, to some extent, they might indicate that niche saturation within the fig prevents recurrent intrahost speciation and host switching. Finally, a comparison of ITS2 sequence divergence of cospeciating pairs of wasps suggests that the diversification of some pollinating and nonpollinating wasps of Galoglychia figs has been synchronous but that pollinating wasps exhibit a higher rate of molecular evolution.

  10. An integrated badnavirus is prevalent in fig germplasm.

    PubMed

    Laney, Alma G; Hassan, Mohamed; Tzanetakis, Ioannis E

    2012-12-01

    Fig mosaic occurs worldwide and is the most common and important viral disease of fig. In the quest to identify the causal agent of the disease, several new viruses have been identified, including a new DNA virus, the subject of this communication. Phylogenetic analysis placed the virus, provisionally named Fig badnavirus-1 (FBV-1), in the genus Badnavirus, family Caulimoviridae. The experimental host range of FBV-1 was evaluated and the virus was mechanically transmitted to several herbaceous hosts. FBV-1 was detected in the National Clonal Germplasm Repository fig collection and additional samples from Arkansas, California, Florida, Michigan, Ohio, Oregon, and South Carolina, suggesting its wide distribution in the United States. Further tests revealed the presence of FBV-1 in seedlings and meristem tissue culture plants. Forty-four isolates were used in a study evaluating the population structure of the virus in the United States. Evidence that FBV-1 is integrated in the fig genome is presented and discussed.

  11. How chimpanzees integrate sensory information to select figs

    PubMed Central

    Yeakel, Justin D.; Bhat, Uttam; Ramsden, Lawrence; Wrangham, Richard W.; Lucas, Peter W.

    2016-01-01

    Figs are keystone resources that sustain chimpanzees when preferred fruits are scarce. Many figs retain a green(ish) colour throughout development, a pattern that causes chimpanzees to evaluate edibility on the basis of achromatic accessory cues. Such behaviour is conspicuous because it entails a succession of discrete sensory assessments, including the deliberate palpation of individual figs, a task that requires advanced visuomotor control. These actions are strongly suggestive of domain-specific information processing and decision-making, and they call attention to a potential selective force on the origin of advanced manual prehension and digital dexterity during primate evolution. To explore this concept, we report on the foraging behaviours of chimpanzees and the spectral, chemical and mechanical properties of figs, with cutting tests revealing ease of fracture in the mouth. By integrating the ability of different sensory cues to predict fructose content in a Bayesian updating framework, we quantified the amount of information gained when a chimpanzee successively observes, palpates and bites the green figs of Ficus sansibarica. We found that the cue eliciting ingestion was not colour or size, but fig mechanics (including toughness estimates from wedge tests), which relays higher-quality information on fructose concentrations than colour vision. This result explains why chimpanzees evaluate green figs by palpation and dental incision, actions that could explain the adaptive origins of advanced manual prehension. PMID:27274803

  12. Discriminative host sanctions in a fig-wasp mutualism.

    PubMed

    Wang, Rui-Wu; Dunn, Derek W; Sun, Bao Fa

    2014-05-01

    In some mutualisms, cooperation in symbionts is promoted by hosts sanctioning "cheats," who obtain benefits but fail to reciprocate. In fig-wasp mutualisms, agaonid wasps pollinate the trees (Ficus spp.), but are also exploitative by using some flowers as larval food. Ficus can sanction cheats that fail to pollinate by aborting some un-pollinated figs. However, in those un-pollinated figs retained by trees, cheats successfully reproduce. When this occurs, wasp broods are reduced, suggesting sanctions increase offspring mortality within un-pollinated figs. We investigated sanction mechanisms of abortion and larval mortality against wasp cheats in the monoecious Ficus racemosa by introducing into figs 1, 3, 5, 7, or 9 female wasps (foundresses) that were either all pollen-laden (P+) or all pollen-free (P-). The abortion rates of P- figs were highest (-60%) when single foundresses were present. Abortion declined with increased foundresses and ceased with seven or more wasps present, irrespective of pollination. In un-aborted figs, wasp fitness (mean offspring per foundress) declined as foundress number increased, especially in P- figs. Reduced broods in P- figs resulted from increased larval mortality of female offspring as foundress number increased, resulting in more male-biased sex ratios. Overall sanctions estimated from both abortion rates and reduced offspring production strengthened as the number of cheats increased. In a second experiment, we decoupled pollination from wasp oviposition by introducing one pollen-free foundress, followed 24 h later by seven pollen-laden ovipositor-excised wasps. Compared with P+ and P- single-foundress figs, delayed pollination resulted in intermediate larval mortality and wasp fitness, which concurred with patterns of female offspring production. We conclude that fig abortion reflects both pollinator numbers and pollen presence. Sanctions within P- figs initiate soon after oviposition and discriminate against female offspring

  13. Pollinating fig wasps: genetic consequences of island recolonization.

    PubMed

    Zavodna, Monika; Arens, Paul; Van Dijk, Peter J; Partomihardjo, Tukirin; Vosman, Ben; Van Damme, Jos M M

    2005-09-01

    The levels of genetic diversity and gene flow may influence the long-term persistence of populations. Using microsatellite markers, we investigated genetic diversity and genetic differentiation in island (Krakatau archipelago, Indonesia) and mainland (Java and Sumatra, Indonesia) populations of Liporrhopalum tentacularis and Ceratosolen bisulcatus, the fig wasp pollinators of two dioecious Ficus (fig tree) species. Genetic diversity in Krakatau archipelago populations was similar to that found on the mainland. Population differentiation between mainland coastal sites and the Krakatau islands was weak in both wasp species, indicating that the intervening 40 km across open sea may not be a barrier for wasp gene flow (dispersal) and colonization of the islands. Surprisingly, mainland populations of the fig waSPS may be more genetically isolated than the islands, as gene flow between populations on the Javan mainland differed between the two wasp species. Contrasting growth forms and relative 'immunity' to the effects of deforestation in their host fig trees may account for these differences.

  14. Regulation of transcription factors on sexual dimorphism of fig wasps.

    PubMed

    Sun, Bao-Fa; Li, Yong-Xing; Jia, Ling-Yi; Niu, Li-Hua; Murphy, Robert W; Zhang, Peng; He, Shunmin; Huang, Da-Wei

    2015-06-02

    Fig wasps exhibit extreme intraspecific morphological divergence in the wings, compound eyes, antennae, body color, and size. Corresponding to this, behaviors and lifestyles between two sexes are also different: females can emerge from fig and fly to other fig tree to oviposit and pollinate, while males live inside fig for all their lifetime. Genetic regulation may drive these extreme intraspecific morphological and behavioral divergence. Transcription factors (TFs) involved in morphological development and physiological activity may exhibit sex-specific expressions. Herein, we detect 865 TFs by using genomic and transcriptomic data of the fig wasp Ceratosolen solmsi. Analyses of transcriptomic data indicated that up-regulated TFs in females show significant enrichment in development of the wing, eye and antenna in all stages, from larva to adult. Meanwhile, TFs related to the development of a variety of organs display sex-specific patterns of expression in the adults and these may contribute significantly to their sexual dimorphism. In addition, up-regulated TFs in adult males exhibit enrichment in genitalia development and circadian rhythm, which correspond with mating and protandry. This finding is consistent with their sex-specific behaviors. In conclusion, our results strongly indicate that TFs play important roles in the sexual dimorphism of fig wasps.

  15. Urbanized landscapes favored by fig-eating birds increase invasive but not native juvenile strangler fig abundance.

    PubMed

    Caughlin, Trevor; Wheeler, Jessica H; Jankowski, Jill; Lichstein, Jeremy W

    2012-07-01

    Propagule pressure can determine the success or failure of invasive plant range expansion. Range expansion takes place at large spatial scales, often encompassing many types of land cover, yet the effect of landscape context on propagule pressure remains largely unknown. Many studies have reported a positive correlation between invasive plant abundance and human land use; increased propagule pressure in these landscapes may be responsible for this correlation. We tested the hypothesis that increased rates of seed dispersal by fig-eating birds, which are more common in urban habitats, result in an increase in invasive strangler fig abundance in landscapes dominated by human land use. We quantified abundance of an invasive species (Ficus microcarpa) and a native species (F. aurea) of strangler fig in plots spanning the entire range of human land use in South Florida, USA, from urban parking lots to native forest. We then compared models that predicted juvenile fig abundance based on distance to adult fig seed sources and fig-eating bird habitat quality with models that lacked one or both of these terms. The best model for juvenile invasive fig abundance included both distance to adult and fig-eating bird habitat terms, suggesting that landscape effects on invasive fig abundance are mediated by seed-dispersing birds. In contrast, the best model for juvenile native fig abundance included only presence/absence of adults, suggesting that distance from individual adult trees may have less effect on seed limitation for a native species compared to an invasive species undergoing range expansion. However, models for both species included significant effects of adult seed sources, implying that juvenile abundance is limited by seed arrival. This result was corroborated by a seed addition experiment that indicated that both native and invasive strangler figs were strongly seed limited. Understanding how landscape context affects the mechanisms of plant invasion may lead to

  16. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Enforcement hotline. 1b..., DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.21 Enforcement hotline. (a) The Hotline Staff may provide information to the public and give informal staff opinions. The opinions...

  17. DSCOVR_EPIC_L1B

    Atmospheric Science Data Center

    2017-01-04

    DSCOVR_EPIC_L1B Full sun-light Earth images, georectified to the same ... 551NM 680NM 688NM 764NM 780NM DSCOVR EPIC IMAGERY L1B LAGRANGE Order Data:  Earthdata ...   Order Data Readme Files:  EPIC Data Format Control Book SCAR-B Block:  ...

  18. How to be a fig wasp down under: The diversity and structure of an Australian fig wasp community

    NASA Astrophysics Data System (ADS)

    Segar, Simon T.; Dunn, Derek W.; Darwell, Clive T.; Cook, James M.

    2014-05-01

    Endophytic insects and their parasitoids provide valuable models for community ecology. The wasp communities in inflorescences of fig trees have great potential for comparative studies, but we must first describe individual communities. Here, we add to the few detailed studies of such communities by describing the one associated with Ficus rubiginosa in Australia. First, we describe community composition, using two different sampling procedures. Overall, we identified 14 species of non-pollinating fig wasp (NPFW) that fall into two size classes. Small wasps, including pollinators, gallers and their parasitoids, were more abundant than large wasps (both galler and parasitoid species). We show that in figs where wasps emerge naturally, the presence of large wasps may partly explain the low emergence of small wasps. During fig development, large gallers oviposit first, before and around the time of pollination, while parasitoids lay eggs after pollination. We further show that parasitoids in the subfamily Sycoryctinae, which comprise the majority of all individual NPFWs, segregate temporally by laying eggs at different stages of fig development. We discuss our results in terms of species co-existence and community structure and compare our findings to those from fig wasp communities on other continents.

  19. ALA Pretreatment Improves Waterlogging Tolerance of Fig Plants

    PubMed Central

    An, Yuyan; Qi, Lin; Wang, Liangju

    2016-01-01

    5-aminolevulinic acid (ALA), a natural and environmentally friendly plant growth regulator, can improve plant tolerance to various environmental stresses. However, whether ALA can improve plant waterlogging tolerance is unknown. Here, we investigated the effects of ALA pretreatment on the waterlogging-induced damage of fig (Ficus carica Linn.) plants, which often suffer from waterlogging stress. ALA pretreatment significantly alleviated stress-induced morphological damage, increased leaf relative water content (RWC), and reduced leaf superoxide anion (O2⋅¯) production rate and malonaldehyde (MDA) content in fig leaves, indicating ALA mitigates waterlogging stress of fig plants. We further demonstrated that ALA pretreatment largely promoted leaf chlorophyll content, photosynthetic electron transfer ability, and photosynthetic performance index, indicating ALA significantly improves plant photosynthetic efficiency under waterlogging stress. Moreover, ALA pretreatment significantly increased activities of leaf superoxide dismutase (SOD) and peroxidase (POD), root vigor, and activities of root alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH), indicating ALA also significantly improves antioxidant ability and root function of fig plants under waterlogging stress. Taken together, ALA pretreatment improves waterlogging tolerance of fig plants significantly, and the promoted root respiration, leaf photosynthesis, and antioxidant ability may contribute greatly to this improvement. Our data firstly shows that ALA can improve plant waterlogging tolerance. PMID:26789407

  20. ALA Pretreatment Improves Waterlogging Tolerance of Fig Plants.

    PubMed

    An, Yuyan; Qi, Lin; Wang, Liangju

    2016-01-01

    5-aminolevulinic acid (ALA), a natural and environmentally friendly plant growth regulator, can improve plant tolerance to various environmental stresses. However, whether ALA can improve plant waterlogging tolerance is unknown. Here, we investigated the effects of ALA pretreatment on the waterlogging-induced damage of fig (Ficus carica Linn.) plants, which often suffer from waterlogging stress. ALA pretreatment significantly alleviated stress-induced morphological damage, increased leaf relative water content (RWC), and reduced leaf superoxide anion ([Formula: see text]) production rate and malonaldehyde (MDA) content in fig leaves, indicating ALA mitigates waterlogging stress of fig plants. We further demonstrated that ALA pretreatment largely promoted leaf chlorophyll content, photosynthetic electron transfer ability, and photosynthetic performance index, indicating ALA significantly improves plant photosynthetic efficiency under waterlogging stress. Moreover, ALA pretreatment significantly increased activities of leaf superoxide dismutase (SOD) and peroxidase (POD), root vigor, and activities of root alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH), indicating ALA also significantly improves antioxidant ability and root function of fig plants under waterlogging stress. Taken together, ALA pretreatment improves waterlogging tolerance of fig plants significantly, and the promoted root respiration, leaf photosynthesis, and antioxidant ability may contribute greatly to this improvement. Our data firstly shows that ALA can improve plant waterlogging tolerance.

  1. Antioxidant activity of a Mediterranean food product: "fig syrup".

    PubMed

    Puoci, Francesco; Iemma, Francesca; Spizzirri, Umile G; Restuccia, Donatella; Pezzi, Vincenzo; Sirianni, Rosa; Manganaro, Lillo; Curcio, Manuela; Parisi, Ortensia I; Cirillo, Giuseppe; Picci, Nevio

    2011-03-01

    In this work, the efficacy of fig syrup, a Mediterranean fig derivative, as a nutraceutical supplement, was demonstrated. Fig syrup is a fruit concentrate used as a common ingredient in the preparation of typical foods, and particularly in cakes. In vitro assays were performed to determine the amount of nutraceutical ingredients, such as phenolic compounds (3.92 mg equivalent of gallic acid per g) and flavonoids (0.35 mg equivalent of catechin per g), while HPLC analyses provided specific information about the composition of antioxidants in the syrup. Furthermore, total antioxidant activity, scavenging properties against DPPH and peroxyl radicals, and the anticholinesterase activity, clearly showed the efficacy of the syrup in preventing damage induced by free radicals and, thus, the applicability of this food derivative as a nutraceutical supplement.

  2. Identification of phenylpropanoids in fig (Ficus carica L.) leaves.

    PubMed

    Takahashi, Toru; Okiura, Aya; Saito, Keita; Kohno, Masahiro

    2014-10-15

    In this study, the phenylpropanoid composition and antioxidant activity of identified components in fig (Ficus carica L.) leaves were examined. Known polyphenols rutin, isoschaftoside, isoquercetin, and chlorogenic acid were identified. Furthermore, caffeoylmalic acid (CMA) was the most abundant polyphenol and was identified for the first time. CMA exhibited antioxidant activity similar to that of vitamin C or catechin. Psoralen and bergapten were identified as known furanocoumarins, with psoralen being the most abundant. Moreover, psoralic acid glucoside (PAG) was identified for the first time. As a precursor of psoralen, PAG content was equivalent to the psoralen content in moles. Notably, the content of these compounds varied between the five fig varieties, and the furanocoumarin and PAG contents varied more than that of the polyphenols. Further investigations concerning the influence of CMA and PAG on human health are necessary to elucidate functionalities of fig leaves.

  3. Interference competition and high temperatures reduce the virulence of fig wasps and stabilize a fig-wasp mutualism.

    PubMed

    Wang, Rui-Wu; Ridley, Jo; Sun, Bao-Fa; Zheng, Qi; Dunn, Derek W; Cook, James; Shi, Lei; Zhang, Ya-Ping; Yu, Douglas W

    2009-11-12

    Fig trees are pollinated by fig wasps, which also oviposit in female flowers. The wasp larvae gall and eat developing seeds. Although fig trees benefit from allowing wasps to oviposit, because the wasp offspring disperse pollen, figs must prevent wasps from ovipositing in all flowers, or seed production would cease, and the mutualism would go extinct. In Ficus racemosa, we find that syconia ('figs') that have few foundresses (ovipositing wasps) are underexploited in the summer (few seeds, few galls, many empty ovules) and are overexploited in the winter (few seeds, many galls, few empty ovules). Conversely, syconia with many foundresses produce intermediate numbers of galls and seeds, regardless of season. We use experiments to explain these patterns, and thus, to explain how this mutualism is maintained. In the hot summer, wasps suffer short lifespans and therefore fail to oviposit in many flowers. In contrast, cooler temperatures in the winter permit longer wasp lifespans, which in turn allows most flowers to be exploited by the wasps. However, even in winter, only in syconia that happen to have few foundresses are most flowers turned into galls. In syconia with higher numbers of foundresses, interference competition reduces foundress lifespans, which reduces the proportion of flowers that are galled. We further show that syconia encourage the entry of multiple foundresses by delaying ostiole closure. Taken together, these factors allow fig trees to reduce galling in the wasp-benign winter and boost galling (and pollination) in the wasp-stressing summer. Interference competition has been shown to reduce virulence in pathogenic bacteria. Our results show that interference also maintains cooperation in a classic, cooperative symbiosis, thus linking theories of virulence and mutualism. More generally, our results reveal how frequency-dependent population regulation can occur in the fig-wasp mutualism, and how a host species can 'set the rules of the game' to ensure

  4. FOLH1B — EDRN Public Portal

    Cancer.gov

    FOLH1B, or PSMAL, is a cytoplasmic protein. It has been found in the kidney and liver, and has not been detected in the prostate. GO annotations related to this gene include metallopeptidase activity and dipeptidase activity.

  5. Development of an In Vitro Model to Screen CYP1B1-Targeted Anticancer Prodrugs.

    PubMed

    Wang, Zhiying; Chen, Yao; Drbohlav, Laura M; Wu, Judy Qiju; Wang, Michael Zhuo

    2016-12-01

    Cytochrome P450 1B1 (CYP1B1) is an anticancer therapeutic target due to its overexpression in a number of steroid hormone-related cancers. One anticancer drug discovery strategy is to develop prodrugs specifically activated by CYP1B1 in malignant tissues to cytotoxic metabolites. Here, we aimed to develop an in vitro screening model for CYP1B1-targeted anticancer prodrugs using the KLE human endometrial carcinoma cell line. KLE cells demonstrated superior stability of CYP1B1 expression relative to transiently transfected cells and did not express any appreciable amount of cognate CYP1A1 or CYP1A2, which would have compromised the specificity of the screening assay. The effect of two CYP1B1-targeted probe prodrugs on KLE cells was evaluated in the absence and presence of a CYP1B1 inhibitor to chemically "knock out" CYP1B1 activity (CYP1B1 inhibited). Both probe prodrugs were more toxic to KLE cells than to CYP1B1-inhibited KLE cells and significantly induced G0/G1 arrest and decreased the S phase in KLE cells. They also exhibited pro-apoptotic effects in KLE cells, which were attenuated in CYP1B1-inhibited KLE cells. In summary, a KLE cell-based model has been characterized to be suitable for identifying CYP1B1-targeted anticancer prodrugs and should be further developed and employed for screening chemical libraries.

  6. 21 CFR 145.134 - Canned preserved figs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... section are whole mature figs of the light or dark varieties that may be either peeled or unpeeled. (c)(1... words “Preserved Figs”, but there shall be no intervening written, printed, or graphic matter, and the... precede or follow such name without intervening written, printed, or graphic matter, except that...

  7. 21 CFR 145.134 - Canned preserved figs.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... section are whole mature figs of the light or dark varieties that may be either peeled or unpeeled. (c)(1... words “Preserved Figs”, but there shall be no intervening written, printed, or graphic matter, and the... precede or follow such name without intervening written, printed, or graphic matter, except that...

  8. 21 CFR 145.134 - Canned preserved figs.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... section are whole mature figs of the light or dark varieties that may be either peeled or unpeeled. (c)(1... words “Preserved Figs”, but there shall be no intervening written, printed, or graphic matter, and the... precede or follow such name without intervening written, printed, or graphic matter, except that...

  9. 21 CFR 145.134 - Canned preserved figs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... section are whole mature figs of the light or dark varieties that may be either peeled or unpeeled. (c)(1... words “Preserved Figs”, but there shall be no intervening written, printed, or graphic matter, and the... precede or follow such name without intervening written, printed, or graphic matter, except that...

  10. 21 CFR 145.134 - Canned preserved figs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... section are whole mature figs of the light or dark varieties that may be either peeled or unpeeled. (c)(1... words “Preserved Figs”, but there shall be no intervening written, printed, or graphic matter, and the... precede or follow such name without intervening written, printed, or graphic matter, except that...

  11. 21 CFR 145.131 - Artificially sweetened canned figs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Artificially sweetened canned figs. 145.131 Section 145.131 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION CANNED FRUITS Requirements for Specific Standardized Canned...

  12. Genetic characterization of fig tree mutants with molecular markers.

    PubMed

    Rodrigues, M G F; Martins, A B G; Desidério, J A; Bertoni, B W; Alves, M C

    2012-08-06

    The fig (Ficus carica L.) is a fruit tree of great world importance and, therefore, the genetic improvement becomes an important field of research for better crops, being necessary to gather information on this species, mainly regarding its genetic variability so that appropriate propagation projects and management are made. The improvement programs of fig trees using conventional procedures in order to obtain new cultivars are rare in many countries, such as Brazil, especially due to the little genetic variability and to the difficulties in obtaining plants from gamete fusion once the wasp Blastophaga psenes, responsible for the natural pollinating, is not found in Brazil. In this way, the mutagenic genetic improvement becomes a solution of it. For this reason, in an experiment conducted earlier, fig plants formed by cuttings treated with gamma ray were selected based on their agronomic characteristics of interest. We determined the genetic variability in these fig tree selections, using RAPD and AFLP molecular markers, comparing them to each other and to the Roxo-de-Valinhos, used as the standard. For the reactions of DNA amplification, 140 RAPD primers and 12 primer combinations for AFLP analysis were used. The selections did not differ genetically between themselves and between them and the Roxo-de-Valinhos cultivar. Techniques that can detect polymorphism between treatments, such as DNA sequencing, must be tested. The phenotypic variation of plants may be due to epigenetic variation, necessitating the use of techniques with methylation-sensitive restriction enzymes.

  13. 21 CFR 145.131 - Artificially sweetened canned figs.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... artificially sweetened food is subject to the requirements for label statement of ingredients used, as... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Artificially sweetened canned figs. 145.131 Section 145.131 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  14. 21 CFR 145.131 - Artificially sweetened canned figs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... artificially sweetened food is subject to the requirements for label statement of ingredients used, as... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Artificially sweetened canned figs. 145.131 Section 145.131 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  15. 21 CFR 145.131 - Artificially sweetened canned figs.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... artificially sweetened food is subject to the requirements for label statement of ingredients used, as... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Artificially sweetened canned figs. 145.131 Section 145.131 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  16. Aflatoxins in hazelnuts and dried figs: Occurrence and exposure assessment.

    PubMed

    Kabak, Bulent

    2016-11-15

    A total of 300 samples of hazelnuts and dried fig were analysed for the incidence of any aflatoxins (AFs). High-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) method was used to quantify the amounts of AFs. The limit of quantification varied from 0.21 to 0.30μgkg(-1). No AFs were detected in shells of the hazelnuts, while six raw hazelnut kernel samples (12%) and five roasted hazelnut kernel samples (8.3%) contained AFs ranging from 0.09 to 11.3μgkg(-1) and from 0.17 to 11.2μgkg(-1), respectively. Sixteen dried fig samples (12.3%) contained AFs ranging from 0.1 to 28.2μgkg(-1) and a mean value of 3.8μgkg(-1). Three hazelnuts and six dried fig samples exceeded the European maximum limits (MLs) of 5 and 2μgkg(-1) for aflatoxin B1 (AFB1), respectively. The contribution of hazelnuts to AFs exposure is higher than that of dried figs.

  17. Genetic structure and differentiation in cultivated fig (Ficus carica L.)

    PubMed Central

    Stover, Ed; Velasco, Dianne; Koehmstedt, Anne

    2010-01-01

    One hundred ninety-four germplasm accessions of fig representing the four fig types, Common, Smyrna, San Pedro, and Caprifig were analyzed for genetic diversity, structure, and differentiation using genetic polymorphism at 15 microsatellite loci. The collection showed considerable polymorphism with observed number of alleles per locus ranging from four for five different loci, MFC4, LMFC14, LMFC22, LMFC31 and LMFC35 to nine for LMFC30 with an average of 4.9 alleles per locus. Seven of the 15 loci included in the genetic structure analyses exhibited significant deviation from panmixia, of which two showed excess and five showed deficiency of heterozygote. The cluster analysis (CA) revealed ten groups with 32 instances of synonymy among cultivars and groups differed significantly for frequency and composition of alleles for different loci. The principal components analysis (PCA) confirmed the results of CA with some groups more differentiated than the others. Further, the model based Bayesian approach clustering suggested a subtle population structure with mixed ancestry for most figs. The gene diversity analysis indicated that much of the total variation is found within groups (HG/HT = 0.853; 85.3%) and the among groups within total component (GGT = 0.147) accounted for the remaining 14.7%, of which ~64% accounted for among groups within clusters (GGC = 0.094) and ~36% among clusters (GCT = 0.053). The analysis of molecular variance (AMOVA) showed approximately similar results with nearly 87% of variation within groups and ~10% among groups within clusters, and ~3% among clusters. Overall, the gene pool of cultivated fig analyzed possesses substantial genetic polymorphism but exhibits narrow differentiation. It is evident that fig accessions from Turkmenistan are somewhat genetically different from the rest of the Mediterranean and the Caucasus figs. The long history of domestication and cultivation with widespread dispersal of cultivars with many synonyms

  18. Genetic structure and differentiation in cultivated fig (Ficus carica L.).

    PubMed

    Aradhya, Mallikarjuna K; Stover, Ed; Velasco, Dianne; Koehmstedt, Anne

    2010-06-01

    One hundred ninety-four germplasm accessions of fig representing the four fig types, Common, Smyrna, San Pedro, and Caprifig were analyzed for genetic diversity, structure, and differentiation using genetic polymorphism at 15 microsatellite loci. The collection showed considerable polymorphism with observed number of alleles per locus ranging from four for five different loci, MFC4, LMFC14, LMFC22, LMFC31 and LMFC35 to nine for LMFC30 with an average of 4.9 alleles per locus. Seven of the 15 loci included in the genetic structure analyses exhibited significant deviation from panmixia, of which two showed excess and five showed deficiency of heterozygote. The cluster analysis (CA) revealed ten groups with 32 instances of synonymy among cultivars and groups differed significantly for frequency and composition of alleles for different loci. The principal components analysis (PCA) confirmed the results of CA with some groups more differentiated than the others. Further, the model based Bayesian approach clustering suggested a subtle population structure with mixed ancestry for most figs. The gene diversity analysis indicated that much of the total variation is found within groups (H (G) /H (T) = 0.853; 85.3%) and the among groups within total component (G (GT) = 0.147) accounted for the remaining 14.7%, of which approximately 64% accounted for among groups within clusters (G (GC) = 0.094) and approximately 36% among clusters (G (CT) = 0.053). The analysis of molecular variance (AMOVA) showed approximately similar results with nearly 87% of variation within groups and approximately 10% among groups within clusters, and approximately 3% among clusters. Overall, the gene pool of cultivated fig analyzed possesses substantial genetic polymorphism but exhibits narrow differentiation. It is evident that fig accessions from Turkmenistan are somewhat genetically different from the rest of the Mediterranean and the Caucasus figs. The long history of domestication and cultivation

  19. Initial assessment of natural diversity in Mexican fig landraces.

    PubMed

    García-Ruiz, M T; Mendoza-Castillo, V M; Valadez-Moctezuma, E; Muratalla-Lúa, A

    2013-09-23

    The common fig (Ficus carica L.) was introduced into Mexico by Spanish Franciscan missionaries in the 16th century. It is widely assumed that Mexican figs are the Spanish cultivar Black Mission. We collected and propagated 12 fig plants from six landraces from different states in Central Mexico that represent different climate. All of them were grown in a greenhouse at Universidad Autónoma Chapingo, in the State of Mexico. During the experimental period, the greenhouse had an average temperature and relative humidity of 29.2° ± 5.4°C (SEM) and 78.1 ± 6.7% (SEM), respectively. Morphological characterization was done following a selected set of quantitative and qualitative descriptors established by the IPGRI. DNA analysis was based on a combination of ISSR and RFLP markers. We observed great diversity mainly in fruit weight (28.1-96.2 g), fruit shape (ovoid, pyriform), and neck length (0.97-3.80 cm), which could not be explained by environmental conditions such as temperature and relative humidity. The Nei and Li/Dice similarity coefficient between landraces was determined by cluster analysis using the UPGMA method. Based on the morphological characterization and DNA fingerprinting data presented in this study, our results showed that after hundreds of years, black figs have adapted to local environmental condition in Central Mexico, yielding at least six clearly distinct landraces that represent valuable and previously undescribed genetic diversity. We also suggested names for those landraces according to their location and established a basis for further agronomic and molecular characterization of fig landraces.

  20. Therapeutic effects of fig tree latex on bovine papillomatosis.

    PubMed

    Hemmatzadeh, F; Fatemi, A; Amini, F

    2003-12-01

    The effects of fig tree latex in treating teat papillomatosis in cow in comparison with salicylic acid were evaluated. For this purpose, 12 cows of 1-3 years of age (average 2.25) affected by teat papillomatosis were divided into three groups. In group A, four cows were treated by fig tree (Ficus carica) latex; in group B, four cows were treated with 10% salicylic acid solution and in group C, four cows were kept as control animals receiving no treatment. Animals in each treatment group received their treatment once every 5 days. In groups A and B, de-epithelialization and shrinking of the warts began from the fifth day of treatment and all the warts disappeared within 30 days. However, in the control group no changes in the number of warts were observed until day 15 but thereafter a number of warts disappeared spontaneously in some of the animals. Both salicylic acid and fig tree latex were evaluated as having similar therapeutic effects in treating teat papillomatosis in cow.

  1. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Enforcement hotline. 1b... or writing to the Hotline at the telephone number and address in paragraph (f) of this section. The... matter. A caller may terminate use of the Hotline procedure at any time. (f) The Hotline may be...

  2. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Enforcement hotline. 1b... or writing to the Hotline at the telephone number and address in paragraph (f) of this section. The... matter. A caller may terminate use of the Hotline procedure at any time. (f) The Hotline may be...

  3. 7 CFR 1b.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.1 Purpose. (a) This part supplements the regulations for implementation of the National Environmental Policy Act (NEPA), for which regulations were published by the Council on Environmental Quality (CEQ) in 40 CFR parts 1500 through 1508. This...

  4. Experimental Reproduction of Type 1B Chondrules

    NASA Technical Reports Server (NTRS)

    Lofgren, G. E.; Le, L.

    2002-01-01

    We have replicated type 1B chondrule textures and compositions with crystallization experiments in which UOC material was melted at 1400 deg.C and cooled at 5-1000 deg.C/hr using graphite crucibles in evacuated silica tubes to provide a reducing environment. Additional information is contained in the original extended abstract.

  5. Aldo-keto Reductase 1B15 (AKR1B15)

    PubMed Central

    Weber, Susanne; Salabei, Joshua K.; Möller, Gabriele; Kremmer, Elisabeth; Bhatnagar, Aruni; Adamski, Jerzy; Barski, Oleg A.

    2015-01-01

    Aldo-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues. PMID:25577493

  6. The effect of fig wall thickness in Ficus erecta var. beecheyana on parasitism

    NASA Astrophysics Data System (ADS)

    Tzeng, Hsy-Yu; Ou, Chern-Hsiung; Lu, Fu-Yuan; Bain, Anthony; Chou, Lien-Siang; Kjellberg, Finn

    2014-05-01

    Fig wasp communities constitute a model system to analyse determinants of community complexity and to investigate how biological interaction networks are maintained. It has been suggested for monoecious figs, that fig pollinating wasps avoid ovipositing in flowers located close to the fig wall because of strong parasitic pressure by wasps ovipositing through the fig wall. This behaviour could help explain why mainly seeds are produced in flowers located close to the fig wall, thus stabilizing the fig-pollinating wasp mutualism. In this contribution we explore, for dioecious figs, whether ovipositor length of parasitic species may really be limiting. In dioecious figs, functionally male figs produce pollinating wasps and pollen while female figs produce only seeds, facilitating selection of traits favouring pollinator reproduction in male figs. We show in Ficus erecta that fig walls are thicker in male figs than in female figs. Male figs presenting thick walls, thicker than the length of the parasites' ovipositors, went unparasitized while male figs presenting thinner walls were systematically parasitized. Hence, in F. erecta, ovipositor length of the parasites is limiting access to some figs. However, we also show that in another dioecious species, Ficus formosana, presenting thin walled male figs, no fig is protected against oviposition by its two parasites. Hence in dioecious as well as in monoecious figs, in some Ficus species, ovipositors of the parasites are limiting access to ovules, while in other Ficus species all ovules are exposed to parasitism.

  7. Multiple Intravenous Infusions Phase 1b

    PubMed Central

    Cassano-Piché, A; Fan, M; Sabovitch, S; Masino, C; Easty, AC

    2012-01-01

    Background Minimal research has been conducted into the potential patient safety issues related to administering multiple intravenous (IV) infusions to a single patient. Previous research has highlighted that there are a number of related safety risks. In Phase 1a of this study, an analysis of 2 national incident-reporting databases (Institute for Safe Medical Practices Canada and United States Food and Drug Administration MAUDE) found that a high percentage of incidents associated with the administration of multiple IV infusions resulted in patient harm. Objectives The primary objectives of Phase 1b of this study were to identify safety issues with the potential to cause patient harm stemming from the administration of multiple IV infusions; and to identify how nurses are being educated on key principles required to safely administer multiple IV infusions. Data Sources and Review Methods A field study was conducted at 12 hospital clinical units (sites) across Ontario, and telephone interviews were conducted with program coordinators or instructors from both the Ontario baccalaureate nursing degree programs and the Ontario postgraduate Critical Care Nursing Certificate programs. Data were analyzed using Rasmussen’s 1997 Risk Management Framework and a Health Care Failure Modes and Effects Analysis. Results Twenty-two primary patient safety issues were identified with the potential to directly cause patient harm. Seventeen of these (critical issues) were categorized into 6 themes. A cause-consequence tree was established to outline all possible contributing factors for each critical issue. Clinical recommendations were identified for immediate distribution to, and implementation by, Ontario hospitals. Future investigation efforts were planned for Phase 2 of the study. Limitations This exploratory field study identifies the potential for errors, but does not describe the direct observation of such errors, except in a few cases where errors were observed. Not all

  8. Yif1B Is Involved in the Anterograde Traffic Pathway and the Golgi Architecture.

    PubMed

    Alterio, Jeanine; Masson, Justine; Diaz, Jorge; Chachlaki, Konstantina; Salman, Haysam; Areias, Julie; Al Awabdh, Sana; Emerit, Michel Boris; Darmon, Michèle

    2015-09-01

    Yif1B is an intracellular membrane-bound protein belonging to the Yip family, shown previously to control serotonin 5-HT1A receptor targeting to dendrites. Because some Yip proteins are involved in the intracellular traffic between the ER and the Golgi, here we investigated the precise localization of Yif1B in HeLa cells. We found that Yif1B is not resident into the Golgi, but rather belongs to the IC compartment. After analyzing the role of Yif1B in protein transport, we showed that the traffic of the VSVG protein marker was accelerated in Yif1B depleted HeLa cells, as well as in hippocampal neurons from Yif1B KO mice. Conversely, Yif1B depletion in HeLa cells did not change the retrograde traffic of ShTx. Interestingly, in long term depletion of Yif1B as in Yif1B KO mice, we observed a disorganized Golgi architecture in CA1 pyramidal hippocampal neurons, which was confirmed by electron microscopy. However, because short term depletion of Yif1B did not change Golgi structure, it is likely that the implication of Yif1B in anterograde traffic does not rely on its role in structural organization of the Golgi apparatus, but rather on its shuttling between the ER, the IC and the Golgi compartments.

  9. PTP1B inhibitors from Saussrurea lappa.

    PubMed

    Li, S; An, T-Y; Li, J; Shen, Q; Lou, F-C; Hu, L-H

    2006-01-01

    A new lignan glycoside, named 1,5-dihydroxypinoresinol-4'-O-beta-d-glucopyranoside (1), has been isolated from the EtOH extract of the roots of Saussurea lappa, together with twenty known compounds: (+)-1-hydroxypinoresinol-1-O-beta-D-glucopyranoside (2), fraxiresinol-4'-O-beta-D-glucopyranoside (3), (-)-olivil-4''-O-beta-D-glucopyranoside (4), 4-allyl-2,6-dimethoxybenzene-1-O-beta-D-glucopyranoside, syringin, costunolide-15-O-beta-D-glucopyranoside, chlorogenic acid, aloe-emodin-8-O-beta-D-glucopyranoside (5), rhein-8-O-beta-D-glucopyranoside (6), chrysophanol (7), emodin, dehydrocostus lactone, costunolide, beta-costic acid, reynosin, arbusculin A, alpha-cyclocostunolide, beta-cyclocostunolide, santamarine and magnolialide. Three anthraquinones (5-7) showed moderate bioactivity against human Protein Tyrosine Phosphatase 1B (hPTP1B) in vitro.

  10. Papain Induced Occupational Asthma with Kiwi and Fig Allergy.

    PubMed

    Jiang, Nannan; Yin, Jia; Wen, Liping

    2016-03-01

    Papain is a proteolytic enzyme which is widely used in food industry, pharmaceuticals, and cosmetics. Occupational and non-occupational papain allergies have previously been documented; however, there are limited publications about papain allergy with its relative fruit allergy. Here, we present a case of occupational, IgE-mediated papain allergy with kiwi fruit and fig fruit allergy. A 53-year-old man suffered from rhinitis for several years, with the onset of his symptoms coinciding with the time he started to work at a sausage processing plant where papain is often used as a meat tenderizer. He began to experience symptoms of chest tightness, shortness of breath and wheezing shortly after starting work 5 years ago. Furthermore, he experienced several episodes of oral itching, and tongue and oropharyngeal angioedema after injestion of kiwi fruit and fig fruit. The patient had a lifelong history of allergic conjunctivitis, allergic rhinitis, and childhood asthma. Specific IgE was positive to kiwi fruit, papain and chymopapain (2.95 kUA/L, >100 kUA/L, and 95.0 kUA/L, respectively). Similar bands at 10-15 kDa in blotting with papain and kiwi fruit extracts were found. This patient showed a potential association between papain allergy and sensitization to kiwi fruit. We also reviewed 13 patients with papain allergy published in the literature, with 85% (11/13) of the patients sensitized through the respiratory tract, and 40% (4/11) having atopy. Further studies should focus on the determination of cross-reactive allergens between papain and its fruit relatives, and the prevalence of food allergy in patients with papain allergy should be investigated in a relatively large cohort.

  11. Oleanane triterpenes as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Camellia japonica.

    PubMed

    Uddin, Mohammad Nasir; Sharma, Govinda; Yang, Jun-Li; Choi, Hong Seok; Lim, Seong-Il; Kang, Keon Wook; Oh, Won Keun

    2014-07-01

    Protein tyrosine phosphatase 1B (PTP1B) plays a key role in metabolic signaling, thereby making it an exciting drug target for type 2 diabetes and obesity. Besides, there is substantial evidence that shows its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. As part of our continuous research on PTP1B inhibitors from medicinal plants, four oleanane-type triterpenes were isolated from an EtOAc-soluble extract of fruit peels of Camellia japonica (Theaceae), together with 6 previously known compounds of this class. Their structures were determined on the basis of spectroscopic data analysis (UV, IR, (1)H and (13)CNMR, HMBC, HSQC, NOESY, and MS). All isolates were evaluated for their inhibitory effects on PTP1B, as well as their cytotoxic effects against human breast cancer cell lines MCF7, MCF7/ADR, and MDA-MB-231. Several compounds with OH-3 or/and COOH-28 functionalities showed strong PTP1B inhibitory activity (IC50 values ranging from 3.77±0.11 to 6.40±0.81 μM) as well as significant cytotoxicity (IC50 values ranging from 0.51±0.05 to 13.55±1.44 μM).

  12. Zinc ions modulate protein tyrosine phosphatase 1B activity.

    PubMed

    Bellomo, Elisa; Massarotti, Alberto; Hogstrand, Christer; Maret, Wolfgang

    2014-07-01

    Protein tyrosine phosphatases (PTPs) are key enzymes in cellular regulation. The 107 human PTPs are regulated by redox signalling, phosphorylation, dimerisation, and proteolysis. Recent findings of very strong inhibition of some PTPs by zinc ions at concentrations relevant in a cellular environment suggest yet another mechanism of regulation. One of the most extensively investigated PTPs is PTP1B (PTPN1). It regulates the insulin and leptin signalling pathway and is implicated in cancer and obesity/diabetes. The development of novel assay conditions to investigate zinc inhibition of PTP1B provides estimates of about 5.6 nM affinity for inhibitory zinc(II) ions. Analysis of three PTP1B 3D structures (PDB id: 2CM2, 3I80 and 1A5Y) identified putative zinc binding sites and supports the kinetic studies in suggesting an inhibitory zinc only in the closed and cysteinyl-phosphate intermediate forms of the enzyme. These observations gain significance with regard to recent findings of regulatory roles of zinc ions released from the endoplasmic reticulum.

  13. Cytotoxicity of fig fruit latex against human cancer cells.

    PubMed

    Wang, Jing; Wang, Xiujie; Jiang, Shu; Lin, Ping; Zhang, Jie; Lu, Yanrong; Wang, Qi; Xiong, Zhujuan; Wu, Yaying; Ren, Jingjing; Yang, Hongliang

    2008-03-01

    Fig fruit latex (FFL) contains significant amounts of polyphenolic compounds and can serve as a source of antioxidants after human consumption. The purpose of this study is to confirm anticancer activity of FFL against human cancer cells and to further elucidate its mechanism of activity. Human glioblastoma, hepatocellular carcinoma, and normal liver cells were used for in vitro tests of FFL effects. Those tests included cytotoxicity, colony formation inhibition, Brdu incorporation, acridine orange/ethidium bromide (AO/EB) staining for apoptotic cells, cell cycle distribution through flow cytometry (FCM), and ADP-ribosyltransferase (NAD+; poly(ADP-ribose) polymerase)-like 1 (ADPERL1) mRNA expression through RT-PCR in response to FFL treatment. After FFL treatment, the proliferation, colony formation, and Brdu labeling indices of cancer cells decreased (P<0.05), while the AO/EB stained apoptotic cells increased (P<0.05). By FCM analysis, an increase of G(0)/G(1) phase cell population and decrease of S and G(2)/M phase cells were observed (P<0.01), while both ADPRTL1 mRNA expression and apoptotic indices increased (P<0.01). The findings in these studies suggested that FFL exhibited potent cytotoxicity in some human cancer cells with little effect in normal cells at certain concentration. The mechanism for such effects might be associated with the inhibition of DNA synthesis, induction of apoptosis, and cell cycle arrest of cancer cells.

  14. TNFRSF1B — EDRN Public Portal

    Cancer.gov

    TNFRSF1B, also known as TNFr2, a single-pass type I member of the TNF-receptor superfamily, forms a heterocomplex with TNF-receptor 1 that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. Although the function of IAPs in TNF-receptor signalling is unknown, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest that TNFr2 plays a role in protecting neurons from apoptosis by stimulating antioxidative pathways.

  15. Skylab Saturn 1B flight manual

    NASA Technical Reports Server (NTRS)

    1972-01-01

    A Saturn 1B Flight Manual provides launch vehicle systems descriptions and predicted performance data for the Skylab missions. Vehicle SL-2 (SA-206) is the baseline for this manual; but, as a result of the great similarity, the material is representative of SL-3 and SL-4 launch vehicles, also. The Flight Manual is not a control document but is intended primarily as an aid to astronauts who are training for Skylab missions. In order to provide a comprehensive reference for that purpose, the manual also contains descriptions of the ground support interfaces, prelaunch operations, and emergency procedures. Mission variables and constraints are summarized, and mission control monitoring and data flow during launch preparation and flight are discussed.

  16. Ficus spp. (fig): ethnobotany and potential as anticancer and anti-inflammatory agents.

    PubMed

    Lansky, Ephraim Philip; Paavilainen, Helena M; Pawlus, Alison D; Newman, Robert A

    2008-09-26

    This review explores medieval, ancient and modern sources for ethnopharmacological uses of Ficus (fig) species, specifically for employment against malignant disease and inflammation. The close connection between inflammatory/infectious and cancerous diseases is apparent both from the medieval/ancient merging of these concepts and the modern pharmacological recognition of the initiating and promoting importance of inflammation for cancer growth. Also considered are chemical groups and compounds underlying the anticancer and anti-inflammatory actions, the relationship of fig wasps and fig botany, extraction and storage of fig latex, and traditional methods of preparing fig medicaments including fig lye, fig wine and medicinal poultices.

  17. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

    PubMed

    Schubert, Julian; Siekierska, Aleksandra; Langlois, Mélanie; May, Patrick; Huneau, Clément; Becker, Felicitas; Muhle, Hiltrud; Suls, Arvid; Lemke, Johannes R; de Kovel, Carolien G F; Thiele, Holger; Konrad, Kathryn; Kawalia, Amit; Toliat, Mohammad R; Sander, Thomas; Rüschendorf, Franz; Caliebe, Almuth; Nagel, Inga; Kohl, Bernard; Kecskés, Angela; Jacmin, Maxime; Hardies, Katia; Weckhuysen, Sarah; Riesch, Erik; Dorn, Thomas; Brilstra, Eva H; Baulac, Stephanie; Møller, Rikke S; Hjalgrim, Helle; Koeleman, Bobby P C; Jurkat-Rott, Karin; Lehman-Horn, Frank; Roach, Jared C; Glusman, Gustavo; Hood, Leroy; Galas, David J; Martin, Benoit; de Witte, Peter A M; Biskup, Saskia; De Jonghe, Peter; Helbig, Ingo; Balling, Rudi; Nürnberg, Peter; Crawford, Alexander D; Esguerra, Camila V; Weber, Yvonne G; Lerche, Holger

    2014-12-01

    Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

  18. GIFTS SM EDU Level 1B Algorithms

    NASA Technical Reports Server (NTRS)

    Tian, Jialin; Gazarik, Michael J.; Reisse, Robert A.; Johnson, David G.

    2007-01-01

    The Geosynchronous Imaging Fourier Transform Spectrometer (GIFTS) SensorModule (SM) Engineering Demonstration Unit (EDU) is a high resolution spectral imager designed to measure infrared (IR) radiances using a Fourier transform spectrometer (FTS). The GIFTS instrument employs three focal plane arrays (FPAs), which gather measurements across the long-wave IR (LWIR), short/mid-wave IR (SMWIR), and visible spectral bands. The raw interferogram measurements are radiometrically and spectrally calibrated to produce radiance spectra, which are further processed to obtain atmospheric profiles via retrieval algorithms. This paper describes the GIFTS SM EDU Level 1B algorithms involved in the calibration. The GIFTS Level 1B calibration procedures can be subdivided into four blocks. In the first block, the measured raw interferograms are first corrected for the detector nonlinearity distortion, followed by the complex filtering and decimation procedure. In the second block, a phase correction algorithm is applied to the filtered and decimated complex interferograms. The resulting imaginary part of the spectrum contains only the noise component of the uncorrected spectrum. Additional random noise reduction can be accomplished by applying a spectral smoothing routine to the phase-corrected spectrum. The phase correction and spectral smoothing operations are performed on a set of interferogram scans for both ambient and hot blackbody references. To continue with the calibration, we compute the spectral responsivity based on the previous results, from which, the calibrated ambient blackbody (ABB), hot blackbody (HBB), and scene spectra can be obtained. We now can estimate the noise equivalent spectral radiance (NESR) from the calibrated ABB and HBB spectra. The correction schemes that compensate for the fore-optics offsets and off-axis effects are also implemented. In the third block, we developed an efficient method of generating pixel performance assessments. In addition, a

  19. Tumor-specific expression of cytochrome P450 CYP1B1.

    PubMed

    Murray, G I; Taylor, M C; McFadyen, M C; McKay, J A; Greenlee, W F; Burke, M D; Melvin, W T

    1997-07-15

    Cytochrome P450 CYP1B1 is a recently cloned dioxin-inducible form of the cytochrome P450 family of xenobiotic metabolizing enzymes. An antibody raised against a peptide specific for CYP1B1 was found to recognize CYP1B1 expressed in human lymphoblastoid cells but not to recognize other forms of cytochrome P450, particularly CYP1A1 and CYP1A2. Using this antibody, the cellular distribution and localization of CYP1B1 were investigated by immunohistochemistry in a range of malignant tumors and corresponding normal tissues. CYP1B1 was found to be expressed at a high frequency in a wide range of human cancers of different histogenetic types, including cancers of the breast, colon, lung, esophagus, skin, lymph node, brain, and testis. There was no detectable immunostaining for CYP1B1 in normal tissues. These results provide the basis for the development of novel methods of cancer diagnosis based on the identification of CYP1B1 in tumor cells and the development of anticancer drugs that are selectively activated in tumors by CYP1B1.

  20. Low-temperature brewing using yeast immobilized on dried figs.

    PubMed

    Bekatorou, A; Sarellas, A; Ternan, N G; Mallouchos, A; Komaitis, M; Koutinas, A A; Kanellaki, M

    2002-12-04

    Dried figs, following exhaustive extraction of their residual sugars with water, were used for immobilization of Saccharomyces cerevisiae AXAZ-1. The immobilized biocatalyst was used in repeated batch fermentations of glucose at 30 degrees C, where significant reduction of the fermentation time was observed, falling from 65 h in the first batch to 7 h after the sixth batch. Repeated fermentations of wort at room and low temperatures resulted in fermentation times that fell from 26 to 20 h and from 27 to 24 days at 18 and 3 degrees C, respectively. Ethanol and beer productivities were high, showing suitability of the biocatalyst for low-temperature brewing. Diacetyl concentrations were low (0.3-0.5 mg/L), and polyphenols were lower than in commercial products and decreased as the fermentation temperature was decreased (126-50 mg/L). Ethyl acetate concentrations increased from 53 to 88 mg/L as the temperature was decreased, while the concentration of amyl alcohols at 3 degrees C (58 mg/L) was lower than half of that at 18 degrees C (125 mg/L). The beers produced at the end of the main fermentation had a fine clarity and a special fruity figlike aroma and taste, distinct from commercial products and more intense than beers produced by cells immobilized on other food-grade supports (gluten pellets or delignified cellulosic materials). GC-MS analysis did not show significant differences in the qualitative composition of the aroma compounds of the beers produced by immobilized and free cells.

  1. Protein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer’s Therapy?

    PubMed Central

    Vieira, Marcelo N. N.; Lyra e Silva, Natalia M.; Ferreira, Sergio T.; De Felice, Fernanda G.

    2017-01-01

    Despite significant advances in current understanding of mechanisms of pathogenesis in Alzheimer’s disease (AD), attempts at drug development based on those discoveries have failed to translate into effective, disease-modifying therapies. AD is a complex and multifactorial disease comprising a range of aberrant cellular/molecular processes taking part in different cell types and brain regions. As a consequence, therapeutics for AD should be able to block or compensate multiple abnormal pathological events. Here, we examine recent evidence that inhibition of protein tyrosine phosphatase 1B (PTP1B) may represent a promising strategy to combat a variety of AD-related detrimental processes. Besides its well described role as a negative regulator of insulin and leptin signaling, PTB1B recently emerged as a modulator of various other processes in the central nervous system (CNS) that are also implicated in AD. These include signaling pathways germane to learning and memory, regulation of synapse dynamics, endoplasmic reticulum (ER) stress and microglia-mediated neuroinflammation. We propose that PTP1B inhibition may represent an attractive and yet unexplored therapeutic approach to correct aberrant signaling pathways linked to AD. PMID:28197094

  2. Patterns of diversification of Afrotropical Otiteselline fig wasps: phylogenetic study reveals a double radiation across host figs and conservatism of host association.

    PubMed

    Jousselin, E; Van Noort, S; Rasplus, J-Y; Greeff, J M

    2006-01-01

    We studied the phylogenetic relationships of Otiteselline fig waSPS associated with Ficus in the Afrotropical region using rDNA sequences. African fig species usually host two species of Otiteselline fig waSPS. Phylogenetic analyses reveal that this pattern of association results from the radiation of two clades of waSPS superimposed on the fig system. Within each clade, wasp species generally cluster according to their host classification. The phylogenies of the two clades are also generally more congruent than expected by chance. Together these results suggest that Otiteselline wasp speciation is largely constrained by the diversification of their hosts. Finally, we show a difference in ovipositor length between the two Otiteselline species coexisting in the same Ficus species, which probably corresponds to ecological differences. The diversification of ecological niches within the fig is probably, with cospeciation, one of the key factors explaining the diversification and maintenance of species of parasites of the fig/pollinator system.

  3. Phenological Adaptations in Ficus tikoua Exhibit Convergence with Unrelated Extra-Tropical Fig Trees

    PubMed Central

    Zhao, Ting-Ting; Compton, Stephen G.; Yang, Yong-Jiang; Wang, Rong; Chen, Yan

    2014-01-01

    Flowering phenology is central to the ecology and evolution of most flowering plants. In highly-specific nursery pollination systems, such as that involving fig trees (Ficus species) and fig wasps (Agaonidae), any mismatch in timing has serious consequences because the plants must balance seed production with maintenance of their pollinator populations. Most fig trees are found in tropical or subtropical habitats, but the dioecious Chinese Ficus tikoua has a more northerly distribution. We monitored how its fruiting phenology has adapted in response to a highly seasonal environment. Male trees (where fig wasps reproduce) had one to three crops annually, whereas many seed-producing female trees produced only one fig crop. The timing of release of Ceratosolen fig wasps from male figs in late May and June was synchronized with the presence of receptive figs on female trees, at a time when there were few receptive figs on male trees, thereby ensuring seed set while allowing remnant pollinator populations to persist. F. tikoua phenology has converged with those of other (unrelated) northern Ficus species, but there are differences. Unlike F. carica in Europe, all F. tikoua male figs contain male flowers, and unlike F. pumila in China, but like F. carica, it is the second annual generation of adult wasps that pollinate female figs. The phenologies of all three temperate fig trees generate annual bottlenecks in the size of pollinator populations and for female F. tikoua also a shortage of fig wasps that results in many figs failing to be pollinated. PMID:25474008

  4. Phenological adaptations in Ficus tikoua exhibit convergence with unrelated extra-tropical fig trees.

    PubMed

    Zhao, Ting-Ting; Compton, Stephen G; Yang, Yong-Jiang; Wang, Rong; Chen, Yan

    2014-01-01

    Flowering phenology is central to the ecology and evolution of most flowering plants. In highly-specific nursery pollination systems, such as that involving fig trees (Ficus species) and fig wasps (Agaonidae), any mismatch in timing has serious consequences because the plants must balance seed production with maintenance of their pollinator populations. Most fig trees are found in tropical or subtropical habitats, but the dioecious Chinese Ficus tikoua has a more northerly distribution. We monitored how its fruiting phenology has adapted in response to a highly seasonal environment. Male trees (where fig wasps reproduce) had one to three crops annually, whereas many seed-producing female trees produced only one fig crop. The timing of release of Ceratosolen fig wasps from male figs in late May and June was synchronized with the presence of receptive figs on female trees, at a time when there were few receptive figs on male trees, thereby ensuring seed set while allowing remnant pollinator populations to persist. F. tikoua phenology has converged with those of other (unrelated) northern Ficus species, but there are differences. Unlike F. carica in Europe, all F. tikoua male figs contain male flowers, and unlike F. pumila in China, but like F. carica, it is the second annual generation of adult wasps that pollinate female figs. The phenologies of all three temperate fig trees generate annual bottlenecks in the size of pollinator populations and for female F. tikoua also a shortage of fig wasps that results in many figs failing to be pollinated.

  5. Expression and evolutionary divergence of the non-conventional olfactory receptor in four species of fig wasp associated with one species of fig

    PubMed Central

    Lu, Bin; Wang, Nina; Xiao, Jinhua; Xu, Yongyu; Murphy, Robert W; Huang, Dawei

    2009-01-01

    Background The interactions of fig wasps and their host figs provide a model for investigating co-evolution. Fig wasps have specialized morphological characters and lifestyles thought to be adaptations to living in the fig's syconium. Although these aspects of natural history are well documented, the genetic mechanism(s) underlying these changes remain(s) unknown. Fig wasp olfaction is the key to host-specificity. The Or83b gene class, an unusual member of olfactory receptor family, plays a critical role in enabling the function of conventional olfactory receptors. Four Or83b orthologous genes from one pollinator (PFW) (Ceratosolen solmsi) and three non-pollinator fig wasps (NPFWs) (Apocrypta bakeri, Philotrypesis pilosa and Philotrypesis sp.) associated with one species of fig (Ficus hispida) can be used to better understand the molecular mechanism underlying the fig wasp's adaptation to its host. We made a comparison of spatial tissue-specific expression patterns and substitution rates of one orthologous gene in these fig wasps and sought evidence for selection pressures. Results A newly identified Or83b orthologous gene was named Or2. Expressions of Or2 were restricted to the heads of all wingless male fig wasps, which usually live in the dark cavity of a fig throughout their life cycle. However, expressions were widely detected in the antennae, legs and abdomens of all female fig wasps that fly from one fig to another for oviposition, and secondarily pollination. Weak expression was also observed in the thorax of PFWs. Compared with NPFWs, the Or2 gene in C. solmsi had an elevated rate of substitutions and lower codon usage. Analyses using Tajima's D, Fu and Li's D* and F* tests indicated a non-neutral pattern of nucleotide variation in all fig wasps. Unlike in NPFWs, this non-neutral pattern was also observed for synonymous sites of Or2 within PFWs. Conclusion The sex- and species-specific expression patterns of Or2 genes detected beyond the known primary

  6. A functional null mutation of SCN1B in a patient with Dravet syndrome.

    PubMed

    Patino, Gustavo A; Claes, Lieve R F; Lopez-Santiago, Luis F; Slat, Emily A; Dondeti, Raja S R; Chen, Chunling; O'Malley, Heather A; Gray, Charles B B; Miyazaki, Haruko; Nukina, Nobuyuki; Oyama, Fumitaka; De Jonghe, Peter; Isom, Lori L

    2009-08-26

    Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-) versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.

  7. Practical route to the left wing of CTX1B and total syntheses of CTX1B and 54-deoxyCTX1B.

    PubMed

    Yamashita, Shuji; Takeuchi, Katsutoshi; Koyama, Takuya; Inoue, Masayuki; Hayashi, Yujiro; Hirama, Masahiro

    2015-02-02

    Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant-sensitive bisallylic ether moiety, by a 6-exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B.

  8. Kinetics and Mechanism of Protein Tyrosine Phosphatase 1B (PTP1B) Inactivation by Acrolein

    PubMed Central

    Seiner, Derrick R.; LaButti, Jason N.; Gates, Kent S.

    2010-01-01

    Human cells are exposed to the electrophilic α,β-unsaturated aldehyde acrolein from a variety of sources. Reaction of acrolein with functionally critical protein thiol residues can yield important biological consequences. Protein tyrosine phosphatases (PTPs) are an important class of cysteine-dependent enzymes whose reactivity with acrolein previously has not been well characterized. These enzymes catalyze the dephosphorylation of phosphotyrosine residues on proteins via a phosphocysteine intermediate. PTPs work in tandem with protein tyrosine kinases to regulate a number of critically important mammalian signal transduction pathways. We find that acrolein is a potent time-dependent inactivator of the enzyme PTP1B (kinact = 0.02 ± 0.005 s−1, KI = 2.3 ± 0.6 × 10−4 M). Enzyme activity does not return upon gel filtration of the inactivated enzyme and addition of the competitive phosphatase inhibitor vanadate slows inactivation of PTP1B by acrolein. Together these observations suggest that acrolein covalently modifies the active site of PTP1B. Mass spectrometric analysis reveals that acrolein modifies the catalytic cysteine residue at the active site of the enzyme. Aliphatic aldehydes such as glyoxal, acetaldehyde, and propanal are relatively weak inactivators of PTP1B under the conditions employed here. Similarly, unsaturated aldehydes such as crotonaldehyde and 3-methyl-2-butenal bearing substitution at the alkene terminus are poor inactivators of the enzyme. Overall, the data suggest that enzyme inactivation occurs via conjugate addition of the catalytic cysteine residue to the carbon-carbon double bond of acrolein. The results indicate that inactivation of PTPs should be considered as a possible contributor to the diverse biological activities of acrolein and structurally-related α,β-unsaturated aldehydes. PMID:17655273

  9. AP-1/σ1B-adaptin mediates endosomal synaptic vesicle recycling, learning and memory

    PubMed Central

    Glyvuk, Nataliya; Tsytsyura, Yaroslav; Geumann, Constanze; D'Hooge, Rudi; Hüve, Jana; Kratzke, Manuel; Baltes, Jennifer; Böning, Daniel; Klingauf, Jürgen; Schu, Peter

    2010-01-01

    Synaptic vesicle recycling involves AP-2/clathrin-mediated endocytosis, but it is not known whether the endosomal pathway is also required. Mice deficient in the tissue-specific AP-1–σ1B complex have impaired synaptic vesicle recycling in hippocampal synapses. The ubiquitously expressed AP-1–σ1A complex mediates protein sorting between the trans-Golgi network and early endosomes. Vertebrates express three σ1 subunit isoforms: A, B and C. The expressions of σ1A and σ1B are highest in the brain. Synaptic vesicle reformation in cultured neurons from σ1B-deficient mice is reduced upon stimulation, and large endosomal intermediates accumulate. The σ1B-deficient mice have reduced motor coordination and severely impaired long-term spatial memory. These data reveal a molecular mechanism for a severe human X-chromosome-linked mental retardation. PMID:20203623

  10. Olfactive detection of fig wasps as prey by the ant Crematogaster scutellaris (Formicidae; Myrmicinae).

    PubMed

    Schatz, Bertrand; Anstett, Marie-Charlotte; Out, Welmoed; Hossaert-McKey, Martine

    2003-10-01

    In the species-specific and obligate mutualism between the fig (Ficus carica) and its pollinator (the fig wasps Blastophaga psenes), a third participant, the ant Crematogaster scutellaris, is a predator of the wasps. Here, we ask how ant workers can rapidly localise such prey, whose availability is limited in time and space. Using a Y-tube olfactometer, we tested ant response to odours emitted by different types of figs (receptive female, ripe female or male figs) and by fig wasps (pollinators or non-pollinators). We demonstrate that ants were significantly attracted only to odours emitted by pollinators, either alone or associated with odours of male figs (releasing wasps). Detection of prey odour by ants is an important trait that can explain their observed high rate of predation on pollinators, and could have important implications on the stability of the fig/fig wasp mutualism.

  11. The incidence and pattern of copollinator diversification in dioecious and monoecious figs

    PubMed Central

    Yang, Li-Yuan; Machado, Carlos A; Dang, Xiao-Dong; Peng, Yan-Qiong; Yang, Da-Rong; Zhang, Da-Yong; Liao, Wan-Jin

    2015-01-01

    Differences in breeding system are associated with correlated ecological and morphological changes in plants. In Ficus, dioecy and monoecy are strongly associated with different suites of traits (tree height, population density, fruiting frequency, pollinator dispersal ecology). Although approximately 30% of fig species are pollinated by multiple species of fig-pollinating wasps, it has been suggested that copollinators are rare in dioecious figs. Here, we test whether there is a connection between the fig breeding system and copollinator incidence and diversification by conducting a meta-analysis of molecular data from pollinators of 119 fig species that includes new data from 15 Asian fig species. We find that the incidence of copollinators is not significantly different between monoecious and dioecious Ficus. Surprisingly, while all copollinators in dioecious figs are sister taxa, only 32.1% in monoecious figs are sister taxa. We present hypotheses to explain those patterns and discuss their consequences on the evolution of this mutualism. PMID:25495152

  12. Sensory profiles for dried fig (Ficus carica L.) cultivars commercially grown and processed in California.

    PubMed

    Haug, Megan T; King, Ellena S; Heymann, Hildegarde; Crisosto, Carlos H

    2013-08-01

    A trained sensory panel evaluated the 6 fig cultivars currently sold in the California dried fig market. The main flavor and aroma attributes determined by the sensory panel were "caramel," "honey," "raisin," and "fig," with additional aroma attributes: "common date," "dried plum," and "molasses." Sensory differences were observed between dried fig cultivars. All figs were processed by 2 commercial handlers. Processing included potassium sorbate as a preservative and SO2 application as an antibrowning agent for white cultivars. As a consequence of SO2 use during processing, high sulfite residues affected the sensory profiles of the white dried fig cultivars. Significant differences between dried fig cultivars and sources demonstrate perceived differences between processing and storage methods. The panel-determined sensory lexicon can help with California fig marketing.

  13. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  14. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  15. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  16. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.9 Confidentiality of...

  17. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  18. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  19. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.20 Request...

  20. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  1. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.9 Confidentiality of...

  2. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.20 Request...

  3. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  4. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  5. 7 CFR 1b.4 - Exclusion of agencies.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Exclusion of agencies. 1b.4 Section 1b.4 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.4 Exclusion of agencies. (a... activities that have been found to have no individual or cumulative effect on the human environment. The...

  6. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  7. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  8. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  9. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  10. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  11. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  12. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  13. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  14. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  15. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  16. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  17. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  18. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  19. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  20. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  1. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  2. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  3. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  4. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  5. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  6. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  7. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  8. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  9. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  10. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  11. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  12. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  13. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  14. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  15. Identifying and structurally characterizing CD1b in Aotus nancymaae owl monkeys.

    PubMed

    Castillo, Fabio; Guerrero, Carlos; Trujillo, Esperanza; Delgado, Gabriela; Martinez, Pilar; Salazar, Luz M; Barato, Paola; Patarroyo, Manuel E; Parra-López, Carlos

    2004-10-01

    This study reports the molecular characterization and tissue expression of the non-human Aotus nancymaae primate CD1b isoform in the search for an experimental animal model to be used in evaluating the role of non-peptide antigen-presentation molecules in the immune response to infectious agents. CD1b expression on the surface of A. nancymaae peripheral blood monocyte-derived dendritic cells, shown by flow cytometry, was made possible by using human CD1b isoform antibodies. Studying the expression of CD1b-encoded transcripts revealed this molecule's broad distribution in several tissues. The A. nancymaae CD1b transcript-encoded amino-acid sequence showed 95.5% identity with the human sequence. Such high sequence homology was reflected in the identical structural conservation of how pockets A', C' and F' and tunnel T' conforming the antigen's binding site are organized, the similar arrangement of those amino-acids interacting with the T-cell receptor (TCR) during antigen presentation, and the conservation of YQNI-motif sequence in the cytoplasmatic tail (responsible for the molecule's intracellular trafficking in humans). Comparing the structure of human CD1a and CD1b and mouse CD1d proteins with CD1b structure in A. nancymaae obtained by minimization revealed that changes in the latter molecule's alpha1 and alpha2 domains imposed a narrowing of the antigen-binding groove in A. nancymaae CD1b. The high structural similarity between A. nancymaae CD1b and that from humans presented in this study leads to A. nancymaae being proposed as a suitable experimental animal model for analyzing CD1b in vivo, mainly in bacterial and parasite infections such as tuberculosis and malaria, respectively.

  16. Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A

    PubMed Central

    Gupta, Swati; Fahiminiya, Somayyeh; Wang, Tracy; Dempsey Nunez, Laura; Rosenblatt, David S.; Gibson, William T.; Gilfix, Brian; Bergeron, John J. M.; Jerome-Majewska, Loydie A.

    2016-01-01

    Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (p.M400I) and MAN1B1 c.1000C>T (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in SEC23A only. Mutations in SEC23A are responsible for craniolenticosultura dysplasia (CLSD). CLSD patients are short, have late-closing fontanels, and have reduced procollagen (pro-COL1A1) secretion because of abnormal pro-COL1A1 retention in the endoplasmic reticulum (ER). The mutation we identified in MAN1B1 was previously associated with reduced MAN1B1 protein and congenital disorders of glycosylation (CDG). CDG patients are also short, are obese, and have abnormal glycan remodeling. Molecular analysis of fibroblasts from the family revealed normal levels of SEC23A in all cells and reduced levels of MAN1B1 in cells with heterozygous or homozygous mutations in SEC23A and MAN1B1. Secretion of pro-COL1A1 was increased in fibroblasts from the siblings and patients, and pro-COL1A1 was retained in Golgi of heterozygous and homozygous mutant cells, although intracellular pro-COL1A1 was increased in patient fibroblasts only. We postulate that increased pro-COL1A1 secretion is responsible for tall stature in these patients and an unaffected sibling, and not previously discovered in patients with mutations in either SEC23A or MAN1B1. The patients in this study share biochemical and cellular characteristics consistent with mutations in MAN1B1 and SEC23A, indicating a digenic disease. PMID:27148587

  17. Tracking the elusive history of diversification in plant-herbivorous insect-parasitoid food webs: insights from figs and fig wasps.

    PubMed

    Kjellberg, Finn; Proffit, Magali

    2016-02-01

    The food webs consisting of plants, herbivorous insects and their insect parasitoids are a major component of terrestrial biodiversity. They play a central role in the functioning of all terrestrial ecosystems, and the number of species involved is mind-blowing (Nyman et al. 2015). Nevertheless, our understanding of the evolutionary and ecological determinants of their diversity is still in its infancy. In this issue of Molecular Ecology, Sutton et al. (2016) open a window into the comparative analysis of spatial genetic structuring in a set of comparable multitrophic models, involving highly species-specific interactions: figs and fig wasps. This is the first study to compare genetic structure using population genetics tools in a fig-pollinating wasp (Pleistodontes imperialis sp1) and its main parasitoid (Sycoscapter sp.A). The fig-pollinating wasp has a discontinuous spatial distribution that correlates with genetic differentiation, while the parasitoid bridges the discontinuity by parasitizing other pollinator species on the same host fig tree and presents basically no spatial genetic structure. The full implications of these results for our general understanding of plant-herbivorous insect-insect parasitoids diversification become apparent when envisioned within the framework of recent advances in fig and fig wasp biology.

  18. Equal Educational Opportunity: Hearings Before the Select Committee on Equal Educational Opportunity of the United States Senate, Ninety-First Congress, Second Session on Equal Educational Opportunity. Parts 1A, 1B, 2, 3A, 3B, 3C, and 3D.

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. Senate Select Committee on Equal Educational Opportunity.

    These hearings before the Senate Select Committee on Equal Educational Opportunity are organized in three parts, the contents of which are as follows: Part 1A and Part 2 comprise the "Introduction," with opening statements by a number of Senators, followed by the presentations of other witnesses. The focus of these two parts is on such…

  19. Development of molecular tools for characterization and genetic diversity analysis in Tunisian fig (Ficus carica) cultivars.

    PubMed

    Chatti, Khaled; Baraket, Ghada; Ben Abdelkrim, Ahmed; Saddoud, Olfa; Mars, Messaoud; Trifi, Mokhtar; Salhi Hannachi, Amel

    2010-10-01

    Fig, Ficus carica L., is a useful genetic resource for commercial cultivation. In this study, RAPD (60), ISSR (48), RAMPO (63), and SSR (34) markers were compared to detect polymorphism and to establish genetic relationships among Tunisian fig tree cultivars. The statistical procedures conducted on the combined data show considerable genetic diversity, and the tested markers discriminated all fig genotypes studied. The identification key established on the basis of SSR permitted the unambiguous discrimination of cultivars and confirmed the reliability of SSR for fingerprinting fig genotypes. The study findings are discussed in relation to the establishment of a national reference collection that will aid in the conservation of Tunisian fig resources.

  20. Multiple Horizontal Transfers of Bacteriophage WO and Host Wolbachia in Fig Wasps in a Closed Community

    PubMed Central

    Wang, Ningxin; Jia, Sisi; Xu, Heng; Liu, Yong; Huang, Dawei

    2016-01-01

    Wolbachia-bacteriophage WO is a good model system for studying interactions between bacteria and viruses. Previous surveys of insect hosts have been conducted via sampling from open or semi-open communities; however, no studies have reported the infection patterns of phage WO of insects living in a closed community. Figs and fig wasps form a peculiar closed community in which the Ficus tree provides a compact syconium habitat for a variety of fig wasp. Therefore, in this study, we performed a thorough survey of Wolbachia and bacteriophage WO infection patterns in a total of 1406 individuals from 23 fig wasps species living on three different fig tree species. The infection rates of Wolbachia and phage WO were 82.6% (19/23) and 39.1% (9/23), respectively. Additionally, phage WO from fig wasps showed strong insect host specificity based on orf7 sequences from fig wasps and 21 other insect species. Probably due to the physical barrier of fig syconium, most phage WO from fig wasps form a specific clade. Phylogenetic analysis showed the absence of congruence between WO and host Wolbachia, WO and insect host, as well as Wolbachia and fig wasps, suggesting that both Wolbachia and phage WO exchanged frequently and independently within the closed syconium. Thus, the infection pattern of bacteriophage WO from fig wasps appeared quite different from that in other insects living outside, although the effect and the transfer routes of phage WO are unclear, which need to be investigated in the future. PMID:26913026

  1. Multiple Horizontal Transfers of Bacteriophage WO and Host Wolbachia in Fig Wasps in a Closed Community.

    PubMed

    Wang, Ningxin; Jia, Sisi; Xu, Heng; Liu, Yong; Huang, Dawei

    2016-01-01

    Wolbachia-bacteriophage WO is a good model system for studying interactions between bacteria and viruses. Previous surveys of insect hosts have been conducted via sampling from open or semi-open communities; however, no studies have reported the infection patterns of phage WO of insects living in a closed community. Figs and fig wasps form a peculiar closed community in which the Ficus tree provides a compact syconium habitat for a variety of fig wasp. Therefore, in this study, we performed a thorough survey of Wolbachia and bacteriophage WO infection patterns in a total of 1406 individuals from 23 fig wasps species living on three different fig tree species. The infection rates of Wolbachia and phage WO were 82.6% (19/23) and 39.1% (9/23), respectively. Additionally, phage WO from fig wasps showed strong insect host specificity based on orf7 sequences from fig wasps and 21 other insect species. Probably due to the physical barrier of fig syconium, most phage WO from fig wasps form a specific clade. Phylogenetic analysis showed the absence of congruence between WO and host Wolbachia, WO and insect host, as well as Wolbachia and fig wasps, suggesting that both Wolbachia and phage WO exchanged frequently and independently within the closed syconium. Thus, the infection pattern of bacteriophage WO from fig wasps appeared quite different from that in other insects living outside, although the effect and the transfer routes of phage WO are unclear, which need to be investigated in the future.

  2. Spatial-Temporal Study of Rab1b Dynamics and Function at the ER-Golgi Interface.

    PubMed

    Martinez, Hernán; García, Iris A; Sampieri, Luciana; Alvarez, Cecilia

    2016-01-01

    The GTPase Rab1b is involved in ER to Golgi transport, with multiple Rab1b effectors (located at ERES, VTCs and the Golgi complex) being required for its function. In this study, we performed live-cell dual-expression studies to analyze the dynamics of Rab1b and some effectors located at the ERES-Golgi interface. Rab1b occupied widely distributed mobile punctate and tubular structures, displaying a transient overlaps with its effectors and showing that these overlaps occurred at the same time in spatially distinct steps of ER to Golgi transport. In addition, we assessed Rab1b dynamics during cargo sorting by analyzing the concentration at ERES of a Golgi protein (SialT2-CFP) during Brefeldin A washout (BFA WO). Rab1b was associated to most of the ERES structures, but at different times during BFA WO, and recurrently SialT2-CFP was sorted in the ERES-Rab1b positive structures. Furthermore, we reveal for first time that Rab1b localization time at ERES depended on GBF1, a Rab1b effector that acts as the guanine nucleotide exchange factor of Arf1, and that Rab1b membrane association/dissociation dynamics at ERES was dependent on the GBF1 membrane association and activity, which strongly suggests that GBF1 activity modulates Rab1b membrane cycling dynamic.

  3. Spatial-Temporal Study of Rab1b Dynamics and Function at the ER-Golgi Interface

    PubMed Central

    Martinez, Hernán; García, Iris A.; Sampieri, Luciana

    2016-01-01

    The GTPase Rab1b is involved in ER to Golgi transport, with multiple Rab1b effectors (located at ERES, VTCs and the Golgi complex) being required for its function. In this study, we performed live-cell dual-expression studies to analyze the dynamics of Rab1b and some effectors located at the ERES-Golgi interface. Rab1b occupied widely distributed mobile punctate and tubular structures, displaying a transient overlaps with its effectors and showing that these overlaps occurred at the same time in spatially distinct steps of ER to Golgi transport. In addition, we assessed Rab1b dynamics during cargo sorting by analyzing the concentration at ERES of a Golgi protein (SialT2-CFP) during Brefeldin A washout (BFA WO). Rab1b was associated to most of the ERES structures, but at different times during BFA WO, and recurrently SialT2-CFP was sorted in the ERES-Rab1b positive structures. Furthermore, we reveal for first time that Rab1b localization time at ERES depended on GBF1, a Rab1b effector that acts as the guanine nucleotide exchange factor of Arf1, and that Rab1b membrane association/dissociation dynamics at ERES was dependent on the GBF1 membrane association and activity, which strongly suggests that GBF1 activity modulates Rab1b membrane cycling dynamic. PMID:27500526

  4. Deep mtDNA divergences indicate cryptic species in a fig-pollinating wasp

    PubMed Central

    Haine, Eleanor R; Martin, Joanne; Cook, James M

    2006-01-01

    Background Figs and fig-pollinating wasps are obligate mutualists that have coevolved for ca 90 million years. They have radiated together, but do not show strict cospeciation. In particular, it is now clear that many fig species host two wasp species, so there is more wasp speciation than fig speciation. However, little is known about how fig wasps speciate. Results We studied variation in 71 fig-pollinating wasps from across the large geographic range of Ficus rubiginosa in Australia. All wasps sampled belong to one morphological species (Pleistodontes imperialis), but we found four deep mtDNA clades that differed from each other by 9–17% nucleotides. As these genetic distances exceed those normally found within species and overlap those (10–26%) found between morphologically distinct Pleistodontes species, they strongly suggest cryptic fig wasp species. mtDNA clade diversity declines from all four present in Northern Queensland to just one in Sydney, near the southern range limit. However, at most sites multiple clades coexist and can be found in the same tree or even the same fig fruit and there is no evidence for parallel sub-division of the host fig species. Both mtDNA data and sequences from two nuclear genes support the monophyly of the "P. imperialis complex" relative to other Pleistodontes species, suggesting that fig wasp divergence has occurred without any host plant shift. Wasps in clade 3 were infected by a single strain (W1) of Wolbachia bacteria, while those in other clades carried a double infection (W2+W3) of two other strains. Conclusion Our study indicates that cryptic fig-pollinating wasp species have developed on a single host plant species, without the involvement of host plant shifts, or parallel host plant divergence. Despite extensive evidence for coevolution between figs and fig wasps, wasp speciation may not always be linked strongly with fig speciation. PMID:17040562

  5. Selectivity and potency of microcystin congeners against OATP1B1 and OATP1B3 expressing cancer cells.

    PubMed

    Niedermeyer, Timo H J; Daily, Abigail; Swiatecka-Hagenbruch, Monika; Moscow, Jeffrey A

    2014-01-01

    Microcystins are potent phosphatase inhibitors and cellular toxins. They require active transport by OATP1B1 and OATP1B3 transporters for uptake into human cells, and the high expression of these transporters in the liver accounts for their selective hepatic toxicity. Several human tumors have been shown to have high levels of expression of OATP1B3 but not OATP1B1, the main transporter in liver cells. We hypothesized that microcystin variants could be isolated that are transported preferentially by OATP1B3 relative to OATP1B1 to advance as anticancer agents with clinically tolerable hepatic toxicity. Microcystin variants have been isolated and tested for cytotoxicity in cancer cells stably transfected with OATP1B1 and OATP1B3 transporters. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. As microcystin structure has a significant impact on transporter selectivity, it is potentially possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs.

  6. SMC1B is present in mammalian somatic cells and interacts with mitotic cohesin proteins

    PubMed Central

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Amato, Clelia; Tinti, Mara; Tana, Luigi; Frattini, Annalisa; Delia, Domenico; Krantz, Ian D.; Jessberger, Rolf; Musio, Antonio

    2015-01-01

    Cohesin is an evolutionarily conserved protein complex that plays a role in many biological processes: it ensures faithful chromosome segregation, regulates gene expression and preserves genome stability. In mammalian cells, the mitotic cohesin complex consists of two structural maintenance of chromosome proteins, SMC1A and SMC3, the kleisin protein RAD21 and a fourth subunit either STAG1 or STAG2. Meiotic paralogs in mammals were reported for SMC1A, RAD21 and STAG1/STAG2 and are called SMC1B, REC8 and STAG3 respectively. It is believed that SMC1B is only a meiotic-specific cohesin member, required for sister chromatid pairing and for preventing telomere shortening. Here we show that SMC1B is also expressed in somatic mammalian cells and is a member of a mitotic cohesin complex. In addition, SMC1B safeguards genome stability following irradiation whereas its ablation has no effect on chromosome segregation. Finally, unexpectedly SMC1B depletion impairs gene transcription, particularly at genes mapping to clusters such as HOX and PCDHB. Genome-wide analyses show that cluster genes changing in expression are enriched for cohesin-SMC1B binding. PMID:26673124

  7. Cooperative Stimulation of Megakaryocytic Differentiation by Gfi1b Gene Targets Kindlin3 and Talin1

    PubMed Central

    Singh, Divya; Upadhyay, Ghanshyam; Sengupta, Ananya; Biplob, Mohammed A.; Chakyayil, Shaleen; George, Tiji; Saleque, Shireen

    2016-01-01

    Understanding the production and differentiation of megakaryocytes from progenitors is crucial for realizing the biology and functions of these vital cells. Previous gene ablation studies demonstrated the essential role of the transcriptional repressor Gfi1b (growth factor independence 1b) in the generation of both erythroid and megakaryocytic cells. However, our recent work has demonstrated the down-regulation of this factor during megakaryocytic differentiation. In this study we identify two new gene targets of Gfi1b, the cytoskeletal proteins Kindlin3 and Talin1, and demonstrate the inverse expression and functions of these cytoskeletal targets relative to Gfi1b, during megakaryocytic differentiation. Both kindlin3 and talin1 promoters exhibit dose dependent Gfi1b and LSD1 (lysine specific demethylase 1; a Gfi1b cofactor) enrichment in megakaryocytes and repression in non-hematopoietic cells. Accordingly the expression of these genes is elevated in gfi1b mutant and LSD1 inhibited hematopoietic cells, while during megakaryocytic differentiation, declining Gfi1b levels fostered the reciprocal upregulation of these cytoskeletal factors. Concordantly, manipulation of Kindlin3 and Talin1 expression demonstrated positive correlation with megakaryocytic differentiation with over-expression stimulating, and inhibition diminishing, this process. Co-operativity between these factors and integrins in promoting differentiation was further underscored by physical interactions between them and integrinβ3/CD61 and by stimulation of differentiation by the Talin1 head domain, which is necessary and sufficient for integrin activation. Therefore this study demonstrates the significance of Gfi1b regulated Kindlin3-Talin1 expression in driving megakaryocytic differentiation and highlights the contribution of cytoskeletal agents in the developmental progression of these platelet progenitors. PMID:27768697

  8. Relative investment in egg load and poison sac in fig wasps: Implications for physiological mechanisms underlying seed and wasp production in figs

    NASA Astrophysics Data System (ADS)

    Martinson, Ellen O.; Jandér, K. Charlotte; Peng, Yan-Qiong; Chen, Huan-Huan; Machado, Carlos A.; Arnold, A. Elizabeth; Herre, Edward Allen

    2014-05-01

    Fig pollinating wasps and most non-pollinator wasps apply secretions from their poison sacs into oviposited flowers that appear necessary to the formation of the galls that their developing offspring consume. Thus, both eggs and poison sac secretions appear to be essential for wasp reproduction, but the relative investment in each is unknown. We measured relative investment in poison sac and egg production in pollinating and non-pollinating wasps associated with seven species of monoecious Panamanian figs representing both active and passive pollination syndromes. We then collected similar data for four fig hosts in China, where some wasp species in the genus Eupristina have lost the ability to pollinate ("cheaters"). All wasps examined possessed large poison sacs, and we found a strong positive correlation between poison sac size and absolute egg production. In the Panamanian species, the relative poison sac to egg investment was highest in the externally ovipositing non-pollinator wasps, followed by active pollinators, then by passive pollinators. Further, pollinator wasps of fig species with demonstrated host sanctions against "cheating" wasps showed higher investment in the poison sac than wasps of species without sanctions. In the Chinese samples, relative investment in the poison sac was indistinguishable between pollinators and "cheaters" associated with the same fig species. We suggest that higher relative investment in poison sac across fig wasp species reflects higher relative difficulty in initiating formation of galls and subsequently obtaining resources from the fig. We discuss the implications for the stability of the fig-wasp mutualism, and for the ability of non-pollinators to exploit this mutualism.

  9. The Response of Marine Biota to OAE 1b

    NASA Astrophysics Data System (ADS)

    Herrle, J. O.

    2006-12-01

    The latest Aptian to earliest Albian is characterized by the first appearance of a distinctly modern phytoplankton community accompanied by a cold episode during a generally extreme greenhouse climate. Massive burial of organic matter caused the formation of the black shale `Niveaus' Jacob, Kilian, Paquier and Leenhardt in the Vocontian Basin (SE France). This interval is reported as the Oceanic Anoxic Event 1b (OAE1b) following the definition of Leckie et al. (2002). Lasting about four million years, OAE1b facilitates analysis of rapid climate change in a greenhouse world, and crucial for understanding climate change. During latest Aptian angiosperms and diatoms became abundant in the terrestrial and marine environments (Gersonde & Haywood 1990; Heimhofer et al. 2005). Planktic foraminifera experienced their greatest turnover rates since their first appearance, accompanied by a decrease in test size and changes of the ultrastructures of their shells (Leckie et al. 2002). Calcareous nannoplankton show a major change characterized by the influx of the boreal cool water indicator Repagulum parvidentatum into the Tethyan Realm (Herrle & Mutterlose 2003). Moreover, ammonite faunas became more cosmopolitan at the expense of Tethyan taxa during this period. Both the influx of boreal nannoplankton taxa and the trend to more cosmopolitian ammonite assemblages in the Tethyan Realm was probably favored by a long-term sea level rise accompanied by a global cooling during the late Aptian to early Albian interval. Most dramatic changes of the marine carbonate system are reflected by the stepwise decrease of nannoconids and carbonate platform drowning accompanied by a positive carbon isotope excursion which is similar to the biocalcification crisis associated with the early Aptian OAE1a (Erba 1994, Weissert et al., 1998). The massive change in the global carbon cycle is probably linked to a major change in global marine productivity from a calcareous system (nannoconids

  10. Same but different: Larval development and gall-inducing process of a non-pollinating fig wasp compared to that of pollinating fig-wasps

    NASA Astrophysics Data System (ADS)

    Jansen-González, Sergio; Teixeira, Simone de Padua; Kjellberg, Finn; Pereira, Rodrigo A. Santinelo

    2014-05-01

    The receptacles of fig trees (Ficus spp.) can harbor a highly diversified and complex community of chalcid wasps. Functional groups of fig wasps (e.g. gallers, cleptoparasites and parasitoids) oviposit into the fig at different developmental stages, reflecting different feeding regimes for these insect larvae. There are few direct data available on larval feeding regimes and access to resources. We studied the gall induction and larval feeding strategy of an Idarnes (group flavicollis) species, a non-pollinating fig wasp (NPFW) associated to Ficus citrifolia P. Miller in Brazil. This Idarnes species shares with the pollinator characteristics such as time of oviposition, ovipositor insertion through flower and location of the egg inside plant ovaries. Nevertheless, we show that the gall induction differs considerably from that of the pollinating species. This Idarnes species relies on the induction of nucellus cell proliferation for gall formation and as the main larval resource. This strategy enables it to develop in both pollinated and unpollinated figs. The large differences between this NPFW and other fig wasps in how ovules are galled suggest that there are different ways to be a galler. A functional analysis of NPFW community structure may require descriptions of the histological processes associated with larval development.

  11. Pollinator sharing and gene flow among closely related sympatric dioecious fig taxa.

    PubMed

    Wang, Gang; Cannon, Charles H; Chen, Jin

    2016-04-13

    Hybridization and insect pollination are widely believed to increase rates of plant diversification. The extreme diversity of figs (Ficus) and their obligate pollinators, fig wasps (Agaonidae), provides an opportunity to examine the possible role of pollinator-mediated hybridization in plant diversification. Increasing evidence suggests that pollinator sharing and hybridization occurs among fig taxa, despite relatively strict coevolution with the pollinating wasp. Using five sympatric dioecious fig taxa and their pollinators, we examine the degree of pollinator sharing and inter-taxa gene flow. We experimentally test pollinator preference for floral volatiles, the main host recognition signal, from different figs. All five fig taxa shared pollinators with other taxa, and gene flow occurred between fig taxa within and between sections. Floral volatiles of each taxon attracted more than one pollinator species. Floral volatiles were more similar between closely related figs, which experienced higher levels of pollinator sharing and inter-taxa gene flow. This study demonstrates that pollinator sharing and inter-taxa gene flow occurs among closely related sympatric dioecious fig taxa and that pollinators choose the floral volatiles of multiple fig taxa. The implications of pollinator sharing and inter-taxa gene flow on diversification, occurring even in this highly specialized obligate pollination system, require further study.

  12. Amyloid-beta peptide binds to microtubule-associated protein 1B (MAP1B).

    PubMed

    Gevorkian, Goar; Gonzalez-Noriega, Alfonso; Acero, Gonzalo; Ordoñez, Jorge; Michalak, Colette; Munguia, Maria Elena; Govezensky, Tzipe; Cribbs, David H; Manoutcharian, Karen

    2008-05-01

    Extracellular and intraneuronal formation of amyloid-beta aggregates have been demonstrated to be involved in the pathogenesis of Alzheimer's disease. However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of targets have deleterious effects on cellular functions. In the present study we have shown for the first time that amyloid-beta 1-42 bound to a peptide comprising the microtubule binding domain of the heavy chain of microtubule-associated protein 1B by the screening of a human brain cDNA library expressed on M13 phage. This interaction may explain, in part, the loss of neuronal cytoskeletal integrity, impairment of microtubule-dependent transport and synaptic dysfunction observed previously in Alzheimer's disease.

  13. AMYLOID-β PEPTIDE BINDS TO MICROTUBULE-ASSOCIATED PROTEIN 1B (MAP1B)

    PubMed Central

    Gevorkian, Goar; Gonzalez-Noriega, Alfonso; Acero, Gonzalo; Ordoñez, Jorge; Michalak, Colette; Munguia, Maria Elena; Govezensky, Tzipe; Cribbs, David H.; Manoutcharian, Karen

    2008-01-01

    Extracellular and intraneuronal formation of amyloid-beta aggregates have been demonstrated to be involved in the pathogenesis of Alzheimer’s disease. However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of targets have deleterious effects on cellular functions. In the present study we have shown for the first time that amyloid-beta 1-42 bound to a peptide comprising the microtubule binding domain of the heavy chain of microtubule-associated protein 1B by the screening of a human brain cDNA library expressed on M13 phage. This interaction may explain, in part, the loss of neuronal cytoskeletal integrity, impairment of microtubule-dependent transport and synaptic dysfunction observed previously in Alzheimer’s disease. PMID:18079022

  14. Curated human hyperbilirubinemia data and the respective OATP1B1 and 1B3 inhibition predictions.

    PubMed

    Kotsampasakou, Eleni; Escher, Sylvia E; Ecker, Gerhard F

    2017-04-01

    Hyperbilirubinemia is a pathological condition, very often indicative of underlying liver condition that is characterized by excessive accumulation of conjugated or unconjugated bilirubin in sinusoidal blood. In literature there are several indications associating the inhibition of the basolateral hepatic transporters Organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and 1B3) with hyperbilirubinemia. In this article, we present a curated human hyperbilirubinemia dataset and the respective OATP1B1 and 1B3 inhibition predictions obtained from an effort to generate a classification model for hyperbilirubinemia. These data originate from the research article "Linking organic anion transporting polypeptide 1b1 and 1b3 (oatp1b1 and oatp1b3) interaction profiles to hepatotoxicity- the hyperbilirubinemia use case" (E. Kotsampasakou, S.E. Escher, G.F. Ecker, 2017) [1]. We further provide the full list of descriptors used for generating the hyperbilirubinemia classification models as well as the calculated descriptors for each compound of the dataset that was used to build the classification model.

  15. Overexpression and enhanced specific activity of aldoketo reductases (AKR1B1 & AKR1B10) in human breast cancers.

    PubMed

    Reddy, K Ashok; Kumar, P Uday; Srinivasulu, M; Triveni, B; Sharada, K; Ismail, Ayesha; Reddy, G Bhanuprakash

    2017-02-01

    The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors.

  16. Distinct Features of Cap Binding by eIF4E1b Proteins

    PubMed Central

    Kubacka, Dorota; Miguel, Ricardo Núñez; Minshall, Nicola; Darzynkiewicz, Edward; Standart, Nancy; Zuberek, Joanna

    2015-01-01

    eIF4E1b, closely related to the canonical translation initiation factor 4E (eIF4E1a), cap-binding protein is highly expressed in mouse, Xenopus and zebrafish oocytes. We have previously characterized eIF4E1b as a component of the CPEB mRNP translation repressor complex along with the eIF4E-binding protein 4E-Transporter, the Xp54/DDX6 RNA helicase and additional RNA-binding proteins. eIF4E1b exhibited only very weak interactions with m7GTP-Sepharose and, rather than binding eIF4G, interacted with 4E-T. Here we undertook a detailed examination of both Xenopus and human eIF4E1b interactions with cap analogues using fluorescence titration and homology modeling. The predicted structure of eIF4E1b maintains the α + β fold characteristic of eIF4E proteins and its cap-binding pocket is similarly arranged by critical amino acids: Trp56, Trp102, Glu103, Trp166, Arg112, Arg157 and Lys162 and residues of the C-terminal loop. However, we demonstrate that eIF4E1b is 3-fold less well able to bind the cap than eIF4E1a, both proteins being highly stimulated by methylation at N7 of guanine. Moreover, eIF4E1b proteins are distinguishable from eIF4E1a by a set of conserved amino acid substitutions, several of which are located near to cap-binding residues. Indeed, eIF4E1b possesses several distinct features, namely, enhancement of cap binding by a benzyl group at N7 position of guanine, a reduced response to increasing length of the phosphate chain and increased binding to a cap separated by a linker from Sepharose, suggesting differences in the arrangement of the protein's core. In agreement, mutagenesis of the amino acids differentiating eIF4E1b from eIF4E1a reduces cap binding by eIF4E1a 2-fold, demonstrating their role in modulating cap binding. PMID:25463438

  17. Utilisation of chemical signals by inquiline wasps in entering their host figs.

    PubMed

    Gu, Ding; Yang, Da-Rong

    2013-10-01

    The fig tree, Ficus curtipes, hosts an obligate pollinating wasp, an undescribed Eupristina sp., but can also be pollinated by two inquiline (living in the burrow, nest, gall, or other habitation of another animal) wasps, Diaziella yangi and an undescribed Lipothymus sp. The two inquilines are unable to independently induce galls and depend on the galls induced by the obligate pollinator for reproduction and, therefore, normally enter receptive F. curtipes figs colonised by the obligate pollinators. However, sometimes the inquilines also enter figs that are not colonised by the pollinators, despite consequent reproductive failure. It is still unknown which signal(s) the inquilines use in entering the colonised and non-colonised figs. We conducted behavioural experiments to investigate several possible signals utilised by the inquilines in entering their host receptive figs. Our investigation showed that both inquiline species enter the receptive F. curtipes figs in response to the body odours of the obligate wasps and one of the main compounds emitted by the figs, 6-methyl-5-hepten-2-one. The compound was not found in the pollinator body odours, suggesting that the two inquiline wasps can utilise two signals to enter their host figs, which is significant for the evolution of the fig-fig wasp system. These inquilines could evolve to become mutualists of the figs if they evolve the ability to independently gall fig flowers; there is, however, another possibility that a monoecious Ficus species hosting such inquilines may evolve into a dioecious one if these inquilines cannot evolve the above-mentioned ability. Additionally, this finding provides evidence for the evolution of chemical communication between plants and insects.

  18. Caprine herpesvirus 1 (CpHV-1) vaginal infection of goats: clinical efficacy of fig latex.

    PubMed

    Camero, Michele; Marinaro, Mariarosaria; Losurdo, Michele; Larocca, Vittorio; Bodnar, Livia; Patruno, Giovanni; Buonavoglia, Canio; Tempesta, Maria

    2016-01-01

    The latex of Ficus carica Linn. (Moraceae) has been shown to interfere with the replication of caprine herpesvirus (CpHV)-1 in vitro. The present study was undertaken to determine the efficacy of vaginal administration of fig latex in goats experimentally infected with CpHV-1. The fig latex reduced the clinical signs of the herpetic disease although it slightly influenced the titres of CpHV-1 shed. Thus, the fig latex maintained a partial efficacy in vivo.

  19. Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

    PubMed Central

    Ni, Wenjun; Ji, Jia; Dai, Zunyan; Papp, Audrey; Johnson, Amy J.; Ahn, Sunjoo; Farley, Katherine L.; Lin, Thomas S.; Dalton, James T.; Li, Xiaobai; Jarjoura, David; Byrd, John C.; Sadee, Wolfgang; Grever, Michael R.; Phelps, Mitch A.

    2010-01-01

    Background Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy. Methodology/Principal Findings Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent. Conclusions/Significance Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other

  20. ARID1B-mediated disorders: Mutations and possible mechanisms

    PubMed Central

    Sim, Joe C. H.; White, Susan M; Lockhart, Paul J.

    2015-01-01

    Summary Mutations in the gene encoding AT-rich interactive domain-containing protein 1B (ARID1B) were recently associated with multiple syndromes characterized by developmental delay and intellectual disability, in addition to nonsyndromic intellectual disability. While the majority of ARID1B mutations identified to date are predicted to result in haploinsufficiency, the underlying pathogenic mechanisms have yet to be fully understood. ARID1B is a DNA-binding subunit of the Brahma-associated factor chromatin remodelling complexes, which play a key role in the regulation of gene activity. The function of remodelling complexes can be regulated by their subunit composition, and there is some evidence that ARID1B is a component of the neuron-specific chromatin remodelling complex. This complex is involved in the regulation of stem/progenitor cells exiting the cell cycle and differentiating into postmitotic neurons. Recent research has indicated that alterations in the cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency in fibroblasts derived from affected individuals. This review describes studies linking ARID1B to neurodevelopmental disorders and it summarizes the function of ARID1B to provide insights into the pathogenic mechanisms underlying ARID1B-mediated disorders. In conclusion, ARID1B is likely to play a key role in neurodevelopment and reduced levels of wild-type protein compromise normal brain development. Additional studies are required to determine the mechanisms by which impaired neural development contributes to the intellectual disability and speech impairment that are consistently observed in individuals with ARID1B haploinsufficiency. PMID:25674384

  1. Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

    PubMed Central

    Jiang, Cheng-shi; Liang, Lin-fu; Guo, Yue-wei

    2012-01-01

    This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented. PMID:22941286

  2. Host range of the potential biopesticide Pea Albumin 1b (PA1b) is limited to insects.

    PubMed

    Rahioui, Isabelle; Eyraud, Vanessa; Karaki, Lamis; Sasse, Florenz; Carre-Pierrat, Maïté; Qin, An; Zheng, Ming H; Toepfer, Stefan; Sivignon, Catherine; Royer, Corinne; Da Silva, Pedro; Gressent, Frédéric

    2014-10-01

    The Pea Albumin 1 subunit b (PA1b) peptide is an entomotoxin extracted from legume seeds with lethal activity towards several insect pests. Its toxic activity occurs after the perception of PA1b by a plasmalemmic proton pump (V-ATPase) in the insects. Assays revealed that PA1b showed no activity towards mammalian cells displaying high V-ATPase activity. Similarly, PA1b displayed no binding activity and no biological activity towards other non-insect organisms. We demonstrate here that binding to labelled PA1b was found in all the insect families tested, regardless of the sensitivity or insensitivity of the individual species. The coleopteran Bruchidae, which are mainly legume seed pests, were found to be fully resistant. A number of insect species were seen to be insensitive to the toxin although they exhibited binding activity for the labelled PA1b. The fruit fly, Drosophila melanogaster (Diptera), was generally insensitive when maintained on an agar diet, but the fly appeared to be sensitive to PA1b in bioassays using a different diet. In conclusion, the PA1b toxin provides legumes with a major source of resistance to insects, and insects feeding on legume seeds need to overcome this plant resistance by disrupting the PA1b - V-ATPase interaction.

  3. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  4. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  5. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  6. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... of facts or memoranda of law for the purpose of explaining said person's position or...

  7. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... investigations should set forth the alleged violation of law with supporting documentation and information...

  8. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... of facts or memoranda of law for the purpose of explaining said person's position or...

  9. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... laws of the United States and the regulations of the Commission. Investigating Officers shall have...

  10. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... laws of the United States and the regulations of the Commission. Investigating Officers shall have...

  11. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... investigations should set forth the alleged violation of law with supporting documentation and information...

  12. Acute myelogenous leukemia and glycogen storage disease 1b.

    PubMed

    Pinsk, Maury; Burzynski, Jeffrey; Yhap, Margaret; Fraser, Robert B; Cummings, Brian; Ste-Marie, Micheline

    2002-12-01

    Glycogen storage disease 1b (GSD 1b) is caused by a deficiency of glucose-6-phosphate translocase and the intracellular accumulation of glycogen. The disease presents with failure to thrive, hepatomegaly, hypoglycemia, lactic acidosis, as well as neutropenia causing increased susceptibility to pyogenic infections. We present a case of a young woman with GSD 1b who developed acute myelogenous leukemia while on long-term granulocyte colony-stimulating factor therapy. The presence of two rare diseases in a single patient raises suspicion that GSD 1b and acute myelogenous leukemia are linked. Surveillance for acute myelogenous leukemia should become part of the long-term follow-up for GSD 1b.

  13. Fentanyl pharmacokinetics is not dependent on hepatic uptake by organic anion-transporting polypeptide 1B1 in human beings.

    PubMed

    Ziesenitz, Victoria C; König, Sonja K; Mahlke, Nina; Jantos, Ricarda; Skopp, Gisela; Weiss, Johanna; Haefeli, Walter E; Mikus, Gerd

    2013-07-01

    A recent study investigating the pharmacokinetics of fentanyl in Sprague-Dawley rats suggested fentanyl to be a substrate of rat organic anion-transporting polypeptide Oatp. In human beings, the most important OATP for the pharmacokinetics of many drugs is OATP1B1. Therefore, genetic variants of OATP1B1 (SLCO1B1) might modulate fentanyl pharmacokinetics and efficacy in human beings. Sixteen healthy male and female volunteers, homozygous for SLCO1B1*1a (genetic wild-type) (n = 11) or *15 (deficient haplotype carrying the single-nucleotide polymorphisms rs2306283 and rs4149056 and exhibiting altered transport activity; n = 5), were included in this randomized crossover study. The participants received fentanyl (5 μg/kg) intravenously alone or with the OATP inhibitor rifampicin (600 mg single oral dose). The pharmacokinetics of fentanyl and norfentanyl were determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). In addition, fentanyl uptake in vitro was evaluated in OATP1B1 overexpressing HEK293 cells and compared to a mock-transfected cell line. In the clinical trial, fentanyl clearance was 18.8 ± 8.2 mL/min. kg in SLCO1B1*1a and 19.5 ± 1.8 mL/min/kg in SLCO1B1*15 carriers and not significantly different between the genotypes. During rifampicin, fentanyl clearance was 15.0 ± 4.4 mL/min/kg in SLCO1B1*1a and 16.7 ± 5.9 mL/min/kg in SLCO1B1*15 carriers (p > 0.5). In addition, in vitro data also indicate that fentanyl is not transported by OATP1B1. In conclusion, our data indicate that OATP1B1 has no impact on fentanyl pharmacokinetics in human beings.

  14. CYP1B1 and hormone-induced cancer.

    PubMed

    Gajjar, Ketan; Martin-Hirsch, Pierre L; Martin, Francis L

    2012-11-01

    Cancers in hormone-responsive tissues (e.g., breast, ovary, endometrium, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to date suggest that endogenous/exogenous oestrogen and environmental carcinogens may play a role in development and/or progression of hormone-induced cancers via oxidative oestrogen metabolism. Cytochrome P450 1B1 is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Although CYP1B1 is expressed in many cancers, particularly high levels of expression are observed in oestrogen-mediated disease. CYP1B1 is more readily found in tumour tissue compared to normal. Given the role of CYP1B1 in pro-carcinogen and oestrogen metabolism, polymorphisms in CYP1B1 could result in modifications in its enzyme activity and subsequently lead to hormone-mediated carcinogenesis. CYP1B1 may also be involved in progression of the disease by altering the tissue response to hormones and clinical response to chemotherapy. The exact mechanism behind these events is complex and unclear. Only a few functional single nucleotide polymorphisms of CYP1B1 are known to result in amino acid substitutions and have been extensively investigated. Studies examining the contribution of different CYP1B1 alleles to hormone-mediated cancer risks are inconsistent. The main focus of this review is to appraise the available studies linking the pathogenesis of the hormone-induced cancers to various CYP1B1 polymorphisms. Additionally, we explore the role of a neuronal protein, γ-synuclein, in CYP1B1-mediated pathogenesis.

  15. Myelin protein zero gene sequencing diagnoses Charcot-Marie-Tooth Type 1B disease

    SciTech Connect

    Su, Y.; Zhang, H.; Madrid, R.

    1994-09-01

    Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, affects about 1 in 2600 people in Norway and is found worldwide. CMT Type 1 (CMT1) has slow nerve conduction with demyelinated Schwann cells. Autosomal dominant CMT Type 1B (CMT1B) results from mutations in the myelin protein zero gene which directs the synthesis of more than half of all Schwann cell protein. This gene was mapped to the chromosome 1q22-1q23.1 borderline by fluorescence in situ hybridization. The first 7 of 7 reported CMT1B mutations are unique. Thus the most effective means to identify CMT1B mutations in at-risk family members and fetuses is to sequence the entire coding sequence in dominant or sporadic CMT patients without the CMT1A duplication. Of the 19 primers used in 16 pars to uniquely amplify the entire MPZ coding sequence, 6 primer pairs were used to amplify and sequence the 6 exons. The DyeDeoxy Terminator cycle sequencing method used with four different color fluorescent lables was superior to manual sequencing because it sequences more bases unambiguously from extracted genomic DNA samples within 24 hours. This protocol was used to test 28 CMT and Dejerine-Sottas patients without CMT1A gene duplication. Sequencing MPZ gene-specific amplified fragments identified 9 polymorphic sites within the 6 exons that encode the 248 amino acid MPZ protein. The large number of major CMT1B mutations identified by single strand sequencing are being verified by reverse strand sequencing and when possible, by restriction enzyme analysis. This protocol can be used to distringuish CMT1B patients from othre CMT phenotypes and to determine the CMT1B status of relatives both presymptomatically and prenatally.

  16. Seasonally Changing Cryptochrome 1b Expression in the Retinal Ganglion Cells of a Migrating Passerine Bird

    PubMed Central

    Nießner, Christine; Gross, Julia Christina; Denzau, Susanne; Peichl, Leo; Fleissner, Gerta; Wiltschko, Wolfgang; Wiltschko, Roswitha

    2016-01-01

    Cryptochromes, blue-light absorbing proteins involved in the circadian clock, have been proposed to be the receptor molecules of the avian magnetic compass. In birds, several cryptochromes occur: Cryptochrome 2, Cryptochrome 4 and two splice products of Cryptochrome 1, Cry1a and Cry1b. With an antibody not distinguishing between the two splice products, Cryptochrome 1 had been detected in the retinal ganglion cells of garden warblers during migration. A recent study located Cry1a in the outer segments of UV/V-cones in the retina of domestic chickens and European robins, another migratory species. Here we report the presence of cryptochrome 1b (eCry1b) in retinal ganglion cells and displaced ganglion cells of European Robins, Erithacus rubecula. Immuno-histochemistry at the light microscopic and electron microscopic level showed eCry1b in the cell plasma, free in the cytosol as well as bound to membranes. This is supported by immuno-blotting. However, this applies only to robins in the migratory state. After the end of the migratory phase, the amount of eCry1b was markedly reduced and hardly detectable. In robins, the amount of eCry1b in the retinal ganglion cells varies with season: it appears to be strongly expressed only during the migratory period when the birds show nocturnal migratory restlessness. Since the avian magnetic compass does not seem to be restricted to the migratory phase, this seasonal variation makes a role of eCry1b in magnetoreception rather unlikely. Rather, it could be involved in physiological processes controlling migratory restlessness and thus enabling birds to perform their nocturnal flights. PMID:26953690

  17. Longevity, early emergence and body size in a pollinating fig wasp--implications for stability in a fig-pollinator mutualism.

    PubMed

    Dunn, Derek W; Yu, Douglas W; Ridley, Jo; Cook, James M

    2008-09-01

    1. Fig trees (Ficus) are pollinated only by agaonid wasps, whose larvae also gall fig ovules. Each ovule develops into either a seed (when pollinated) or a wasp (when an egg is also laid inside) but not both. 2. Ovipositing wasps (foundresses) favour ovules near the centre of the enclosed inflorescence (syconium or 'fig'), leaving ovules near the outer wall to develop into seeds. This spatial stratification of wasps and seeds ensures reproduction in both partners, and thereby enables mutualism persistence. However, the mechanism(s) responsible remain(s) unknown. 3. Theory shows that foundresses will search for increasingly rare inner ovules and ignore outer ovules, as long as ovipositing in outer ovules is sufficiently slow and/or if inner ovules confer greater fitness to wasps. The fig-pollinator mutualism can therefore be stabilized by strong time constraints on foundresses and by offspring fitness gradients over variation in ovule position. 4. Female fig wasps cannot leave their galls without male assistance. We found that females in outer ovules were unlikely to be released. Inner ovules thus have added value to foundresses, because their female offspring are more likely to mate and disperse. 5. For those offspring that did emerge, gall position (inner/outer) and body size did not influence the order in which female pollinators exited syconia, nor did early emerging wasps enjoy increased life spans. 6. We also found that the life spans of female wasps nearly doubled when given access to moisture. We suggest that conflict resolution in the fig-pollinator mutualism may thus be influenced by tropical seasonality, because wasps may be less able to over-exploit ovules in dry periods due to time constraints.

  18. Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis

    PubMed Central

    Jankovic, Slobodan M

    2010-01-01

    Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%–15%) or relapsing-remitting (85%–90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions), insomnia, influenza-like syndrome, asthenia, headache, myalgia, hypoesthesia, nausea, paresthesia, myasthenia

  19. Study on Optimal Extracting Conditions and Anti-Cancer Effects of Fig Flavones

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As dietary components, flavones have health-promoting properties due to their high antioxidant capacity both in vivo and in vitro systems. Figs have been consumed as both herb medicine and popular fruit in daily life due to its polyphones, flavones and anthocyanins. However, fig residue from juice...

  20. Asymmetric interaction and indeterminate fitness correlation between cooperative partners in the fig–fig wasp mutualism

    PubMed Central

    Wang, Rui-Wu; Sun, Bao-Fa; Zheng, Qi; Shi, Lei; Zhu, Lixing

    2011-01-01

    Empirical observations have shown that cooperative partners can compete for common resources, but what factors determine whether partners cooperate or compete remain unclear. Using the reciprocal fig–fig wasp mutualism, we show that nonlinear amplification of interference competition between fig wasps—which limits the fig wasps' ability to use a common resource (i.e. female flowers)—keeps the common resource unsaturated, making cooperation locally stable. When interference competition was manually prevented, the fitness correlation between figs and fig wasps went from positive to negative. This indicates that genetic relatedness or reciprocal exchange between cooperative players, which could create spatial heterogeneity or self-restraint, was not sufficient to maintain stable cooperation. Moreover, our analysis of field-collected data shows that the fitness correlation between cooperative partners varies stochastically, and that the mainly positive fitness correlation observed during the warm season shifts to a negative correlation during the cold season owing to an increase in the initial oviposition efficiency of each fig wasp. This implies that the discriminative sanction of less-cooperative wasps (i.e. by decreasing the egg deposition efficiency per fig wasp) but reward to cooperative wasps by fig, a control of the initial value, will facilitate a stable mutualism. Our finding that asymmetric interaction leading to an indeterminate fitness interaction between symbiont (i.e. cooperative actors) and host (i.e. recipient) has the potential to explain why conflict has been empirically observed in both well-documented intraspecific and interspecific cooperation systems. PMID:21490005

  1. Evolution and Expression Plasticity of Opsin Genes in a Fig Pollinator, Ceratosolen solmsi

    PubMed Central

    Bian, Sheng-Nan; Niu, Li-Ming; Murphy, Robert W.; Huang, Da-Wei

    2013-01-01

    Figs and fig pollinators have co-evolved species-specific systems of mutualism. So far, it was unknown how visual opsin genes of pollinators have evolved in the light conditions inside their host figs. We cloned intact full-length mRNA sequences of four opsin genes from a species of fig pollinator, Ceratosolen solmsi, and tested for selective pressure and expressional plasticity of these genes. Molecular evolutionary analysis indicated that the four opsin genes evolved under different selective constraints. Subsets of codons in the two long wavelength sensitive opsin (LW1, LW2) genes were positively selected in ancestral fig pollinators. The ultraviolet sensitive opsin (UV) gene was under strong purifying selection, whereas a relaxation of selective constrains occurred on several amino acids in the blue opsin. RT-qPCR analysis suggested that female and male fig pollinators had different expression patterns possibly due to their distinct lifestyles and different responses to light within the syconia. Co-evolutionary history with figs might have influenced the evolution and expression plasticity of opsin genes in fig pollinators. PMID:23342036

  2. Host-Plant Species Conservatism and Ecology of a Parasitoid Fig Wasp Genus (Chalcidoidea; Sycoryctinae; Arachonia)

    PubMed Central

    McLeish, Michael J.; Beukman, Gary; van Noort, Simon; Wossler, Theresa C.

    2012-01-01

    Parasitoid diversity in terrestrial ecosystems is enormous. However, ecological processes underpinning their evolutionary diversification in association with other trophic groups are still unclear. Specialisation and interdependencies among chalcid wasps that reproduce on Ficus presents an opportunity to investigate the ecology of a multi-trophic system that includes parasitoids. Here we estimate the host-plant species specificity of a parasitoid fig wasp genus that attacks the galls of non-pollinating pteromalid and pollinating agaonid fig wasps. We discuss the interactions between parasitoids and the Ficus species present in a forest patch of Uganda in context with populations in Southern Africa. Haplotype networks are inferred to examine intraspecific mitochondrial DNA divergences and phylogenetic approaches used to infer putative species relationships. Taxonomic appraisal and putative species delimitation by molecular and morphological techniques are compared. Results demonstrate that a parasitoid fig wasp population is able to reproduce on at least four Ficus species present in a patch. This suggests that parasitoid fig wasps have relatively broad host-Ficus species ranges compared to fig wasps that oviposit internally. Parasitoid fig wasps did not recruit on all available host plants present in the forest census area and suggests an important ecological consequence in mitigating fitness trade-offs between pollinator and Ficus reproduction. The extent to which parasitoid fig wasps exert influence on the pollination mutualism must consider the fitness consequences imposed by the ability to interact with phenotypes of multiple Ficus and fig wasps species, but not equally across space and time. PMID:22970309

  3. Codivergence and multiple host species use by fig wasp populations of the Ficus pollination mutualism

    PubMed Central

    2012-01-01

    Background The interaction between insects and plants takes myriad forms in the generation of spectacular diversity. In this association a species host range is fundamental and often measured using an estimate of phylogenetic concordance between species. Pollinating fig wasps display extreme host species specificity, but the intraspecific variation in empirical accounts of host affiliation has previously been underestimated. In this investigation, lineage delimitation and codiversification tests are used to generate and discuss hypotheses elucidating on pollinating fig wasp associations with Ficus. Results Statistical parsimony and AMOVA revealed deep divergences at the COI locus within several pollinating fig wasp species that persist on the same host Ficus species. Changes in branching patterns estimated using the generalized mixed Yule coalescent test indicated lineage duplication on the same Ficus species. Conversely, Elisabethiella and Alfonsiella fig wasp species are able to reproduce on multiple, but closely related host fig species. Tree reconciliation tests indicate significant codiversification as well as significant incongruence between fig wasp and Ficus phylogenies. Conclusions The findings demonstrate more relaxed pollinating fig wasp host specificity than previously appreciated. Evolutionarily conservative host associations have been tempered by horizontal transfer and lineage duplication among closely related Ficus species. Independent and asynchronistic diversification of pollinating fig wasps is best explained by a combination of both sympatric and allopatric models of speciation. Pollinator host preference constraints permit reproduction on closely related Ficus species, but uncertainty of the frequency and duration of these associations requires better resolution. PMID:22214193

  4. Chaos of Wolbachia Sequences Inside the Compact Fig Syconia of Ficus benjamina (Ficus: Moraceae)

    PubMed Central

    Niu, Li-Ming; Ma, Guang-Chang; Cook, James M.; Bian, Sheng-Nan; Fu, Yue-Guan; Huang, Da-Wei

    2012-01-01

    Figs and fig wasps form a peculiar closed community in which the Ficus tree provides a compact syconium (inflorescence) habitat for the lives of a complex assemblage of Chalcidoid insects. These diverse fig wasp species have intimate ecological relationships within the closed world of the fig syconia. Previous surveys of Wolbachia, maternally inherited endosymbiotic bacteria that infect vast numbers of arthropod hosts, showed that fig wasps have some of the highest known incidences of Wolbachia amongst all insects. We ask whether the evolutionary patterns of Wolbachia sequences in this closed syconium community are different from those in the outside world. In the present study, we sampled all 17 fig wasp species living on Ficus benjamina, covering 4 families, 6 subfamilies, and 8 genera of wasps. We made a thorough survey of Wolbachia infection patterns and studied evolutionary patterns in wsp (Wolbachia Surface Protein) sequences. We find evidence for high infection incidences, frequent recombination between Wolbachia strains, and considerable horizontal transfer, suggesting rapid evolution of Wolbachia sequences within the syconium community. Though the fig wasps have relatively limited contact with outside world, Wolbachia may be introduced to the syconium community via horizontal transmission by fig wasps species that have winged males and visit the syconia earlier. PMID:23145008

  5. Evolution and expression plasticity of opsin genes in a fig pollinator, Ceratosolen solmsi.

    PubMed

    Wang, Bo; Xiao, Jin-Hua; Bian, Sheng-Nan; Niu, Li-Ming; Murphy, Robert W; Huang, Da-Wei

    2013-01-01

    Figs and fig pollinators have co-evolved species-specific systems of mutualism. So far, it was unknown how visual opsin genes of pollinators have evolved in the light conditions inside their host figs. We cloned intact full-length mRNA sequences of four opsin genes from a species of fig pollinator, Ceratosolen solmsi, and tested for selective pressure and expressional plasticity of these genes. Molecular evolutionary analysis indicated that the four opsin genes evolved under different selective constraints. Subsets of codons in the two long wavelength sensitive opsin (LW1, LW2) genes were positively selected in ancestral fig pollinators. The ultraviolet sensitive opsin (UV) gene was under strong purifying selection, whereas a relaxation of selective constrains occurred on several amino acids in the blue opsin. RT-qPCR analysis suggested that female and male fig pollinators had different expression patterns possibly due to their distinct lifestyles and different responses to light within the syconia. Co-evolutionary history with figs might have influenced the evolution and expression plasticity of opsin genes in fig pollinators.

  6. Pollinator-mediated reproductive isolation among dioecious fig species (Ficus, Moraceae).

    PubMed

    Moe, Annika M; Weiblen, George D

    2012-12-01

    The extent of isolation among closely related sympatric plant species engaged in obligate pollination mutualisms depends on the fitness consequences of interspecies floral visitation. In figs (Ficus), interspecific gene flow may occur when pollinating wasps (Agaonidae) visit species other than their natal fig species. We studied reproductive isolation in a clade of six sympatric dioecious fig species in New Guinea. Microsatellite genotyping and Bayesian clustering analysis of the fig community indicated strong reproductive barriers among sympatric species. A total of 1-2% of fig populations consisted of hybrid individuals. A new experimental method of manipulating fig wasps investigated the reproductive consequences of conspecific and heterospecific pollinator visitation for both mutualists. Fig wasps introduced to Ficus hispidioides pollinated and oviposited in receptive figs. Seed development and seedling growth were largely comparable between conspecific and heterospecific crosses. Heterospecific pollinator fitness, however, was significantly less than that of conspecific pollinators. Heterospecific pollinators induced gall formation but offspring did not develop to maturity in the new host. Selection on pollinators maintaining host specificity appears to be an important mechanism of contemporary reproductive isolation among these taxa that could potentially influence their diversification.

  7. Describing the appearance and flavor profiles of fresh fig (Ficus carica L.) cultivars.

    PubMed

    King, Ellena S; Hopfer, Helene; Haug, Megan T; Orsi, Jennifer D; Heymann, Hildegarde; Crisosto, Gayle M; Crisosto, Carlos H

    2012-12-01

    Twelve fig cultivars, including cultivars destined for the fresh and dried markets, were harvested from 6 locations and evaluated by a trained panel using descriptive sensory analysis. Instrumental measurements were taken at harvest and also during sensory analysis. Each fresh fig cultivar had a characteristic appearance and flavor sensory profile regardless of the source. The primary flavor attributes used to describe the fig cultivars were "fruity,"melon,"stone fruit,"berry,"citrus,"honey,"green," and "cucumber." Maturity levels significantly affected the chemical composition and sensory profiles of the fig cultivars. Less mature figs had a higher compression force, a thicker outer skin, and higher ratings for "green" and "latex" flavors, firmness, graininess, bitterness, tingling, and seed adhesiveness. Meanwhile, more mature figs had higher soluble solids concentration, and were perceptibly higher in "fruit" flavors, juiciness, stickiness, sliminess, and sweetness. The specific sensory terminology used for fig appearance and flavor profiles will assist with communication between marketers and consumers, which can increase fresh fig consumption.

  8. Host-plant species conservatism and ecology of a parasitoid fig wasp genus (Chalcidoidea; Sycoryctinae; Arachonia).

    PubMed

    McLeish, Michael J; Beukman, Gary; van Noort, Simon; Wossler, Theresa C

    2012-01-01

    Parasitoid diversity in terrestrial ecosystems is enormous. However, ecological processes underpinning their evolutionary diversification in association with other trophic groups are still unclear. Specialisation and interdependencies among chalcid wasps that reproduce on Ficus presents an opportunity to investigate the ecology of a multi-trophic system that includes parasitoids. Here we estimate the host-plant species specificity of a parasitoid fig wasp genus that attacks the galls of non-pollinating pteromalid and pollinating agaonid fig wasps. We discuss the interactions between parasitoids and the Ficus species present in a forest patch of Uganda in context with populations in Southern Africa. Haplotype networks are inferred to examine intraspecific mitochondrial DNA divergences and phylogenetic approaches used to infer putative species relationships. Taxonomic appraisal and putative species delimitation by molecular and morphological techniques are compared. Results demonstrate that a parasitoid fig wasp population is able to reproduce on at least four Ficus species present in a patch. This suggests that parasitoid fig wasps have relatively broad host-Ficus species ranges compared to fig wasps that oviposit internally. Parasitoid fig wasps did not recruit on all available host plants present in the forest census area and suggests an important ecological consequence in mitigating fitness trade-offs between pollinator and Ficus reproduction. The extent to which parasitoid fig wasps exert influence on the pollination mutualism must consider the fitness consequences imposed by the ability to interact with phenotypes of multiple Ficus and fig wasps species, but not equally across space and time.

  9. Chaos of Wolbachia sequences inside the compact fig syconia of Ficus benjamina (Ficus: moraceae).

    PubMed

    Yang, Chun-Yan; Xiao, Jin-Hua; Niu, Li-Ming; Ma, Guang-Chang; Cook, James M; Bian, Sheng-Nan; Fu, Yue-Guan; Huang, Da-Wei

    2012-01-01

    Figs and fig wasps form a peculiar closed community in which the Ficus tree provides a compact syconium (inflorescence) habitat for the lives of a complex assemblage of Chalcidoid insects. These diverse fig wasp species have intimate ecological relationships within the closed world of the fig syconia. Previous surveys of Wolbachia, maternally inherited endosymbiotic bacteria that infect vast numbers of arthropod hosts, showed that fig wasps have some of the highest known incidences of Wolbachia amongst all insects. We ask whether the evolutionary patterns of Wolbachia sequences in this closed syconium community are different from those in the outside world. In the present study, we sampled all 17 fig wasp species living on Ficus benjamina, covering 4 families, 6 subfamilies, and 8 genera of wasps. We made a thorough survey of Wolbachia infection patterns and studied evolutionary patterns in wsp (Wolbachia Surface Protein) sequences. We find evidence for high infection incidences, frequent recombination between Wolbachia strains, and considerable horizontal transfer, suggesting rapid evolution of Wolbachia sequences within the syconium community. Though the fig wasps have relatively limited contact with outside world, Wolbachia may be introduced to the syconium community via horizontal transmission by fig wasps species that have winged males and visit the syconia earlier.

  10. Wine and vinegar-based attractants for the African fig fly (Diptera: Drosophilidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The African fig fly (AFF), Zaprionus indianus Gupta (Diptera: Drosophilidae), is an invasive fruit pest that has spread rapidly through much of the eastern United States after first being detected in Florida in 2005. This drosophilid is a primary pest of figs in Brazil, so there were initial concern...

  11. Could the 5-HT1B receptor inverse agonism affect learning consolidation?

    PubMed

    Meneses, A

    2001-03-01

    Diverse evidence indicates that, the 5-HT system might play a role in learning and memory, since it occurs in brain areas mediating such processes and 5-HT drugs modulate them. Hence in this work, in order to explore further 5-HT involvement on learning and memory 5-HT1B receptors' role is investigated. Evidence indicates that SB-224289 (a 5-HT1B receptor inverse agonist) post-training injection facilitated learning consolidation in an associative autoshaping learning task, this effect was partially reversed by GR 127935 (a 5-HT1B/1D receptor antagonist), but unaffected by MDL 100907 (a 5-HT2A receptor antagonist) or ketanserin (a 5-HT1D/2A/7 receptor antagonist) at low doses. Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT1A/1B/1D receptor agonist), mCPP (a 5-HT2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose). SB-224289 did not alter the 8-OH-DPAT (a 5-HT1A/7 receptor agonist) learning facilitatory effect. SB-224289 eliminated the deficit learning produced by the anticholinergic muscarinic scopolamine or the glutamatergic antagonist dizocilpine. Administration of both, GR 127935 (5mg/kg) plus ketanserin (0.01 mg/kg) did not modify learning consolidation; nevertheless, when ketanserin dose was increased (0.1-1.0mg/kg) and SB-224289 dose was maintained constant, a learning facilitation effect was observed. Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose. Collectively, the data confirm and extend the earlier findings with GR 127935 and the effects of non-selective 5-HT(1B) receptor agonists. Clearly 5-HT1B agonists induced a learning deficit which can be reversed with SB-224289. Perhaps more importantly, SB-224289 enhances learning consolidation when given alone and can reverse the deficits

  12. 9. WEST SIDE, TEST STAND AND SUPERSTRUCTURE. TEST STAND 1B ...

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

    9. WEST SIDE, TEST STAND AND SUPERSTRUCTURE. TEST STAND 1-B IN DISTANCE. Looking east. - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Test Stand 1-A, Test Area 1-120, north end of Jupiter Boulevard, Boron, Kern County, CA

  13. Host-specificity and coevolution among pollinating and nonpollinating New World fig wasps.

    PubMed

    Marussich, Wendy A; Machado, Carlos A

    2007-05-01

    Figs (Ficus spp., Moraceae) and their pollinating wasps (Hymenoptera, Agaonidae, Chalcidoidea) constitute a classic example of an obligate plant-pollinator mutualism, and have become an ideal system for addressing questions on coevolution, speciation, and the maintenance of mutualisms. In addition to pollinating wasps, figs host several types of nonpollinating, parasitic wasps from a diverse array of Chalcid subfamilies with varied natural histories and ecological strategies (e.g. competitors, gallers, and parasitoids). Although a few recent studies have addressed the question of codivergence between specific genera of pollinating and nonpollinating fig wasps, no study has addressed the history of divergence of a fig wasp community comprised of multiple genera of wasps associated with a large number of sympatric fig hosts. Here, we conduct phylogenetic analyses of mitochondrial DNA sequences (COI) using 411 individuals from 69 pollinating and nonpollinating fig wasp species to assess relationships within and between five genera of fig wasps (Pegoscapus, Idarnes, Heterandrium, Aepocerus, Physothorax) associated with 17 species of New World Urostigma figs from section Americana. We show that host-switching and multiple wasp species per host are ubiquitous across Neotropical nonpollinating wasp genera. In spite of these findings, cophylogenetic analyses (TREEMAP 1.0, TREEMAP 2.02beta, and parafit) reveal evidence of codivergence among fig wasps from different ecological guilds. Our findings further challenge the classical notion of strict-sense coevolution between figs and their associated wasps, and mirror conclusions from detailed molecular studies of other mutualisms that have revealed common patterns of diffuse coevolution and asymmetric specialization among the participants.

  14. Reduced ultrasonic vocalizations in vasopressin 1b knockout mice.

    PubMed

    Scattoni, M L; McFarlane, H G; Zhodzishsky, V; Caldwell, H K; Young, W S; Ricceri, L; Crawley, J N

    2008-03-05

    The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages.

  15. Transcription Factor GFI1B in Health and Disease

    PubMed Central

    Anguita, Eduardo; Candel, Francisco J.; Chaparro, Alberto; Roldán-Etcheverry, Juan J.

    2017-01-01

    Many human diseases arise through dysregulation of genes that control key cell fate pathways. Transcription factors (TFs) are major cell fate regulators frequently involved in cancer, particularly in leukemia. The GFI1B gene, coding a TF, was identified by sequence homology with the oncogene growth factor independence 1 (GFI1). Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain. Gfi1 is essential for neutrophil differentiation in mice. In humans, GFI1 mutations are associated with severe congenital neutropenia. Gfi1 is also required for B and T lymphopoiesis. However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages. Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function. Loss of Gfi1b in adult mice increases the absolute numbers of hematopoietic stem cells (HSCs) that are less quiescent than wild-type HSCs. In keeping with this key role in cell fate, GFI1B is emerging as a gene involved in cancer, which also includes solid tumors. In fact, abnormal activation of GFI1B and GFI1 has been related to human medulloblastoma and is also likely to be relevant in blood malignancies. Several pieces of evidence supporting this statement will be detailed in this mini review.

  16. Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana.

    PubMed

    Shah, Muhammad Raza; Ishtiaq; Hizbullah, Syed Muhammad; Habtemariam, Solomon; Zarrelli, Armando; Muhammad, Akhtar; Collina, Simona; Khan, Inamulllah

    2016-08-01

    Artemisia roxburghiana is used in traditional medicine for treating various diseases including diabetes. The present study was designed to evaluate the antidiabetic potential of active constituents by using protein tyrosine phosphatase 1B (PTP1B) as a validated target for management of diabetes. Various compounds were isolated as active principles from the crude methanolic extract of aerial parts of A. roxburghiana. All compounds were screened for PTP1B inhibitory activity. Molecular docking simulations were performed to investigate the mechanism behind PTP1B inhibition of the isolated compound and positive control, ursolic acid. Betulinic acid, betulin and taraxeryl acetate were the active PTP1B principles with IC50 values 3.49 ± 0.02, 4.17 ± 0.03 and 87.52 ± 0.03 µM, respectively. Molecular docking studies showed significant molecular interactions of the triterpene inhibitors with Gly220, Cys215, Gly218 and Asp48 inside the active site of PTP1B. The antidiabetic activity of A. roxburghiana could be attributed due to PTP1B inhibition by its triterpene constituents, betulin, betulinic acid and taraxeryl acetate. Computational insights of this study revealed that the C-3 and C-17 positions of the compounds needs extensive optimization for the development of new lead compounds.

  17. Identification of Novel Inhibitors of Organic Anion Transporting Polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) Using a Consensus Vote of Six Classification Models

    PubMed Central

    2015-01-01

    Organic anion transporting polypeptides 1B1 and 1B3 are transporters selectively expressed on the basolateral membrane of the hepatocyte. Several studies reveal that they are involved in drug–drug interactions, cancer, and hyperbilirubinemia. In this study, we developed a set of classification models for OATP1B1 and 1B3 inhibition based on more than 1700 carefully curated compounds from literature, which were validated via cross-validation and by use of an external test set. After combining several sets of descriptors and classifiers, the 6 best models were selected according to their statistical performance and were used for virtual screening of DrugBank. Consensus scoring of the screened compounds resulted in the selection and purchase of nine compounds as potential dual inhibitors and of one compound as potential selective OATP1B3 inhibitor. Biological testing of the compounds confirmed the validity of the models, yielding an accuracy of 90% for OATP1B1 and 80% for OATP1B3, respectively. Moreover, at least half of the new identified inhibitors are associated with hyperbilirubinemia or hepatotoxicity, implying a relationship between OATP inhibition and these severe side effects. PMID:26469880

  18. Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.

    PubMed

    Marada, Venkata V V R; Flörl, Saskia; Kühne, Annett; Burckhardt, Gerhard; Hagos, Yohannes

    2015-03-06

    Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.

  19. CIRSS vertical data integration, San Bernardino County study phases 1-A, 1-B

    NASA Technical Reports Server (NTRS)

    Christenson, J.; Michel, R. (Principal Investigator)

    1981-01-01

    User needs, data types, data automation, and preliminary applications are described for an effort to assemble a single data base for San Bernardino County from data bases which exist at several administrative levels. Each of the data bases used was registered and converted to a grid-based data file at a resolution of 4 acres and used to create a multivariable data base for the entire study area. To this data base were added classified LANDSAT data from 1976 and 1979. The resulting data base thus integrated in a uniform format all of the separately automated data within the study area. Several possible interactions between existing geocoded data bases and LANDSAT data were tested. The use of LANDSAT to update existing data base is to be tested.

  20. Discriminating Type 1a and 1b PSCs in Satellite Data

    NASA Technical Reports Server (NTRS)

    Strawa, Anthony W.; Drdla, Katja; Fromm, Michael; Hoppel, Karl W.; Pueschel, Rudolf; Browell, Edward V.; Hostetler, Chris A.; Hamill, Patrick; Gore, Warren J. (Technical Monitor)

    2000-01-01

    We explore the use of satellite observations in discriminating types of PSCs and their ramifications. Polar Stratospheric Clouds (PSCs), which form in the winter polar vortex, have been identified as effecting ozone loss. One major result from the recent SOLVE mission is in-situ evidence of the existence of very large particles that contain nitric acid. These particles are consistent with Type la PSCs. The significance of this finding is that these large particles will have appreciable sedimentation velocities, taking nitric acid out of the stratospheric regions, causing denitrification. Since nitric acid typically mitigates ozone loss, denitrification leads to increased ozone loss. Type lb PSCs are smaller and do not sediment to any appreciable degree. Satellite measurements are made continuously throughout the winter, and offer more global coverage than in situ measurements. Thus, it would very useful to be able to discriminate PSC types from satellite measurements. Our long-term goals are to better understand the formation mechanisms and effects of PSCs. Discriminating PSC type using satellite data will give us a very important tool in this effort. A multi-wavelength analysis of POAM aerosol extinction during SOLVE has revealed differences in the radiative characteristics of PSC events. We explore the use of POAM observations to discriminate between Type la and lb Pscs. A trajectory model is used to simulate PSC la and lb particles. Calculated radiative properties act as a guide for discriminating the satellite occultation measurements. Aircraft based PSC observations are-used as confirmation of these observations.

  1. [Solubilization Specificities Interferon beta-1b from Inclusion Bodies].

    PubMed

    Zhuravko, A S; Kononova, N V; Bobruskin, A I

    2015-01-01

    A new solubilization method of recombinant interferon beta-1b (IFNβ-1b) from the inclusion bodies was developed. This method allows to extract the target protein selectively in the solutions of different alcohols, such as ethanol, propanol and isopropanol. It was shown that the more effective IFNβ-1b solubilization was achieved in the 55% propanol solution. This method allowed to extract the target protein from inclusion bodies around 85-90%, and significantly reduced Escherichia coli content in the solubilizate, in comparison with standard methods.

  2. PROBING THE EARLIEST STAGE OF PROTOSTELLAR EVOLUTION-BARNARD 1-bN AND BARNARD 1-bS

    SciTech Connect

    Huang, Yun-Hsin; Hirano, Naomi

    2013-04-01

    Two submm/mm sources in the Barnard 1b (B1-b) core, B1-bN and B1-bS, have been observed with the Submillimeter Array (SMA) and the Submillimeter Telescope (SMT). The 1.1 mm continuum map obtained with the SMA reveals that the two sources contain spatially compact components, suggesting that they harbor protostars. The N{sub 2}D{sup +} and N{sub 2}H{sup +} J = 3-2 maps were obtained by combining the SMA and SMT data. The N{sub 2}D{sup +} map clearly shows two peaks at the continuum positions. The N{sub 2}H{sup +} map also peaks at the continuum positions, but is more dominated by the spatially extended component. The N{sub 2}D{sup +}/N{sub 2}H{sup +} ratio was estimated to be {approx}0.2 at the positions of both B1-bN and B1-bS. The derived N{sub 2}D{sup +}/N{sub 2}H{sup +} ratio is comparable to those of the prestellar cores in the late evolutionary stage and the class 0 protostars in the early evolutionary stage. Although B1-bN is bright in N{sub 2}H{sup +} and N{sub 2}D{sup +}, this source was barely seen in H{sup 13}CO{sup +}. This implies that the depletion of carbon-bearing molecules is significant in B1-bN. The chemical property suggests that B1-bN is in the earlier evolutionary stage as compared to B1-bS with the H{sup 13}CO{sup +} counterpart. The N{sub 2}H{sup +} and N{sub 2}D{sup +} lines show that the radial velocities of the two sources are different by {approx}0.9 km s{sup -1}. However, the velocity pattern along the line through B1-bN and B1-bS suggests that these two sources were not formed out of a single rotating cloud. It is likely that the B1-b core consists of two velocity components, each of which harbors a very young source.

  3. Ultrafine carbon particles down-regulate CYP1B1 expression in human monocytes

    PubMed Central

    Eder, Christiane; Frankenberger, Marion; Stanzel, Franz; Seidel, Albrecht; Schramm, Karl-Werner; Ziegler-Heitbrock, Loems; Hofer, Thomas PJ

    2009-01-01

    Background Cytochrome P450 monoxygenases play an important role in the defence against inhaled toxic compounds and in metabolizing a wide range of xenobiotics and environmental contaminants. In ambient aerosol the ultrafine particle fraction which penetrates deeply into the lungs is considered to be a major factor for adverse health effects. The cells mainly affected by inhaled particles are lung epithelial cells and cells of the monocyte/macrophage lineage. Results In this study we have analyzed the effect of a mixture of fine TiO2 and ultrafine carbon black Printex 90 particles (P90) on the expression of cytochrome P450 1B1 (CYP1B1) in human monocytes, macrophages, bronchial epithelial cells and epithelial cell lines. CYP1B1 expression is strongly down-regulated by P90 in monocytes with a maximum after P90 treatment for 3 h while fine and ultrafine TiO2 had no effect. CYP1B1 was down-regulated up to 130-fold and in addition CYP1A1 mRNA was decreased 13-fold. In vitro generated monocyte-derived macrophages (MDM), epithelial cell lines, and primary bronchial epithelial cells also showed reduced CYP1B1 mRNA levels. Benzo[a]pyrene (BaP) is inducing CYB1B1 but ultrafine P90 can still down-regulate gene expression at 0.1 μM of BaP. The P90-induced reduction of CYP1B1 was also demonstrated at the protein level using Western blot analysis. Conclusion These data suggest that the P90-induced reduction of CYP gene expression may interfere with the activation and/or detoxification capabilities of inhaled toxic compounds. PMID:19835593

  4. Expression Profiling of CYP1B1 in Oral Squamous Cell Carcinoma: Counterintuitive Downregulation in Tumors

    PubMed Central

    Pradhan, Shalmali; Nagashri, M. N.; Gopinath, K. S.; Kumar, Arun

    2011-01-01

    Oral Squamous Cell Carcinoma (OSCC) has a very flagitious treatment regime. A prodrug approach is thought to aid in targeting chemotherapy. CYP1B1, a member of cytochrome P450 family, has been implicated in chemical carcinogenesis. There exists a general accordance that this protein is overexpressed in a variety of cancers, making it an ideal candidate for a prodrug therapy. The activation of the prodrug facilitated by CYP1B1 would enable the targeting of chemotherapy to tumor tissues in which CYP1B1 is specifically overexpressed as a result reducing the non-specific side effects that the current chemotherapy elicits. This study was aimed at validating the use of CYP1B1 as a target for the prodrug therapy in OSCC. The expression profile of CYP1B1 was analysed in a panel of 51 OSCC tumors, their corresponding normal tissues, an epithelial dysplasia lesion and its matched normal tissue by qRT-PCR, Western blotting and Immunohistochemistry. CYP1B1 was found to be downregulated in 77.78% (28/36) tumor tissues in comparison to their corresponding normal tissues as well as in the epithelial dysplasia lesion compared to its matched normal tissue at the transcriptional level, and in 92.86% (26/28) of tumor tissues at the protein level. This report therefore clearly demonstrates the downregulation of CYP1B1 at the transcriptional and translational levels in tumor tissues in comparison to their corresponding normal tissues. These observations indicate that caution should be observed as this therapy may not be applicable universally to all cancers and also suggest the possibility of a prophylactic therapy for oral cancer. PMID:22114726

  5. Expression profiling of CYP1B1 in oral squamous cell carcinoma: counterintuitive downregulation in tumors.

    PubMed

    Pradhan, Shalmali; Nagashri, M N; Gopinath, K S; Kumar, Arun

    2011-01-01

    Oral Squamous Cell Carcinoma (OSCC) has a very flagitious treatment regime. A prodrug approach is thought to aid in targeting chemotherapy. CYP1B1, a member of cytochrome P450 family, has been implicated in chemical carcinogenesis. There exists a general accordance that this protein is overexpressed in a variety of cancers, making it an ideal candidate for a prodrug therapy. The activation of the prodrug facilitated by CYP1B1 would enable the targeting of chemotherapy to tumor tissues in which CYP1B1 is specifically overexpressed as a result reducing the non-specific side effects that the current chemotherapy elicits. This study was aimed at validating the use of CYP1B1 as a target for the prodrug therapy in OSCC. The expression profile of CYP1B1 was analysed in a panel of 51 OSCC tumors, their corresponding normal tissues, an epithelial dysplasia lesion and its matched normal tissue by qRT-PCR, Western blotting and Immunohistochemistry. CYP1B1 was found to be downregulated in 77.78% (28/36) tumor tissues in comparison to their corresponding normal tissues as well as in the epithelial dysplasia lesion compared to its matched normal tissue at the transcriptional level, and in 92.86% (26/28) of tumor tissues at the protein level. This report therefore clearly demonstrates the downregulation of CYP1B1 at the transcriptional and translational levels in tumor tissues in comparison to their corresponding normal tissues. These observations indicate that caution should be observed as this therapy may not be applicable universally to all cancers and also suggest the possibility of a prophylactic therapy for oral cancer.

  6. African parasitoid fig wasp diversification is a function of Ficus species ranges.

    PubMed

    McLeish, Michael J; van Noort, Simon; Tolley, Krystal A

    2010-10-01

    Host specificity is a fundamental property implicit in obligate insect-plant associations. Rigid life history constraints exhibited by parasitoid fig wasps are believed to select for specialization directed at fig trees and this is supported by evidence of phenotypic adaptation to figs and partial co-speciation with the fig wasps they attack. Conversely, the ability to colonize such novel communities occurs under relaxed specificity, a behavior typified by more generalist groups such as parasitoids. The specificity directed towards Ficus species by Sycoryctinae parasitoid fig wasps is important in order to understand how this form of specialization influences their diversification and interactions with other fig wasp guilds. We use genetic distance analyses and reconstruct ancestral patterns of Ficus trait association with two genera of Sycoryctinae parasitoid fig wasps to identify evolutionary conservatism in Ficus species utilization. Ancestral state reconstructions of (i) affiliate Ficus subsection and (ii) syconia diameters of natal Ficus species indicate contrasting Ficus species ranges between Arachonia and Sycoryctes parasitoid genera. This work demonstrates that parasitoid speciation is not tightly constrained to Ficus speciation and rather a function of Ficus range limitations. Ficus evolution, ecology, and functional compatibility between parasitoid and Ficus traits appear to constrain parasitoid Ficus utilization. These results suggest that contrasting ecological settings and potential number of hosts available impose different ramifications for the evolution of parasitoid host specificity and so to the species interactions within the communities to which they belong.

  7. [Sex ratio adjustment of a non-pollinating fig wasp species on Ficus semicordata in Xishuangbanna].

    PubMed

    Song, Bo; Peng, Yan-Qiong; Guan, Jun-Ming; Yang, Pei; Yang, Da-Rong

    2008-03-01

    Through controlling the number of ovipositing foundresses inside a fig, and combining with the observation of ovipositing behavior and mating behavior, this paper studied the sex ratio of Apocryptophagus sp., a species of non-pollinating fig wasps hosted on Ficus semicordata in Xishuangbanna. The results showed that female Apocryptophagus sp. started to visit the fig on the 3rd day after pollinator Ceratosolen gravelyi oviposited. Apocryptaphagus sp. oviposited on the outside of the fig, and the ovipositing lasted for 2 days. Male Apocryptophagus sp. emerged at the same time with pollinators. The males opened a small hole on the wall of gall where the females developed, and mated with the females. Mated females emerged from their development fig, and left for a new receptive fig. The sex ratio of Apocryptaphagus sp. was in agreement with local mate competition theory, i. e., it was female-biased. Meanwhile, the total number of offspring increased with increasing foundress number. In contrast, the average number of offspring per foundress decreased. At individual level, when a female laid eggs inside a fig, the sex ratio of offspring correlated negatively with the number of offspring.

  8. Ethanol and Mesolimbic Serotonin/Dopamine Interactions Via 5-HT1B Receptors

    DTIC Science & Technology

    2006-03-01

    5 - HT3 receptor antagonist antagonized systemic ethanol- induced increases o