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Sample records for ah receptor chemicals

  1. Promiscuous ligand-dependent activation of the Ah receptor: chemicals in crude extracts from commercial and consumer products bind to and activate the Ah receptor and Ah receptor-dependent gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Denison, M.; Rogers, W.; Bohonowych, J.; Zhao, B. [Dept. of Environmental Toxicology, Univ. of California, Davis (United States)

    2004-09-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related halogenated and polycyclic aromatic hydrocarbons (HAHs and PAHs) produce a variety of toxic and biological effects, the majority of which are mediated by their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. While previous studies suggested that the physiochemical characteristics of AhR ligands (i.e. HAH and PAH agonists) must meet a defined set of criteria, it has recently become abundantly clear that the AhR can be bound and activated by structurally diverse range of synthetic and naturally occurring chemicals. Based on the spectrum of AhR ligands identified to date, the structural promiscuity of AhR ligands is significantly more diverse than that observed for other liganddependent nuclear receptors. However, a detailed understanding of the structural diversity of AhR ligands and their respective biological and toxicological activities remains to be established and could provide insights into the identity of endogenous ligands. Over the past several years we have developed and utilized several AhR-based in vitro and cell-based bioassay systems to screen pure chemicals and chemical libraries as well as mixtures of chemicals with the goal of defining the spectrum of chemicals that can bind to and activate/inhibit the AhR and AhR-dependent gene expression. In addition, demonstration of the presence of AhR agonists/antagonists in extracts containing complex mixtures of chemicals from a variety of biological and environmental samples, coupled with AhR bioassay-based fractionation procedures, provides an avenue in which to identify novel AhR ligands. In previous preliminary screening studies we demonstrated the presence of AhR agonists in extracts of commercial and consumer products using an in vitro guinea pig hepatic AhR DNA binding and mouse gene induction assays. Here we have extended these studies and have examined the ability of crude DMSO and ethanol extracts

  2. Role of endocrine disrupting chemicals on the tissue levels of AhR and sex steroid receptors in breast tumours

    Directory of Open Access Journals (Sweden)

    Sepideh Arbabi Bidgoli

    2016-09-01

    Full Text Available Breast cancer affects Iranian women at least one decade younger than their counterparts in other countries and the incidence of breast fibroadenoma is growing in the last two decades in Tehran. This study aimed to compare the AhR levels in premenopausal breast cancer and breast fibroadnemo with appropriate normal groups. Possible associations of AhR with lifestyle and reproductive risk factors and other fundamental genes of breast cancer and reproductive disorders were the other major goals of present study. To conduct the comparisons all possible reproductive, environmental and lifestyle risk factors of mentioned diseases were recorded in 100 breast cancer, 100 breast fibroadenoma and compared with 400 women in normal group from 2009 to 2011. AhR overexpression in epithelial cells of premenopausal patients emphasized the susceptibility of these cells to environmental induced reproductive disorders. The AhR overexpression was contributed to ER-/PgR- immunophenotype in malignant tissues. Weight gain (after 18 and after pregnancy, long term (>5yrs OCP consumption, smoking, severe stress ,history of ovarian cysts, hormonal deregulations, living near PAHs producing sources, were correlated with increased risk of breast cancer and reproductive disorders and were correlated with elevated tissue levels of AhR. It seems that increased risk of breast cancer and other reproductive tumours in Tehran may be the result of exposure to environmental endocrine disruptors. Long term exposure to environmental estrogens can increase the tissue levels of AhR and deregulate the expression pattern of sex steroid receptors and other genes in target tissues.

  3. Interaction of Diuron and Related Substituted Phenylureas with the Ah Receptor Pathway

    Science.gov (United States)

    Zhao, Bin; Baston, David S.; Hammock, Bruce; Denison, Michael S.

    2011-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of structurally diverse chemicals, including the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Here, we have examined the ability of diuron, a widely used herbicide, and several structurally related substituted phenylureas to bind to and activate/inhibit the AhR and AhR signal transduction. Diuron induced CYP1A1 mRNA levels in mouse hepatoma (Hepa1c1c7) cells and AhR-dependent luciferase reporter gene expression in stably transfected mouse, rat, guinea pig, and human cell lines. In addition, ligand binding and gel retardation analysis demonstrated the ability of diuron to competitively bind to and stimulate AhR transformation and DNA binding in vitro and in intact cells. Several structurally related substituted phenylureas competitively bound to the guinea pig hepatic cytosolic AhR, inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced AhR-dependent luciferase reporter gene expression in a species-specific manner and stimulated AhR transformation and DNA binding, consistent with their role as partial AhR agonists. These results demonstrate not only that diuron and related substituted phenylureas are AhR ligands but also that exposure to these chemicals could induce/inhibit AhR-dependent biological effects. PMID:16788953

  4. Identification and analysis of novel flavonoid agonists and antagonists for the AH and estrogen receptor

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, B.; Nagy, S.; Rogers, J.; Denison, M. [Dept. of Environmental Toxicology, Univ. of California, Davis (United States); Nantz, M.; Kurth, M.; Springsteel, M. [Dept. of Chemistry, Univ. of California, Davis (United States)

    2004-09-15

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates many of the biological and toxicological effects in a diverse range of species, tissues, and cell types. The most studied effect is induction of gene expression, and, the majority of AhR responsive genes, such as cytochrome P4501A1 (CYP1A1), utilize AhR dependent mechanism of action. While halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs) are the prototypical ligands of the Ah receptor, it has recently identified that the AhR is activated by a structurally diverse array of hydrophobic natural and synthetic chemicals. Given the structural diversity in AhR ligands, the physiochemical characteristics for high and low affinity ligands seems to be established. Environmental contaminants that can disrupt the endocrine homeostasis of an organism have also gained widespread attention in recent years and numerous chemicals have been identified as having either hormone or anti-hormone properties. However, like the AhR, the structural diversity and characteristics of endocrine disrupters that exert their action via nuclear receptors also seems to be depended on the estrogen receptor (ER). The flavonoids are a diverse family of chemicals commonly found in fruits and vegetables. Members of this family exert cytostatic, apoptotic, anti-inflammatory and anti-angiogenic activities. In addition, several flavonoids are potent modulators of both the expression and activities of specific cytochrome P450 genes/proteins and somel others have estrogenic and antiestrogenic activity. Accordingly flavonoids have attracted attention as possible chemoprotective or chemotherapeutic agents. We have previously developed and analyzed a novel chemical library of flavonoids which contained {proportional_to}200 compounds. The ability of these compounds to activate and/or inhibit AhR- and ER- dependent gene expression was examined by using our recently developed AhR- and ER

  5. Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR)

    International Nuclear Information System (INIS)

    Wong, Patrick S; Li, Wen; Vogel, Christoph F; Matsumura, Fumio

    2009-01-01

    Recent reports indicate the existence of breast cancer cells expressing very high levels of the Arylhydrocarbon receptor (AhR), a ubiquitous intracellular receptor best known for mediating toxic action of dioxin and related pollutants. Positive correlation between the degree of AhR overexpression and states of increasing transformation of mammary epithelial cells appears to occur in the absence of any exogenous AhR ligands. These observations have raised many questions such as why and how AhR is overexpressed in breast cancer and its physiological roles in the progression to advanced carcinogenic transformation. To address those questions, we hypothesized that AhR overexpression occurs in cells experiencing deficiencies in normally required estrogen receptor (ER) signaling, and the basic role of AhR in such cases is to guide the affected cells to develop orchestrated cellular changes aimed at substituting the normal functions of ER. At the same time, the AhR serves as the mediator of the cell survival program in the absence of ER signaling. We subjected two lines of Michigan Cancer Foundation (MCF) mammary epithelial cells to 3 different types ER interacting agents for a number of passages and followed the changes in the expression of AhR mRNA. The resulting sublines were analyzed for phenotypical changes and unique molecular characteristics. MCF10AT1 cells continuously exposed to 17-beta-estradiol (E2) developed sub-lines that show AhR overexpression with the characteristic phenotype of increased proliferation, and distinct resistance to apoptosis. When these chemically selected cell lines were treated with a specific AhR antagonist, 3-methoxy-4-nitroflavone (MNF), both of the above abnormal cellular characteristics disappeared, indicating the pivotal role of AhR in expressing those cellular phenotypes. The most prominent molecular characteristics of these AhR overexpressing MCF cells were found to be overexpression of ErbB2 and COX-2. Furthermore, we could

  6. Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables and fruits

    NARCIS (Netherlands)

    Jeuken, A.; Keser, B.J.G.; Khan, E.; Brouwer, A.; Koeman, J.; Denison, M.S.

    2003-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by a structurally diverse range of synthetic and natural chemicals, and it mediates the toxic and biological effects of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

  7. Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables, and fruits

    NARCIS (Netherlands)

    Jeuken, A.; Keser, B.J.G.; Khan, E.; Brouwer, A.; Koeman, J.H.; Denison, M.S.

    2003-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by a structurally diverse range of synthetic and natural chemicals, and it mediates the toxic and biological effects of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

  8. Aryl Hydrocarbon Receptor (AhR Modulates Cockroach Allergen-Induced Immune Responses through Active TGFβ1 Release

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    Yufeng Zhou

    2014-01-01

    Full Text Available Background. Aryl hydrocarbon receptor (AhR, a multifunctional regulator that senses and responds to environmental stimuli, plays a role in normal cell development and immune regulation. Recent evidence supports a significant link between environmental exposure and AhR in the development of allergic diseases. We sought to investigate whether AhR plays a role in mediating cockroach allergen-induced allergic immune responses. Methods. AhR expression in human lung fibroblasts from asthmatic and healthy individuals and in cockroach extract (CRE treated human lung fibroblasts (WI-38 was examined. The role of AhR in modulating CRE induced TGFβ1 production was investigated by using AhR agonist, TCDD, antagonist CH122319, and knockdown of AhR. The role of latent TGFβ1 binding protein-1 (LTBP1 in mediating TCDD induced active TGFβ1 release was also examined. Results. AhR expression was higher in airway fibroblasts from asthmatic subjects as compared to healthy controls. AhR in fibroblasts was activated by TCDD with an increased expression of cyp1a1 and cyp1b1. Increased AhR expression was observed in CRE-treated fibroblasts. Importantly, CRE induced TGFβ1 production in fibroblasts was significantly enhanced by TCDD but inhibited by CH122319. Reduced TGFβ1 production was further confirmed in fibroblasts with AhR knockdown. Moreover, AhR knockdown inhibited CRE induced fibroblast differentiation. Furthermore, TCDD induced active TGFβ1 release was significantly inhibited by LTBP1 knockdown. Conclusion. These results provide evidence for the role of AhR in modulating cockroach allergen-induced immune responses through controlling the active TGFβ1 release, suggesting a possible synergistic effect between exposure to allergens and environmental chemicals on the development of allergic diseases.

  9. Binding Mode and Structure-Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist.

    Science.gov (United States)

    Dolciami, Daniela; Gargaro, Marco; Cerra, Bruno; Scalisi, Giulia; Bagnoli, Luana; Servillo, Giuseppe; Fazia, Maria Agnese Della; Puccetti, Paolo; Quintana, Francisco J; Fallarino, Francesca; Macchiarulo, Antonio

    2018-02-06

    Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Ah receptor mediated suppression of the antibody response in mice is primarily dependent on the Ah phenotype of lymphoid tissue

    International Nuclear Information System (INIS)

    Silkworth, J.B.; Antrim, L.A.; Sack, G.

    1986-01-01

    Halogenated aromatic hydrocarbons act through the aromatic hydrocarbon (Ah) receptor in mice to produce a series of toxic effects of the immune system. The receptor protein is a product of the Ah gene locus. Ah responsive (Ahb/Ahb) mice express a high affinity receptor in both lymphoid and nonlymphoid tissues whereas nonresponsive Ahd/Ahd mice express a poor affinity receptor. To determine the role of the Ah receptor of lymphoid tissue relative to that of nonlymphoid tissue in the induction of immune impairment, bone marrow was used to reconstitute lethally irradiated mice of the same or opposite Ah phenotype. All mice were given 3,3',4,4'-tetrachlorobiphenyl (35 and 350 mumol/kg) ip 2 days before immunization with sheep erythrocytes (SRBC). The immune response to this T dependent antigen and organ weights were determined 5 or 7 days later in normal or chimeric mice, respectively. Monoclonal Lyt 1.1 and Lyt 1.2 antibodies were used to establish the origin of the cells which repopulated the chimeric thymuses. The immune responses of both BALB/cBy (Ahb/Ahb) and the BALB/cBy X DBA/2 hybrid, CByD2F1 (Ahb/Ahd), were significantly suppressed but DBA/2 mice were unaffected. The immune responses of chimeric BALB/cBy----BALB/cBy and BALB/cBy----DBA/2 (donor----recipient) mice were also significantly suppressed and thymic atrophy was observed in both cases. The serum anti-SRBC antibody titers of DBA/2----BALB/cBy chimeras were also significantly decreased although not to the same extent as in BALB/cBy----DBA/2 mice. Chimeric DBA/2----DBA/2 mice were not affected. These results indicate that the sensitivity to Ah receptor mediated suppression of the antibody response is primarily determined by the Ah phenotype of the lymphoid tissue

  11. Flavonoids and resveratrol as regulators of Ah-receptor activity: protection from dioxin toxicity.

    Science.gov (United States)

    Tutel'yan, V A; Gapparov, M M; Telegin, L Yu; Devichenskii, V M; Pevnitskii, L A

    2003-12-01

    In 2002 FAO and WHO published a joint appeal to state and public organizations and scientific community to take every effort to control the contents of dioxin and related biphenyls in the environment and food products. The toxic effects of dioxin are realized via its interaction with the Ah-receptor. Here we reviewed modern notions about the structure and functions of Ah-receptor. Particular attention was given to antagonists and agonists of the Ah-receptor, including various flavonoids and resveratrol.

  12. Detection and characterization of Ah receptor in tissue and cells from human tonsils

    International Nuclear Information System (INIS)

    Lorenzen, A.; Okey, A.B.

    1991-01-01

    Ah receptor was identified and characterized in cytosol and nuclear extracts from human tonsils obtained at surgery from children 2 to 6 years of age. Ah receptor was found in cytosol prepared from whole-tonsil homogenates as well as in cytosol and nuclear fractions prepared from tonsil lymphocytes or tonsil fibroblasts grown in primary culture. Cytosolic Ah receptor was detectable in tonsillar tissue with either halogenated (2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (TCDD)) or nonhalogenated (3-[3H]methylcholanthrene and [3H]benzo[a]pyrene) aromatic hydrocarbons and sedimented at approximately 9 S after velocity sedimentation on sucrose gradients. The apparent binding affinity (Kd) of [3H]TCDD for Ah receptor ranged from 3 to 12 nM in cytosols from seven different donors. The same analyses indicated a concentration of Ah receptor in human tonsils of approximately 100-300 fmol/mg cytosolic protein. Incubation of either tonsil lymphocytes or tonsil fibroblasts with [3H]TCDD resulted in transformation of cytosolic Ah receptor to a nuclear binding form which could be detected as a specifically labeled peak sedimenting at approximately 6 S on sucrose gradients. These data demonstrate the existence of Ah receptor in human tonsils and suggest that this immune organ may be an appropriate model for further studies on the mechanism and manifestation of aromatic hydrocarbon-induced immunotoxicity in man

  13. A human intervention study with foods containing natural Ah-receptor agonists does not significantly show AhR-mediated effects as measured in blood cells and urine

    NARCIS (Netherlands)

    Waard, de W.J.; Peijnenburg, A.A.C.M.; Baykus, H.; Aarts, H.J.M.; Hoogenboom, L.A.P.; Schooten, van F.J.; Kok, E.J.

    2008-01-01

    Binding and activation of the aryl hydrocarbon receptor (AhR) is thought to be an essential step in the toxicity of the environmental pollutants dioxins and dioxin-like PCBs. However, also a number of natural compounds, referred to as NAhRAs (natural Ah-receptor agonists), which are present in, for

  14. Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor

    International Nuclear Information System (INIS)

    Fallone, Frederique; Villard, Pierre-Henri; Seree, Eric; Rimet, Odile; Nguyen, Quock Binh; Bourgarel-Rey, Veronique; Fouchier, Francis; Barra, Yves; Durand, Alain; Lacarelle, Bruno

    2004-01-01

    CYP1A1 isoform is mainly regulated by the transcription factor AhR and to a lesser extent by the nuclear receptor RAR. The effect of a coexposure with 3MC, a AhR ligand, and RA, a RAR ligand, which are, respectively, strong and weak CYP1A1 inducers, is poorly known. We showed in Caco-2 cells that addition of RA significantly decreased 3MC-induced CYP1A1 expression by -55% for mRNA level and -30% for promoter and enzymatic activities. We further showed that RA decreased AhR protein level. Moreover, a physical interaction between AhR and the RAR-corepressor SMRT has been described in vitro. Using the corepressor inhibitor TSA, transfected-cells with SMRT cDNA, and coimmunoprecipitation experiments, we demonstrated that RA addition repressed AhR function through a marked AhR/SMRT physical interaction. This interaction explains the decrease of 3MC-induced CYP1A1 expression. This new mechanism involving the repression of AhR-induced CYP1A1 expression by retinoids allows better knowledge of the CYP1A1 regulation

  15. Divergent Ah Receptor Ligand Selectivity during Hominin Evolution.

    Science.gov (United States)

    Hubbard, Troy D; Murray, Iain A; Bisson, William H; Sullivan, Alexis P; Sebastian, Aswathy; Perry, George H; Jablonski, Nina G; Perdew, Gary H

    2016-10-01

    We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Aryl hydrocarbon receptor (AhR agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study

    Directory of Open Access Journals (Sweden)

    Schlezinger Jennifer J

    2003-12-01

    Full Text Available Abstract Background Bone marrow stromal cells produce cytokines required for the normal growth and development of all eight hematopoietic cell lineages. Aberrant cytokine production by stromal cells contributes to blood cell dyscrasias. Consequently, factors that alter stromal cell cytokine production may significantly compromise the development of normal blood cells. We have shown that environmental chemicals, such as aromatic hydrocarbon receptor (AhR agonists, suppress B lymphopoiesis by modulating bone marrow stromal cell function. Here, we extend these studies to evaluate the potential for two prototypic AhR agonists, 7,12-dimethylbenz [a]anthracene (DMBA and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, to alter stromal cell cytokine responses. Methods Bone marrow stromal cells were treated with AhR agonists and bacterial lipopolysaccharide (LPS to mimic innate inflammatory cytokine responses and to study the effects of AhR ligands on those responses. Steady state cytokine RNA levels were screened by RNAse protection assays (RPA and quantified by real-time PCR. Cytokine (IL-6 protein production was measured by ELISA. NF-κB EMSAs were used to study IL-6 transcriptional regulation. Results RPAs indicated that AhR+ bone marrow stromal cells consistently up-regulated genes encoding IL-6 and LIF in response to LPS, presumably through activation of Toll-like receptor 4. Pre-treatment with low doses of DMBA or TCDD selectively abrogated IL-6 gene induction but had no effect on LIF mRNA. Real-time-PCR indicated a significant inhibition of IL-6 mRNA by AhR ligands within 1 hour of LPS challenge which was reflected in a profound down-regulation of IL-6 protein induction, with DMBA and TCDD suppressing IL-6 levels as much as 65% and 88%, respectively. This potent inhibitory effect persisted for at least 72 hours. EMSAs measuring NF-κB binding to IL-6 promoter sequences, an event known to induce IL-6 transcription, indicated a significant decrease in

  17. Third-generation Ah receptor-responsive luciferase reporter plasmids: amplification of dioxin-responsive elements dramatically increases CALUX bioassay sensitivity and responsiveness.

    Science.gov (United States)

    He, Guochun; Tsutsumi, Tomoaki; Zhao, Bin; Baston, David S; Zhao, Jing; Heath-Pagliuso, Sharon; Denison, Michael S

    2011-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene-based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts.

  18. Combined chemical and toxicological long-term monitoring for AhR agonists with SPMD-based virtual organisms in drinking water Danjiangkou Reservoir, China.

    Science.gov (United States)

    Wang, Jingxian; Song, Guoqiang; Li, Aimin; Henkelmann, Bernhard; Pfister, Gerd; Tong, Anthony Z; Schramm, Karl-Werner

    2014-08-01

    SPMD-based virtual organisms (VOs) were employed for time-integrating, long-term sampling combined biological and chemical analyses for exposure assessment of hydrophobic organic pollutants (HOPs) in a drinking water reservoir, China. The SPMDs were deployed at four and five sites in the Danjiangkou (DJK) reservoir over two periods of 26 and 31 d to sequester the hydrophobic contaminants in water. The chosen bioassay response for the extracts of the SPMDs, the induction of 7-ethoxyresorufin-o-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The known aryl hydrocarbon receptor (AhR) agonists PAHs and PCBs were analyzed by HRGC/HRMS instrument. The cause-effect relationship between the observed AhR activities and chemical concentrations of detected AhR agonists was examined. The results show that the extracts from the SPMD samples could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) was not correlated with the bioassay-derived TCDD equivalent (TEQbio). The known AhR agonists could only account for 2-10% of the observed AhR responses among which the contribution of PCBs could almost be neglected. Unidentified AhR-active compounds represented a greater proportion of the TCDD equivalent (TCDD-EQ) in SPMD samples from DJK. Based on the first assessment, the VO followed by the combination of chemical and biological analyses emerges as a resource efficient water monitoring device in ecotoxicological assessment for toxicologically relevant compounds which are readily available for uptake by resident aquatic biota in drinking water resources. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Aminoflavone, a ligand of the Aryl Hydrocarbon Receptor (AhR), inhibits HIF-1α expression in an AhR-independent fashion

    Science.gov (United States)

    Terzuoli, Erika; Puppo, Maura; Rapisarda, Annamaria; Uranchimeg, Badarch; Cao, Liang; Burger, Angelika M.; Ziche, Marina; Melillo, Giovanni

    2010-01-01

    Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1β/ARNT, which is shared with HIF-1α, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacological activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1α transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1α by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1α expression in AhR100 cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1α in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1α mRNA expression by approximately 50%. Notably, actinomycin-D completely abrogated the ability of AF to down-regulate HIF-1α mRNA, indicating that active transcription was required for the inhibition of HIF-1α expression. Finally, AF inhibited HIF-1α protein accumulation and the expression of HIF-1-target genes in MCF-7 xenografts. These results demonstrate that AF inhibits HIF-1α in an AhR-independent fashion and they unveil additional activities of AF that may be relevant for its further clinical development. PMID:20736373

  20. The effect of benzalkonium chloride additions to AH Plus sealer. Antimicrobial, physical and chemical properties.

    Science.gov (United States)

    Arias-Moliz, M T; Ruiz-Linares, M; Cassar, G; Ferrer-Luque, C M; Baca, P; Ordinola-Zapata, R; Camilleri, J

    2015-07-01

    The aim of this study was to determine the antimicrobial and antibiofilm activities and physicochemical properties of AH Plus sealer mixed with different concentrations of benzalkonium chloride (BC). AH Plus was tested alone and mixed with 1%, 2% and 3% of BC. The antimicrobial and antibiofilm activities of the sealers against Enterococcus faecalis were evaluated by the direct contact test (DCT) and by confocal laser scanning microscopy, respectively. Setting time, flow and solubility were assessed according to ANSI/ADA specifications. Microhardness and contact angle tests were also performed. The chemical changes of the sealers were evaluated by X-ray diffraction analysis, and both Fourier transform infrared spectroscopy (FT-IR) and attenuated total reflectance Fourier transform infrared (ATR FT-IR). AH Plus+3% BC was the only sealer to promote total elimination of E. faecalis and the biovolume in this group was significantly lower than in the rest of the sealers (p>0.05). The physical properties of the sealers were according to the ANSI/ADA specifications. The microhardness decreased significantly when BC was added and a significant reduction in contact angle was obtained when incorporating 2% and 3% BC (p<0.05). No phase changes were observed with the modified sealers. The addition of 2% or higher concentrations BC to AH Plus showed antimicrobial and antibiofilm activities without affecting the properties specified in ANSI/ADA standards. However, additives to the root canal sealer altered other physical and chemical properties that are not commonly found in the literature to evaluate filling materials. The present study highlights that the antimicrobial properties of AH Plus can be significantly improved with the addition of BC. Testing beyond what is specified in standards may be indicated. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. A human intervention study with foods containing natural Ah-receptor agonists does not significantly show AhR-mediated effects as measured in blood cells and urine.

    Science.gov (United States)

    de Waard, Pim W J; Peijnenburg, Ad A C M; Baykus, Hakan; Aarts, Jac M M J G; Hoogenboom, Ron L A P; van Schooten, Frederik J; de Kok, Theo M C M

    2008-10-22

    Binding and activation of the aryl hydrocarbon receptor (AhR) is thought to be an essential step in the toxicity of the environmental pollutants dioxins and dioxin-like PCBs. However, also a number of natural compounds, referred to as NAhRAs (natural Ah-receptor agonists), which are present in, for example, fruits and vegetables, can bind and activate this receptor. To study their potential effects in humans, we first investigated the effect of the prototypical AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression in ex vivo exposed freshly isolated human lymphocytes, and compared the resulting gene expression profile with those caused by the well-known NAhRA indolo[3,2-b]carbazole (ICZ), originating from cruciferous vegetables, and by a hexane extract of NAhRA-containing grapefruit juice (GJE). Only ICZ induced a gene expression profile similar to TCDD in the lymphocytes, and both significantly up-regulated CYP1B1 and TIPARP (TCDD-inducible poly (ADP-ribose) polymerase) mRNA. Next, we performed a human intervention study with NAhRA-containing cruciferous vegetables and grapefruit juice. The expression of the prototypical AhR-responsive genes CYP1A1, CYP1B1 and NQO1 in whole blood cells and in freshly isolated lymphocytes was not significantly affected. Also enzyme activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), as judged by caffeine metabolites in urine, were unaffected, except for a small down-regulation of NAT2 activity by grapefruit juice. Examination of blood plasma with DR CALUX showed a 12% increased AhR agonist activity 3 and 24 h after consumption of cruciferous vegetables, but did not show a significant effect of grapefruit juice consumption. We conclude that intake of NAhRAs from food may result in minor AhR-related effects measurable in human blood and urine.

  2. Essential oils of culinary herbs and spices display agonist and antagonist activities at human aryl hydrocarbon receptor AhR.

    Science.gov (United States)

    Bartoňková, Iveta; Dvořák, Zdeněk

    2018-01-01

    Essential oils (EOs) of culinary herbs and spices are used to flavor, color and preserve foods and drinks. Dietary intake of EOs is significant, deserving an attention of toxicologists. We examined the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of human aryl hydrocarbon receptor (AhR), which is a pivotal xenobiotic sensor, having also multiple roles in human physiology. Tested EOs were sorted out into AhR-inactive ones (14 EOs) and AhR-active ones, including full agonists (cumin, jasmine, vanilla, bay leaf), partial agonists (cloves, dill, thyme, nutmeg, oregano) and antagonists (tarragon, caraway, turmeric, lovage, fennel, spearmint, star anise, anise). Major constituents (>10%) of AhR-active EOs were studied in more detail. We identified AhR partial agonists (carvacrol, ligustilide, eugenol, eugenyl acetate, thymol, ar-turmerone) and antagonists (trans-anethole, butylidine phtalide, R/S-carvones, p-cymene), which account for AhR-mediated activities of EOs of fennel, anise, star anise, caraway, spearmint, tarragon, cloves, dill, turmeric, lovage, thyme and oregano. We also show that AhR-mediated effects of some individual constituents of EOs differ from those manifested in mixtures. In conclusion, EOs of culinary herbs and spices are agonists and antagonists of human AhR, implying a potential for food-drug interactions and interference with endocrine pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Activation of aryl hydrocarbon receptor (AhR leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis.

    Directory of Open Access Journals (Sweden)

    Narendra P Singh

    Full Text Available Aryl hydrocarbon receptor (AhR, a transcription factor of the bHLH/PAS family, is well characterized to regulate the biochemical and toxic effects of environmental chemicals. More recently, AhR activation has been shown to regulate the differentiation of Foxp3(+ Tregs as well as Th17 cells. However, the precise mechanisms are unclear. In the current study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a potent AhR ligand, on epigenetic regulation leading to altered Treg/Th17 differentiation, and consequent suppression of colitis.Dextran sodium sulphate (DSS administration induced acute colitis in C57BL/6 mice, as shown by significant weight loss, shortening of colon, mucosal ulceration, and increased presence of CXCR3(+ T cells as well as inflammatory cytokines. Interestingly, a single dose of TCDD (25 µg/kg body weight was able to attenuate all of the clinical and inflammatory markers of colitis. Analysis of T cells in the lamina propria (LP and mesenteric lymph nodes (MLN, during colitis, revealed decreased presence of Tregs and increased induction of Th17 cells, which was reversed following TCDD treatment. Activation of T cells from AhR(+/+ but not AhR (-/- mice, in the presence of TCDD, promoted increased differentiation of Tregs while inhibiting Th17 cells. Analysis of MLN or LP cells during colitis revealed increased methylation of CpG islands of Foxp3 and demethylation of IL-17 promoters, which was reversed following TCDD treatment.These studies demonstrate for the first time that AhR activation promotes epigenetic regulation thereby influencing reciprocal differentiation of Tregs and Th17 cells, and amelioration of inflammation.

  4. Aryl hydrocarbon receptor (AhR) inducers and estrogen receptor (ER) activities in surface sediments of Three Gorges Reservoir, China evaluated with in vitro cell bioassays

    NARCIS (Netherlands)

    Wang, J.; Bovee, T.F.H.; Bi, Y.; Bernhöft, S.; Schramm, K.W.

    2014-01-01

    Two types of biological tests were employed for monitoring the toxicological profile of sediment cores in the Three Gorges Reservoir (TGR), China. In the present study, sediments collected in June 2010 from TGR were analyzed for estrogen receptor (ER)- and aryl hydrocarbon receptor (AhR)-mediated

  5. Influence of TCDD and natural Ah receptor agonists on benzo[a]pyrene-DNA adduct formation in the Caco-2 human colon cell line

    NARCIS (Netherlands)

    Waard, de W.J.; Kok, de T.M.C.M.; Maas, L.M.; Peijnenburg, A.A.C.M.; Hoogenboom, L.A.P.; Aarts, H.J.M.; Schooten, van F.J.

    2008-01-01

    Several compounds originating from cruciferous vegetables and citrus fruits bind to and activate the aryl hydrocarbon receptor (AhR). This receptor plays an important role in the toxicity of the known tumour promoter and potent AhR-agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However,

  6. Development and characterization of a green fluorescent protein-based rat cell bioassay system for detection of AH receptor ligands

    Energy Technology Data Exchange (ETDEWEB)

    Zhao Bin; Denison, M. [California Univ., Davis, CA (United States). Dept. of Environmental Toxicology

    2004-09-15

    Proper epidemiological, risk assessment and exposure analysis of TCDD and related HAHs requires accurate measurements of these chemicals both in the species of interest and in various exposure matrices (i.e. biological, environmental, food and feed). While high-resolution instrumental analysis techniques are established for these chemicals, these procedures are very costly, time-consuming and are impractical for large scale sampling studies. Accordingly, numerous bioanalytical methods have been developed for the detection of these chemicals in extracts from a variety of matrices, the majority of which take the advantage of the ability of these chemicals to activate one or more aspects of the AhR-dependent mechanism of action. One of the most sensitive bioassay systems developed to date is the so-called CALUX (Chemically Activated Luciferase Expression) assay, which is based on novel recombinant cell lines that contain a stably transfected dioxin (AhR)-responsive firefly luciferase gene. Treatment of these cells with TCDD and related HAHs and polycyclic aromatic hydrocarbons (PAHs), as well as other AhR ligands, results in induction of reporter gene expression in a time-, dose-, AhR-, and chemical-specific manner. The level of reporter gene expression correlates with the total concentration of the TCDD-like AhR inducers (agonists) present in the sample. Although the firefly luciferase reporter gene contributes to the high degree of sensitivity of the assay, it also has limitations with respect to our need for a rapid and inexpensive bioassay for high-throughput screening analysis. Accordingly, we previously developed a stably transfected murine cell line containing an AhRresponsive enhanced green fluorescent protein (EGFP) reporter gene. This cell line provided us with a high-throughput cell bioassay system for identification and characterization of AhR agonists and antagonists. Here we have extended these studies and describe the development, optimization, and

  7. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Xingguo, E-mail: chengx@stjohns.edu [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Vispute, Saurabh G. [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Liu, Jie [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Cheng, Christine; Kharitonenkov, Alexei [Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285 (United States); Klaassen, Curtis D., E-mail: curtisklaassenphd@gmail.com [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States)

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression.

  8. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    International Nuclear Information System (INIS)

    Cheng, Xingguo; Vispute, Saurabh G.; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D.

    2014-01-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression

  9. Aryl hydrocarbon receptor (AhR and its endogenous agonist – indoxyl sulfate in chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Tomasz Kamiński

    2017-07-01

    Full Text Available The indoxyl sulfate (IS, indoxyl sulphate is the end product of dietary tryptophan degradation by indole pathway and significantly higher serum and tissue concentrations of this compound is observed in patients with impaired renal function. Despite the high albumin binding affinity, the remaining free fraction of IS has a number of biological effects related to the generation of oxidative stress andactivation of signaling pathways related to NF-кB, p53 protein, STAT3, TGF-β and Smad2/3. IS induces the inflammatory process, exerts nephrotoxic activity and is also a factor impairing the cardiovascular system.Its high concentrations are associated with the occurrence of cardiovascular incidents, whose frequency is significantly higher in patients with chronic kidney disease. Evaluation of the mechanisms that underlie the high reactivity of indoxyl sulfate and its biological effects showed that this compound is an agonist of the aryl hydrocarbon receptor (AhR. This receptor plays an important role in maintaining homeostasis Moreover, AhR exerts high transcriptional activity, so ligands of obciążethis receptor may exert different biological effects. The following paper describes the role of indoxyl sulfate as AhR ligand in the context of the excessive accumulation, which appears as one of the symptoms associated with chronic kidney disease.

  10. Considerations for potency equivalent calculations in the Ah receptor-based CALUX bioassay: normalization of superinduction results for improved sample potency estimation.

    Science.gov (United States)

    Baston, David S; Denison, Michael S

    2011-02-15

    The chemically activated luciferase expression (CALUX) system is a mechanistically based recombinant luciferase reporter gene cell bioassay used in combination with chemical extraction and clean-up methods for the detection and relative quantitation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like halogenated aromatic hydrocarbons in a wide variety of sample matrices. While sample extracts containing complex mixtures of chemicals can produce a variety of distinct concentration-dependent luciferase induction responses in CALUX cells, these effects are produced through a common mechanism of action (i.e. the Ah receptor (AhR)) allowing normalization of results and sample potency determination. Here we describe the diversity in CALUX response to PCDD/Fs from sediment and soil extracts and not only report the occurrence of superinduction of the CALUX bioassay, but we describe a mechanistically based approach for normalization of superinduction data that results in a more accurate estimation of the relative potency of such sample extracts. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  12. Linking Ah receptor mediated effects of sediments and impacts on fish to key pollutants in the Yangtze Three Gorges Reservoir, China - A comprehensive perspective.

    Science.gov (United States)

    Floehr, Tilman; Scholz-Starke, Björn; Xiao, Hongxia; Hercht, Hendrik; Wu, Lingling; Hou, Junli; Schmidt-Posthaus, Heike; Segner, Helmut; Kammann, Ulrike; Yuan, Xingzhong; Roß-Nickoll, Martina; Schäffer, Andreas; Hollert, Henner

    2015-12-15

    The Three Gorges Reservoir (TGR), created in consequence of the Yangtze River's impoundment by the Three Gorges Dam, faces numerous anthropogenic impacts that challenge its unique ecosystem. Organic pollutants, particularly aryl hydrocarbon receptor (AhR) agonists, have been widely detected in the Yangtze River, but only little research was yet done on AhR-mediated activities. Hence, in order to assess effects of organic pollution, with particular focus on AhR-mediated activities, several sites in the TGR area were examined applying the "triad approach". It combines chemical analysis, in vitro, in vivo and in situ investigations to a holistic assessment. Sediments and the benthic fish species Pelteobagrus vachellii were sampled in 2011/2012, respectively, to identify relevant endpoints. Sediment was tested in vitro with the ethoxyresorufin-O-deethylase (EROD) induction assay, and in vivo with the Fish Embryo Toxicity Test and Sediment Contact Assay with Danio rerio. Activities of phase I (EROD) and phase II (glutathione-S-transferase) biotransformation enzymes, pollutant metabolites and histopathological alterations were studied in situ in P. vachellii. EROD induction was tested in vitro and in situ to evaluate possible relationships. Two sites, near Chongqing and Kaixian city, were identified as regional hot-spots and further investigated in 2013. The sediments induced in the in vitro/in vivo bioassays AhR-mediated activities and embryotoxic/teratogenic effects - particularly on the cardiovascular system. These endpoints could be significantly correlated to each other and respective chemical data. However, particle-bound pollutants showed only low bioavailability. The in situ investigations suggested a rather poor condition of P. vachellii, with histopathological alterations in liver and excretory kidney. Fish from Chongqing city exhibited significant hepatic EROD induction and obvious parasitic infestations. The polycyclic aromatic hydrocarbon (PAH) metabolite 1

  13. An endogenous aryl hydrocarbon receptor (AhR) ligand, ITE induces regulatory T cells (Tregs) and ameliorates experimental colitis.

    Science.gov (United States)

    Abron, Jessicca D; Singh, Narendra P; Mishra, Manoj K; Price, Robert L; Nagarkatti, Mitzi; Nagarkatti, Prakash S; Singh, Udai P

    2018-04-19

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health-care cost. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if nontoxic ligand of AhR, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulphate (DSS)-induced colitis. Our studies demonstrated that in mice that received ITE treatment, in-vivo colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs) and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared to controls. This induction of Tregs was reversed by AhR antagonist treatment in-vitro. ITE treatment also increased dendritic cells (DCs; CD11c+) and decreased F4/80+ (macrophage) from the spleen, MLNs and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6 and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+ T cells and cytokines. Thus, our work demonstrates that the nontoxic endogenous AhR ligand ITE, may serve as a therapeutic modality to treat IBD.

  14. Evaluation of the Ecotoxicity of Sediments from Yangtze River Estuary and Contribution of Priority PAHs to Ah Receptor-Mediated Activities

    Science.gov (United States)

    Liu, Li; Chen, Ling; Shao, Ying; Zhang, Lili; Floehr, Tilman; Xiao, Hongxia; Yan, Yan; Eichbaum, Kathrin; Hollert, Henner; Wu, Lingling

    2014-01-01

    In this study, in vitro bioassays were performed to assess the ecotoxicological potential of sediments from Yangtze River estuary. The cytotoxicity and aryl hydrocarbon receptor (AhR)-mediated toxicity of sediment extracts with rainbow trout (Oncorhynchus mykiss) liver cells were determined by neutral red retention and 7-ethoxyresorufin-O-deethylase assays. The cytotoxicity and AhR-mediated activity of sediments from the Yangtze River estuary ranged from low level to moderate level compared with the ecotoxicity of sediments from other river systems. However, Yangtze River releases approximately 14 times greater water discharge compared with Rhine, a major river in Europe. Thus, the absolute pollution mass transfer of Yangtze River may be detrimental to the environmental quality of estuary and East China Sea. Effect-directed analysis was applied to identify substances causing high dioxin-like activities. To identify unknown substances contributing to dioxin-like potencies of whole extracts, we fractionated crude extracts by open column chromatography. Non-polar paraffinic components (F1), weakly and moderately polar components (F2), and highly polar substances (F3) were separated from each crude extract of sediments. F2 showed the highest dioxin-like activities. Based on the results of mass balance calculation of chemical toxic equivalent concentrations (TEQs), our conclusion is that priority polycyclic aromatic hydrocarbons indicated a low portion of bio-TEQs ranging from 1% to 10% of crude extracts. Further studies should be conducted to identify unknown pollutants. PMID:25111307

  15. Evaluation of the ecotoxicity of sediments from Yangtze river estuary and contribution of priority PAHs to ah receptor--mediated activities.

    Science.gov (United States)

    Liu, Li; Chen, Ling; Shao, Ying; Zhang, Lili; Floehr, Tilman; Xiao, Hongxia; Yan, Yan; Eichbaum, Kathrin; Hollert, Henner; Wu, Lingling

    2014-01-01

    In this study, in vitro bioassays were performed to assess the ecotoxicological potential of sediments from Yangtze River estuary. The cytotoxicity and aryl hydrocarbon receptor (AhR)-mediated toxicity of sediment extracts with rainbow trout (Oncorhynchus mykiss) liver cells were determined by neutral red retention and 7-ethoxyresorufin-O-deethylase assays. The cytotoxicity and AhR-mediated activity of sediments from the Yangtze River estuary ranged from low level to moderate level compared with the ecotoxicity of sediments from other river systems. However, Yangtze River releases approximately 14 times greater water discharge compared with Rhine, a major river in Europe. Thus, the absolute pollution mass transfer of Yangtze River may be detrimental to the environmental quality of estuary and East China Sea. Effect-directed analysis was applied to identify substances causing high dioxin-like activities. To identify unknown substances contributing to dioxin-like potencies of whole extracts, we fractionated crude extracts by open column chromatography. Non-polar paraffinic components (F1), weakly and moderately polar components (F2), and highly polar substances (F3) were separated from each crude extract of sediments. F2 showed the highest dioxin-like activities. Based on the results of mass balance calculation of chemical toxic equivalent concentrations (TEQs), our conclusion is that priority polycyclic aromatic hydrocarbons indicated a low portion of bio-TEQs ranging from 1% to 10% of crude extracts. Further studies should be conducted to identify unknown pollutants.

  16. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

    International Nuclear Information System (INIS)

    Lund, Amie K.; Goens, M. Beth; Nunez, Bethany A.; Walker, Mary K.

    2006-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ET A receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, β-myosin heavy chain (β-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ET A receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and β-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ET A receptor as primary determinants of hypertension and cardiac pathology in AhR null mice

  17. Aryl hydrocarbon receptor (AhR-mediated perturbations in gene expression during early stages of CD4+ T-cell differentiation

    Directory of Open Access Journals (Sweden)

    Diana eRohlman

    2012-08-01

    Full Text Available Activation of the aryl hydrocarbon receptor (AhR by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, mediates potent suppression of T-cell dependent immune responses. The suppressive effects of TCDD occur early during CD4+ T-cell differentiation in the absence of effects on proliferation and have recently been associated with the induction of AhR-dependent regulatory T-cells (Treg. Since AhR functions as a ligand-activated transcription factor, changes in gene expression induced by TCDD during the early stages of CD4+ T-cell differentiation are likely to reflect fundamental mechanisms of AhR action. A custom panel of genes associated with T-cell differentiation was used to query changes in gene expression induced by exposure to 1 nM TCDD. CD4+ T-cells from AhR+/+ and AhR-/- mice were cultured with cytokines known to polarize the differentiation of T-cells to various effector lineages. Treatment with TCDD induced expression of Cyp1a1, Cyp1b1 and Ahrr in CD4+ T-cells from AhR+/+ mice under all culture conditions, validating the presence and activation of AhR in these cells. The highest levels of AhR activation occurred under Th17 conditions at 24 hours and Tr1 conditions at 48 hours. Unexpectedly, expression levels of most genes associated with early T-cell differentiation were unaltered by AhR activation, including lineage-specific genes that drive CD4+ T-cell polarization. The major exception was AhR-dependent up-regulation of Il22 that was seen under all culture conditions. Independent of TCDD, AhR down-regulated the expression of Il17a and Rorc based on increased expression of these genes in AhR-deficient cells across culture conditions. These findings are consistent with a role for AhR in down-regulation of inflammatory immune responses and implicate IL-22 as a potential contributor to the immunosuppressive effects of TCDD.

  18. Characterization and expression analysis of AH receptors in aquatic mammals and birds

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun-Young [Ehime Prefectural Institute of Public Health and Environmental Science, Matsuyama (Japan); Yasui, Tomoko; Hisato, Iwata; Shinsuke, Tanabe [Ehime Univ., Matsuyama (Japan)

    2004-09-15

    The magnitude of the risk that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related planar halogenated aromatic hydrocarbons (PHAHs) pose to the health of aquatic birds and mammals is uncertain, because of the lack of direct information on the sensitivity and toxicity to these chemicals. Exposure to PHAHs is speculated to produce toxicity through changes in the expression of genes involved in the control of cell growth and differentiation. These changes are initiated by the binding to the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor. The AHR and its dimerization partner ARNT belong to the basic-helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcriptional regulation proteins. The bHLH domain was involved in protein-DNA and protein-protein interactions, and the PAS domain forms a secondary dimerization surface for heteromeric interactions between AHR and ARNT. Although the presence and basic function of AHR are known to be conserved in most vertebrates, only a limited number of studies on the structure and functional diversity of AHR in aquatic mammals and birds have been reported, in spite of their high exposure to dioxins and other related chemicals. To understand the molecular mechanism of susceptibility to dioxin exposure and toxic effects that PHAHs pose in wild animals, we investigated the molecular and functional characterization of AHRs from aquatic mammals and birds. Initially, the AHR cDNAs from the livers of Baikal seal (Pusa sibirica), black-footed albatross (Diomedea nigripes) and common cormorant (Phalacrocorax carbo) were cloned and sequenced. We also clarified the tissue-specific expression pattern of AHR mRNA and the relationships among PHAHs, AHR and CYP expression levels in the liver of Baikal seals and common cormorants.

  19. Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: The case of the aryl hydrocarbon receptor

    International Nuclear Information System (INIS)

    Okey, Allan B.; Franc, Monique A.; Moffat, Ivy D.; Tijet, Nathalie; Boutros, Paul C.; Korkalainen, Merja; Tuomisto, Jouko; Pohjanvirta, Raimo

    2005-01-01

    Mechanistic toxicology has predominantly been focused on adverse effects that are caused by reactive metabolites or by reactive oxygen species. However, many important xenobiotics exert their toxicity, not by generating reactive products, but rather by altering expression of specific genes. In particular, some environmental contaminants target nuclear receptors that function as regulators of transcription. For example, binding of xenobiotic chemicals to steroid receptors is a principle mechanism of endocrine disruption. The aryl hydrocarbon receptor (AHR) mediates toxicity of dioxin-like compounds. In mice, a polymorphism in the AHR ligand-binding domain reduces binding affinity by about 10-fold in the DBA/2 strain compared with the C57BL/6 strain; consequently, dose-response curves for numerous biochemical and toxic effects are shifted about one log to the right in DBA/2 mice. In the Han/Wistar (Kuopio) (H/W) rat strain, a polymorphism causes a deletion of 38 or 43 amino acids from the AHR transactivation domain. This deletion is associated with a greater than 1000-fold resistance to lethality from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Genes in the conventional AH gene battery (e.g. CYP1A1, CYP1A2, CYP1B1, ALDH3A1, NQO1 and UGT1A1) remain responsive to TCDD in H/W rats despite the large deletion. However, the deletion may selectively alter the receptor's ability to dysregulate specific genes that are key to dioxin toxicity. We are identifying these genes using an expression array approach in dioxin-sensitive vs. dioxin-resistant rat strains and lines. Polymorphisms exist in the human AH receptor, but thus far they have not been shown to have any substantial effect on human responses to AHR-ligands

  20. Phytomonitoring and phytoremediation of agrochemicals and related compounds based on recombinant cytochrome P450s and aryl hydrocarbon receptors (AhRs).

    Science.gov (United States)

    Shimazu, Sayuri; Inui, Hideyuki; Ohkawa, Hideo

    2011-04-13

    Molecular mechanisms of metabolism and modes of actions of agrochemicals and related compounds are important for understanding selective toxicity, biodegradability, and monitoring of biological effects on nontarget organisms. It is well-known that in mammals, cytochrome P450 (P450 or CYP) monooxygenases metabolize lipophilic foreign compounds. These P450 species are inducible, and both CYP1A1 and CYP1A2 are induced by aryl hydrocarbon receptor (AhR) combined with a ligand. Gene engineering of P450 and NADPH cytochrome P450 oxidoreductase (P450 reductase) was established for bioconversion. Also, gene modification of AhRs was developed for recombinant AhR-mediated β-glucronidase (GUS) reporter assay of AhR ligands. Recombinant P450 genes were transformed into plants for phytoremediation, and recombinant AhR-mediated GUS reporter gene expression systems were each transformed into plants for phytomonitoring. Transgenic rice plants carrying CYP2B6 metabolized the herbicide metolachlor and remarkably reduced the residues in the plants and soils under paddy field conditions. Transgenic Arabidopsis plants carrying recombinant guinea pig (g) AhR-mediated GUS reporter genes detected PCB126 at the level of 10 ng/g soils in the presence of biosurfactants MEL-B. Both phytomonitoring and phytoremediation plants were each evaluated from the standpoint of practical uses.

  1. Aromatic hydrocarbons upregulate glyceraldehyde-3-phosphate dehydrogenase and induce changes in actin cytoskeleton. Role of the aryl hydrocarbon receptor (AhR)

    International Nuclear Information System (INIS)

    Reyes-Hernandez, O.D.; Mejia-Garcia, A.; Sanchez-Ocampo, E.M.; Castro-Munozledo, F.; Hernandez-Munoz, R.; Elizondo, G.

    2009-01-01

    Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme involved in several cellular functions including glycolysis, membrane transport, microtubule assembly, DNA replication and repair, nuclear RNA export, apoptosis, and the detection of nitric oxide stress. Therefore, modifications in the regulatory ability and function of GAPDH may alter cellular homeostasis. We report here that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and β-naphthoflavone, which are well-known ligands for the aryl hydrocarbon receptor (AhR), increase GAPDH mRNA levels in vivo and in vitro, respectively. These compounds fail to induce GAPDH transcription in an AhR-null mouse model, suggesting that the increase in GAPDH level is dependent upon AhR activation. To analyse the consequences of AhR ligands on GAPDH function, mice were treated with TCDD and the level of liver activity of GAPDH was determined. The results showed that TCDD treatment increased GAPDH activity. On the other hand, treatment of Hepa-1 cells with β-naphthoflavone leads to an increase in microfilament density when compared to untreated cultures. Collectively, these results suggest that AhR ligands, such as polycyclic hydrocarbons, can modify GAPDH expression and, therefore, have the potential to alter the multiple functions of this enzyme.

  2. Polycyclic Aromatic Hydrocarbons (PAHs) Mediate Transcriptional Activation of the ATP Binding Cassette Transporter ABCB6 Gene via the Aryl Hydrocarbon Receptor (AhR)*

    Science.gov (United States)

    Chavan, Hemantkumar; Krishnamurthy, Partha

    2012-01-01

    Liver is endowed with a mechanism to induce hepatic cytochromes P450 (CYP450s) in response to therapeutic drugs and environmental contaminants, leading to increased detoxification and elimination of the xenobiotics. Each CYP450 is composed of an apoprotein moiety and a heme prosthetic group, which is required for CYP450 activity. Thus, under conditions of CYP450 induction, there is a coordinate increase in heme biosynthesis to compensate for the increased expression of CYP450s. ABCB6, a mitochondrial ATP binding cassette transporter, which regulates coproporphyrinogen transport from the cytoplasm into the mitochondria to complete heme biosynthesis, represents a previously unrecognized rate-limiting step in heme biosynthesis. However, it is not known if exposure to drugs and environmental contaminants induces ABCB6 expression, to assure an adequate and apparently coordinated supply of heme for the generation of functional cytochrome holoprotein. In the present study, we demonstrate that polycyclic aromatic hydrocarbons (PAHs), the widely distributed environmental toxicants shown to induce porphyrin accumulation causing hepatic porphyria, up-regulate ABCB6 expression in both mice and humans. Using siRNA technology and Abcb6 knock-out mice, we demonstrate that PAH-mediated increase in hepatic porphyrins is compromised in the absence of ABCB6. Moreover, in vivo studies in aryl hydrocarbon receptor (AhR) knock-out mice demonstrate that PAH induction of ABCB6 is mediated by AhR. Promoter activation studies combined with electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrate direct interactions between the AhR binding sites in the ABCB6 promoter and the AhR receptor, implicating drug activation mechanisms for ABCB6 similar to those found in inducible cytochrome P450s. These studies are the first to describe direct transcriptional activation of both mouse and human ABCB6 by xenobiotics. PMID:22761424

  3. Quantitative characterization of changes in bone geometry, mineral density and biomechanical properties in two rat strains with different Ah-receptor structures after long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

    International Nuclear Information System (INIS)

    Herlin, Maria; Kalantari, Fereshteh; Stern, Natalia; Sand, Salomon; Larsson, Sune; Viluksela, Matti; Tuomisto, Jouni T.; Tuomisto, Jouko; Tuukkanen, Juha; Jaemsae, Timo; Lind, P. Monica; Hakansson, Helen

    2010-01-01

    Background: Both industrial chemicals and environmental pollutants can interfere with bone modeling and remodeling. Recently, detailed toxicological bone studies have been performed following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which exerts most of its toxic effects through the aryl hydrocarbon receptor (AhR). Objectives: The aims of the present study were to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following long-term exposure to TCDD, and to further investigate the role of AhR in TCDD-induced bone alterations. To this end, tissue material used in the study was derived from TCDD-exposed Long-Evans (L-E) and Han/Wistar (H/W) rats, which differ markedly in sensitivity to TCDD-induced toxicity due to a strain difference in AhR structure. Methods: Ten weeks old female L-E and H/W rats were administered TCDD s.c. once per week for 20 weeks, at doses corresponding to calculated daily doses of 0, 1, 10, 100 and 1000 ng TCDD/kg bw (H/W only). Femur, tibia and vertebra from the L-E and H/W rats were analyzed by peripheral quantitative computed tomography (pQCT) and biomechanical testing at multiple sites. Dose-response modeling was performed to establish benchmark doses for the analyzed bone parameters, and to quantify strain sensitivity differences for those parameters, which were affected by TCDD exposure in both rat strains. Results: Bone geometry and bone biomechanical parameters were affected by TCDD exposure, while bone mineral density parameters were less affected. The trabecular area at proximal tibia and the endocortical circumference at tibial diaphysis were the parameters that showed the highest maximal responses. Significant strain differences in response to TCDD treatment were observed, with the L-E rat being the most sensitive strain. For the parameters that were affected in both strains, the differences in sensitivity were quantified, showing the most pronounced (about 49-fold) strain

  4. A rapid and reagent-free bioassay for the detection of dioxin-like compounds and other aryl hydrocarbon receptor (AhR) agonists using autobioluminescent yeast.

    Science.gov (United States)

    Xu, Tingting; Young, Anna; Marr, Enolia; Sayler, Gary; Ripp, Steven; Close, Dan

    2018-02-01

    An autonomously bioluminescent Saccharomyces cerevisiae BLYAhS bioreporter was developed in this study for the simple and rapid detection of dioxin-like compounds (DLCs) and aryl hydrocarbon receptor (AhR) agonists. This recombinant yeast reporter was based on a synthetic bacterial luciferase reporter gene cassette (lux) that can produce the luciferase as well as the enzymes capable of self-synthesizing the requisite substrates for bioluminescent production from endogenous cellular metabolites. As a result, bioluminescent signal production is generated continuously and autonomously without cell lysis or exogenous reagent addition. By linking the expression of the autobioluminescent lux reporter cassette to AhR activation via the use of a dioxin-responsive promoter, the S. cerevisiae BLYAhS bioreporter emitted a bioluminescent signal in response to DLC exposure in a dose-responsive manner. The model dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), could be detected within 4 h with a half maximal effective concentration (EC 50 ) of ~ 8.1 nM and a lower detection limit of 500 pM. The autobioluminescent response of BLYAhS to other AhR agonists, including 2,3,7,8-tetrachlorodibenzofuran (TCDF), polychlorinated bisphenyl congener 126 (PCB-126) and 169 (PCB-169), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), benzo[a]pyrene (BaP), and β-naphthoflavone (bNF), were also characterized in this study. The non-destructive and reagent-free nature of the BLYAhS reporter assay facilitated near-continuous, automated signal acquisition without additional hands-on effort and cost, providing a simple and cost-effective method for rapid DLC detection.

  5. Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene

    Energy Technology Data Exchange (ETDEWEB)

    Erichsen, Thomas J; Ehmer, Ursula; Kalthoff, Sandra; Lankisch, Tim O; Mueller, Tordis M [Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany); Munzel, Peter A [Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tubingen, Tubingen (Germany); Manns, Michael P [Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany); Strassburg, Christian P. [Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany)], E-mail: strassburg.christian@mh-hannover.de

    2008-07-15

    UDP glucuronosyltransferases (UGTs) play an important role for drug detoxification and toxicity. UGT function is genetically modulated by single nucleotide polymorphisms (SNPs) which lead to the expression of functionally altered protein, or altered expression levels. UGT1A4 activity includes anticonvulsants, antidepressants and environmental mutagens. In this study the induction of the human UGT1A4 gene and a potential influence of genetic variation in its promoter region were analyzed. SNPs at bp - 219 and - 163 occurred in 9% among 109 blood donors reducing UGT1A4 transcription by 40%. UGT1A4 transcription was dioxin inducible. Reporter gene experiments identified 2 xenobiotic response elements (XRE), which were functionally confirmed by mutagenesis analyses, and binding was demonstrated by electromobility shift assays. Constitutive human UGT1A4 gene expression and induction was aryl hydrocarbon receptor (AhR)-dependent, and reduced in the presence of SNPs at bp - 219 and - 163. AhR-mediated regulation of the human UGT1A4 gene by two XRE and a modulation by naturally occurring genetic variability by SNPs is demonstrated, which indicates gene-environment interaction with potential relevance for drug metabolism.

  6. Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene

    International Nuclear Information System (INIS)

    Erichsen, Thomas J.; Ehmer, Ursula; Kalthoff, Sandra; Lankisch, Tim O.; Mueller, Tordis M.; Munzel, Peter A.; Manns, Michael P.; Strassburg, Christian P.

    2008-01-01

    UDP glucuronosyltransferases (UGTs) play an important role for drug detoxification and toxicity. UGT function is genetically modulated by single nucleotide polymorphisms (SNPs) which lead to the expression of functionally altered protein, or altered expression levels. UGT1A4 activity includes anticonvulsants, antidepressants and environmental mutagens. In this study the induction of the human UGT1A4 gene and a potential influence of genetic variation in its promoter region were analyzed. SNPs at bp - 219 and - 163 occurred in 9% among 109 blood donors reducing UGT1A4 transcription by 40%. UGT1A4 transcription was dioxin inducible. Reporter gene experiments identified 2 xenobiotic response elements (XRE), which were functionally confirmed by mutagenesis analyses, and binding was demonstrated by electromobility shift assays. Constitutive human UGT1A4 gene expression and induction was aryl hydrocarbon receptor (AhR)-dependent, and reduced in the presence of SNPs at bp - 219 and - 163. AhR-mediated regulation of the human UGT1A4 gene by two XRE and a modulation by naturally occurring genetic variability by SNPs is demonstrated, which indicates gene-environment interaction with potential relevance for drug metabolism

  7. Equivalent molecular mass of cytosolic and nuclear forms of Ah receptor from Hepa-1 cells determined by photoaffinity labeling with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin

    International Nuclear Information System (INIS)

    Prokipcak, R.D.; Okey, A.B.

    1990-01-01

    The structure of the Ah receptor previously has been extensively characterized by reversible binding of the high affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. We report the use of [ 3 H]2,3,7,8-tetrachlorodibenzo-p-dioxin as a photoaffinity ligand for Ah receptor from the mouse hepatoma cell line Hepa-1c1c9. Both cytosolic and nuclear forms of Ah receptor could be specifically photoaffinity-labeled, which allowed determination of molecular mass for the two forms under denaturing conditions. After analysis by fluorography of polyacrylamide gels run in the presence of sodium dodecyl sulfate, molecular mass for the cytosolic form of Ah receptor was estimated at 92,000 +/- 4,300 and that for the nuclear form was estimated at 93,500 +/- 3,400. Receptor in mixture of cytosol and nuclear extract (each labeled separately with [ 3 H]2,3,7,8-tetrachlorodibenzo-p-dioxin) migrated as a single band. These results are consistent with the presence of a common ligand-binding subunit of identical molecular mass in both cytosolic and nuclear complexes

  8. Linked expression of Ah receptor, ARNT, CYP1A1, and CYP1B1 in rat mammary epithelia, in vitro, is each substantially elevated by specific extracellular matrix interactions that precede branching morphogenesis.

    Science.gov (United States)

    Larsen, Michele Campaigne; Brake, Paul B; Pollenz, Richard S; Jefcoate, Colin R

    2004-11-01

    Cytochrome P4501B1 (CYP1B1), the major constitutively expressed CYP in the rat mammary gland, is induced by Ah-receptor (AhR) ligands, while CYP1A1 is predominantly expressed only after induction. These CYPs contribute to carcinogenic activation of polycyclic aromatic hydrocarbons (PAHs). AhR, ARNT, and CYP1B1 were only weakly expressed, even after 2,3,7,8-tetrachlorodibenzo-p-dioxin induction, when rat mammary epithelial cells (RMEC) were cultured on plastic. RMEC cultured on the extracellular matrix (ECM), Matrigel, or on a floating gel of collagen I demonstrated branching morphogenesis and substantially increased basal CYP1B1 and induced CYP1A1 expression, in parallel with large increases in AhR and ARNT expression. Branching was more pronounced in the Wistar Kyoto than in the Wistar Furth rat strain. Although EGF enhanced branching, neither strain nor growth factor treatment substantially impacted CYP expression. Increased AhR and ARNT expression is observed within 24 h of dispersal on Matrigel, substantially prior to branch formation. Culture on thin layers of collagen I, collagen IV, and laminin, respectively, failed to reproduce the branching morphogenesis or increases in AhR, ARNT, or CYP expression. However, adherent, gelled collagen I recapitulated the increased protein expression, without supporting branching. This increased protein expression was closely paralleled by enhanced expression of beta-catenin and E-cadherin, components of cell-cell adhesion complexes. A synthetic peptide that selectively antagonizes integrin-ECM interactions reduced branch formation, without diminishing AhR, ARNT, and CYP expression. These data demonstrate that early ECM surface adhesion interactions mediate AhR and ARNT expression, which enhances CYP expression, independent of branching morphogenesis.

  9. Perturbation effect of reduced graphene oxide quantum dots (rGOQDs) on aryl hydrocarbon receptor (AhR) pathway in zebrafish.

    Science.gov (United States)

    Zhang, Jing-Hui; Sun, Tai; Niu, Aping; Tang, Yu-Mei; Deng, Shun; Luo, Wei; Xu, Qun; Wei, Dapeng; Pei, De-Sheng

    2017-07-01

    Graphene quantum dots (GQDs) has been widely used in enormous fields, however, the inherent molecular mechanism of GQDs for potential risks in biological system is still elusive to date. In this study, the outstanding reduced graphene quantum dots (rGOQDs) with the QY as high as 24.62% were successfully synthesized by the improved Hummers method and DMF hydrothermal treatment approach. The rGOQDs were N-doped photoluminescent nanomaterials with functional groups on the surface. The fluorescent bio-imaging was performed by exposing zebrafish in different concentrations of the as-prepared rGOQDs, and the distribution of rGOQDs was successfully observed. Moreover, the developmental toxicity and genotoxicity were evaluated to further investigate the potential hazard of rGOQDs. The result indicated that rGOQDs were responsible for the dose-dependent abnormalities on the development of zebrafish. Since the real-time polymerase chain reaction (RT-PCR) results showed that the expression of cyp1a was the highest expression in the selected genes and significantly up-regulated 8.49 fold in zebrafish, the perturbation of rGOQDs on aryl hydrocarbon receptor (AhR) pathway was investigated by using the Tg(cyp1a:gfp) zebrafish for the first time. The results demonstrated that rGOQDs significantly increased the green fluorescent protein (GFP) expression promoted by cyp1a in a dose-dependent manner, which was also further confirmed by the western blotting. This study offered an opportunity to reveal the potential hazards of in vivo bio-probes, which provided a valuable reference for investigating the graphene-based materials on the disturbance of AhR pathway in biological organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Identification of benzothiazole derivatives and polycyclic aromatic hydrocarbons as aryl hydrocarbon receptor agonists present in tire extracts.

    Science.gov (United States)

    He, Guochun; Zhao, Bin; Denison, Michael S

    2011-08-01

    Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. The ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, but the responsible chemicals and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemicals were metabolically labile. The application of CALUX (chemical-activated luciferase gene expression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. Copyright © 2011 SETAC.

  11. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    International Nuclear Information System (INIS)

    Wei, Min; Yamada, Takanori; Yamano, Shotaro; Kato, Minoru; Kakehashi, Anna; Fujioka, Masaki; Tago, Yoshiyuki; Kitano, Mistuaki; Wanibuchi, Hideki

    2013-01-01

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA

  12. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Min; Yamada, Takanori; Yamano, Shotaro; Kato, Minoru; Kakehashi, Anna; Fujioka, Masaki; Tago, Yoshiyuki; Kitano, Mistuaki; Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp

    2013-11-15

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA.

  13. Binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to the AhR from various species is essentially irreversible

    Energy Technology Data Exchange (ETDEWEB)

    Bohonowych, J.; Denison, M. [California Univ., Davis, CA (United States)

    2004-09-15

    Halogenated aromatic hydrocarbons (HAHs) are a diverse group of widespread, persistent and toxic environmental contaminants that includes the polychlorinated dibenzo-p-dioxins and related chemicals. Exposure to these compounds results in a variety of biochemical and toxic effects, the majority of which are mediated by the aryl hydrocarbon receptor (AhR). 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent activator of the AhR and AhR-dependent effects. Interestingly, while a related class of compounds, the polycyclic aromatic hydrocarbons (PAHs), can bind to and activate the AhR, and produce many of the same biological effects as HAHs, they do not cause HAH-like toxicity. This can be due to differences between these two classes of compounds with respect to their AhR binding affinity, metabolic stability, and/or gene expression. PAHs have a lower affinity for the AhR5 and, unlike TCDD, can be readily metabolized by cytochrome P450 enzymes. In addition to its high affinity for the AhR, TCDD has been shown to stabilize the rat AhR receptor against thermal inactivation and to persistently bind the rat receptor. This persistent occupancy may also contribute to the differential toxicity of HAHs and PAHs. In addition to its biological and toxicological implications, the apparent lack of significant dissociation of TCDD from the AhR also impacts the design and interpretation of competitive binding experiments which assume traditional receptor-ligand equilibrium binding kinetics where binding is reversible and equilibrium of ligand:receptor complex is reached when rates of association and dissociation are equal. In this study we have further examined whether this persistent occupancy is a characteristic of the AhR among different species.

  14. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.

    Directory of Open Access Journals (Sweden)

    Vinicius S Carreira

    Full Text Available The Developmental Origins of Health and Disease (DOHaD Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR, either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.

  15. American Housing Survey (AHS)

    Data.gov (United States)

    Department of Housing and Urban Development — The AHS is the largest, regular national housing sample survey in the United States. The U.S. Census Bureau conducts the AHS to obtain up-to-date housing statistics...

  16. Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin receptor.

    Directory of Open Access Journals (Sweden)

    Bin Zhao

    Full Text Available Activation of the Ah receptor (AhR by halogenated aromatic hydrocarbons (HAHs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin, can produce a wide variety of toxic and biological effects. While recent studies have shown that the AhR can bind and be activated by structurally diverse chemicals, how widespread of these AhR agonists are in environmental, biological and synthetic materials remains to be determined. Using AhR-based assays, we demonstrate the presence of potent AhR agonists in a variety of common commercial and consumer items. Solvent extracts of paper, rubber and plastic products contain chemicals that can bind to and stimulate AhR DNA binding and/or AhR-dependent gene expression in hepatic cytosol, cultured cell lines, human epidermis and zebrafish embryos. In contrast to TCDD and other persistent dioxin-like HAHs, activation of AhR-dependent gene expression by these extracts was transient, suggesting that the agonists are metabolically labile. Solvent extracts of rubber products produce AhR-dependent developmental toxicity in zebrafish in vivo, and inhibition of expression of the metabolic enzyme CYP1A, significantly increased their toxic potency. Although the identity of the responsible AhR-active chemicals and their toxicological impact remain to be determined, our data demonstrate that AhR active chemicals are widely distributed in everyday products.

  17. [125I]2-iodo-3,7,8-trichlorodibenzo-p-dioxin-binding species in mouse liver induced by agonists for the Ah receptor: Characterization and identification

    International Nuclear Information System (INIS)

    Poland, A.; Teitelbaum, P.; Glover, E.

    1989-01-01

    The admininistration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to C57BL/6J mice produces a dose-related increase in the hepatic uptake of [ 125 I]2-iodo-3,7,8-trichlorodibenzo-p-dioxin ([ 125 I]Cl3DpD) in vivo and the binding of the radioligand to liver homogenate in vitro. The TCDD-induced hepatic binding species was found to be predominantly in the microsomal fraction and was inactivated by heating at 60 degree, trypsin, and mercurials. The TCDD-induced binding species was found to have an apparent equilibrium dissociation constant, KD, ([ 125 I]Cl3DpD) of 56 +/- 16 nM and a pool size, Bmax, of 22 +/- 5 nmol/g of liver. A number of halogenated dibenzo-p-dioxins, biphenyls, and polycyclic aromatic hydrocarbons compete with [ 125 I]Cl3DpD binding to this species; all are aromatic and planar. The distinctive profile of this binding species, a protein of large pool size induced in the microsomal fraction of liver but not other tissues and induced by agonists for the Ah receptor, suggested that this moiety might be cytochrome P3-450. The coincidence of the major microsomal species covalently labeled with the photoaffinity ligand [ 125 I]2-iodo-3-azido-7,8-dibromodibenzo-p-dioxin and that immunochemically stained with polyclonal antiserum that binds to cytochrome P3-450 confirms this hypothesis. This is a novel role for a cytochrome P-450 isozyme, as an induced sequestration site that enhances the hepatic localization of the agonist drug

  18. Dissociation of nucleosomal particles by chemical modification. Equivalence of the two binding sites for H2A.H2B dimers

    International Nuclear Information System (INIS)

    Jordano, J.; Nieto, M.A.; Palacian, E.

    1985-01-01

    Treatment of nucleosomal particles with dimethylmaleic anhydride, a reagent for protein amino groups, is accompanied by a biphasic release of histones H2A plus H2B; one H2A.H2B dimer is more easily released than the other. This behavior allows the preparation of nucleosomal particles containing only one H2A.H2B dimer, which were complemented with 125 I-labeled H2A.H2B. These reconstituted particles, which contain one labeled and one unlabeled H2A.H2B dimer, were treated with the amount of reagent needed to release one of the two H2A.H2B dimers. Radioactivity was equally distributed between residual particles and released proteins, which is consistent with equivalent binding sites in the nucleosomal particle for H2A.H2B dimers, rather than with intrinsically different sites. The asymmetric release of H2A.H2B dimers would be caused by a change in the binding site of one dimer following the release of the other. This behavior might be related to the structural dynamics of nucleosomes

  19. Distinct roles for aryl hydrocarbon receptor nuclear translocator and ah receptor in estrogen-mediated signaling in human cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Mark P Labrecque

    Full Text Available The activated AHR/ARNT complex (AHRC regulates the expression of target genes upon exposure to environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. Importantly, evidence has shown that TCDD represses estrogen receptor (ER target gene activation through the AHRC. Our data indicates that AHR and ARNT act independently from each other at non-dioxin response element sites. Therefore, we sought to determine the specific functions of AHR and ARNT in estrogen-dependent signaling in human MCF7 breast cancer and human ECC-1 endometrial carcinoma cells. Knockdown of AHR with siRNA abrogates dioxin-inducible repression of estrogen-dependent gene transcription. Intriguingly, knockdown of ARNT does not effect TCDD-mediated repression of estrogen-regulated transcription, suggesting that AHR represses ER function independently of ARNT. This theory is supported by the ability of the selective AHR modulator 3',4'-dimethoxy-α-naphthoflavone (DiMNF to repress estrogen-inducible transcription. Furthermore, basal and estrogen-activated transcription of the genes encoding cathepsin-D and pS2 are down-regulated in MCF7 cells but up-regulated in ECC-1 cells in response to loss of ARNT. These responses are mirrored at the protein level with cathepsin-D. Furthermore, knock-down of ARNT led to opposite but corresponding changes in estrogen-stimulated proliferation in both MCF7 and ECC-1 cells. We have obtained experimental evidence demonstrating a dioxin-dependent repressor function for AHR and a dioxin-independent co-activator/co-repressor function for ARNT in estrogen signalling. These results provide us with further insight into the mechanisms of transcription factor crosstalk and putative therapeutic targets in estrogen-positive cancers.

  20. Identification of Molecular Markers Associated with Alteration of Receptor-Binding Specificity in a Novel Genotype of Highly Pathogenic Avian Influenza A(H5N1) Viruses Detected in Cambodia in 2013

    Science.gov (United States)

    Rith, Sareth; Davis, C. Todd; Duong, Veasna; Sar, Borann; Horm, Srey Viseth; Chin, Savuth; Ly, Sovann; Laurent, Denis; Richner, Beat; Oboho, Ikwo; Jang, Yunho; Davis, William; Thor, Sharmi; Balish, Amanda; Iuliano, A. Danielle; Sorn, San; Holl, Davun; Sok, Touch; Seng, Heng; Tarantola, Arnaud; Tsuyuoka, Reiko; Parry, Amy; Chea, Nora; Allal, Lotfi; Kitsutani, Paul; Warren, Dora; Prouty, Michael; Horwood, Paul; Widdowson, Marc-Alain; Lindstrom, Stephen; Villanueva, Julie; Donis, Ruben; Cox, Nancy

    2014-01-01

    Human infections with influenza A(H5N1) virus in Cambodia increased sharply during 2013. Molecular characterization of viruses detected in clinical specimens from human cases revealed the presence of mutations associated with the alteration of receptor-binding specificity (K189R, Q222L) and respiratory droplet transmission in ferrets (N220K with Q222L). Discovery of quasispecies at position 222 (Q/L), in addition to the absence of the mutations in poultry/environmental samples, suggested that the mutations occurred during human infection and did not transmit further. PMID:25210193

  1. The interplay of the aryl hydrocarbon receptor and beta-catenin alters both AhR-dependent transcription and Wnt/beta-catenin signaling in liver progenitors

    Czech Academy of Sciences Publication Activity Database

    Procházková, Jiřina; Kabátková, Markéta; Bryja, Vítězslav; Umannová, Lenka; Bernatík, O.; Kozubík, Alois; Machala, M.; Vondráček, Jan

    2011-01-01

    Roč. 122, č. 2 (2011), s. 349-360 ISSN 1096-6080 R&D Projects: GA ČR(CZ) GD204/09/H058 Grant - others:GA ČR(CZ) GA524/09/1337 Program:GA Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : dioxin * beta-catenin * AhR Subject RIV: BO - Biophysics Impact factor: 4.652, year: 2011

  2. Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and iNOS expression during influenza virus infection

    Science.gov (United States)

    Head Wheeler, Jennifer L.; Martin, Kyle C.; Lawrence, B. Paige

    2012-01-01

    The underlying reasons for variable clinical outcomes from respiratory viral infections remain uncertain. Several studies suggest that environmental factors contribute to this variation, but limited knowledge of cellular and molecular targets of these agents hampers our ability to quantify or modify their contribution to disease and improve public health. The aryl hydrocarbon receptor (AhR) is an environment sensing transcription factor that binds many anthropogenic and natural chemicals. The immunomodulatory properties of AhR ligands are best characterized with extensive studies of changes in CD4+ T cell responses. Yet, AhR modulates other aspects of immune function. We previously showed that during influenza virus infection, AhR activation modulates neutrophil accumulation in the lung, and this contributes to increased mortality in mice. Enhanced levels of inducible nitric oxide synthase (iNOS) in infected lungs are observed during the same timeframe as AhR-mediated increased pulmonary neutrophilia. In this study, we evaluated whether these two consequences of AhR activation are causally linked. Reciprocal inhibition of AhR-mediated elevations in iNOS and pulmonary neutrophilia reveal that, although they are contemporaneous, they are not causally related. We show using Cre/loxP technology that elevated iNOS levels and neutrophil number in the infected lung result from separate, AhR-dependent signaling in endothelial and respiratory epithelial cells, respectively. Studies using mutant mice further reveal that AhR-mediated alterations in these innate responses to infection require a functional nuclear localization signal and DNA binding domain. Thus, gene targets of AhR in non-hematopoietic cells are important new considerations for understanding AhR-mediated changes in innate anti-viral immunity. PMID:23233726

  3. The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription.

    Science.gov (United States)

    Sakurai, Shunya; Shimizu, Toshiyuki; Ohto, Umeharu

    2017-10-27

    2,3,7,8-Tetrachlorodibenzo- p -dioxin and related compounds are extraordinarily potent environmental toxic pollutants. Most of the 2,3,7,8-tetrachlorodibenzo- p -dioxin toxicities are mediated by aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor belonging to the basic helix-loop-helix (bHLH) Per-ARNT-Sim (PAS) family. Upon ligand binding, AhR forms a heterodimer with AhR nuclear translocator (ARNT) and induces the expression of genes involved in various biological responses. One of the genes induced by AhR encodes AhR repressor (AhRR), which also forms a heterodimer with ARNT and represses the activation of AhR-dependent transcription. The control of AhR activation is critical for managing AhR-mediated diseases, but the mechanisms by which AhRR represses AhR activation remain poorly understood, because of the lack of structural information. Here, we determined the structure of the AhRR-ARNT heterodimer by X-ray crystallography, which revealed an asymmetric intertwined domain organization presenting structural features that are both conserved and distinct among bHLH-PAS family members. The structures of AhRR-ARNT and AhR-ARNT were similar in the bHLH-PAS-A region, whereas the PAS-B of ARNT in the AhRR-ARNT complex exhibited a different domain arrangement in this family reported so far. The structure clearly disclosed that AhRR competitively represses AhR binding to ARNT and target DNA and further suggested the existence of an AhRR-ARNT-specific repression mechanism. This study provides a structural basis for understanding the mechanism by which AhRR represses AhR-mediated gene transcription. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. LAA~Ah

    Indian Academy of Sciences (India)

    411<0 = 1000 dalton, 1 dalton = 1.66024 x 10-24 g. ______ LAA~Ah ... energy use. These changes led to a reduction in food intake and the percentage of body fat, along with an ... of the brain called the hypothalamus may be important in ...

  5. Aa Ah Nak

    Science.gov (United States)

    Tha, Na Gya; Wus, Thay

    2017-01-01

    In this article, Aa Ah Nak, the authors' methodology presents not only various reflections but also diverse contradictions about the Aa Nii language as well as language revitalization. This article explores language foundation and how the Aa Nii language revitalization is inextricably linked to the genocide and resulting historic trauma pervasive…

  6. American Housing Survey (AHS) 2011

    Data.gov (United States)

    Department of Housing and Urban Development — The AHS is the largest, regular national housing sample survey in the United States. The U.S. Census Bureau conducts the AHS to obtain up-to-date housing statistics...

  7. Modeling of Ah-receptor dependent P450 induction I. Cellular model definition and its incorporation in a PBPK model of 2,3,7,8-TCDD

    NARCIS (Netherlands)

    Zeilmaker MJ; Eijkeren JCH van; LBO

    1997-01-01

    The interspecies extrapolation of chemical toxicity is traditionally based on the daily administered dose of the chemical. However, in the case of compounds with strong bioaccumulating properties, such as 2,3,7,8-TetraChloroDibenzo-p-Dioxin (TCDD), chronic toxicity is expected to scale better with

  8. Characterization of the transgenic CA-AhR mouse - cell specific expression of the CA-AhR using CYP1A1 as a marker

    Energy Technology Data Exchange (ETDEWEB)

    Brunnberg, S.; Lindstam, M.; Andersson, P.; Hanberg, A. [Institute of Environmental Medicine, Stockholm (Sweden); Poellinger, L. [Department of Cell and Molecular Biology, Stockholm (Sweden)

    2004-09-15

    The risk assessments of dioxins and dioxin-like PCBs performed by WHO and EU lead to major concerns. The tolerable daily intake for humans has been assessed to be within the range of human exposures occurring in the general population today. Dioxins are known to adversely impair reproduction and affect development of reproductive organs, as well as the early development of the immune and the nervous systems. The Aryl hydrocarbon Receptor (AhR) mediates most toxic effects of dioxins, such as 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and PCBs. In order to study the mechanisms of toxicity of ligands of the Ah receptor we have created a transgenic mouse model expressing a constitutively active Ah receptor (CA-AhR). The mutant Ah receptor is expressed and functionally active in most (or all) organs. Consequently, the CA-AhR mice show several of the well-known effects of dioxin exposure. Since the CA-AhR is continuously active at a relatively low level and from early development, this model resembles the human exposure scenario and is thus suitable for studies on mechanisms of action of Ah receptor ligands.

  9. Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling

    Directory of Open Access Journals (Sweden)

    Bendik C. Brinchmann

    2018-05-01

    Full Text Available Exposure to diesel exhaust particles (DEPs affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM, dichloromethane (DCM-EOM, methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1 using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE. By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE. Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction

  10. Expression and distribution patterns of Mas-related gene receptor subtypes A-H in the mouse intestine: inflammation-induced changes.

    Science.gov (United States)

    Avula, Leela Rani; Buckinx, Roeland; Favoreel, Herman; Cox, Eric; Adriaensen, Dirk; Van Nassauw, Luc; Timmermans, Jean-Pierre

    2013-05-01

    Mas-related gene (Mrg) receptors constitute a subfamily of G protein-coupled receptors that are implicated in nociception, and are as such considered potential targets for pain therapies. Furthermore, some Mrgs have been suggested to play roles in the regulation of inflammatory responses to non-immunological activation of mast cells and in mast cell-neuron communication. Except for MrgD, E and F, whose changed expression has been revealed during inflammation in the mouse intestine in our earlier studies, information concerning the remaining cloned mouse Mrg subtypes in the gastrointestinal tract during (patho) physiological conditions is lacking. Therefore, the present study aimed at identifying the presence and putative function of these remaining cloned Mrg subtypes (n = 19) in the (inflamed) mouse intestine. Using reverse transcriptase-PCR, quantitative-PCR and multiple immunofluorescence staining with commercial and newly custom-developed antibodies, we compared the ileum and the related dorsal root ganglia (DRG) of non-inflamed mice with those of two models of intestinal inflammation, i.e., intestinal schistosomiasis and 2,4,6-trinitrobenzene sulfonic acid-induced ileitis. In the non-inflamed ileum and DRG, the majority of the Mrg subtypes examined were sparsely expressed, showing a neuron-specific expression pattern. However, significant changes in the expression patterns of multiple Mrg subtypes were observed in the inflamed ileum; for instance, MrgA4, MrgB2and MrgB8 were expressed in a clearly increased number of enteric sensory neurons and in nerve fibers in the lamina propria, while de novo expression of MrgB10 was observed in enteric sensory neurons and in newly recruited mucosal mast cells (MMCs). The MrgB10 expressing MMCs were found to be in close contact with nerve fibers in the lamina propria. This is the first report on the expression of all cloned Mrg receptor subtypes in the (inflamed) mouse intestine. The observed changes in the expression and

  11. AH Cancri: a contact binary in M67

    International Nuclear Information System (INIS)

    Whelan, J.A.J.; Worden, S.P.; Rucinski, S.M.

    1979-01-01

    The W UMa-type contact binary system AH Cnc, which is a member of the old galactic cluster M67, has been studied spectroscopically and photometrically. Estimates of masses, radii, effective temperature and luminosity of AH Cnc have been derived from these data and from cluster membership considerations. The results suggest that AH Cnc is a typical evolved W-type W UMa contact system, although whether the system has evolved as a contact system or has recently become so, could not be determined. The properties of AH Cnc are similar to those of TX Cnc in Praesepe. Information provided by the existence of a gap in the Hertzsprung-Russell diagram for M67 has been coupled with the AH Cnc results to provide further estimates of the chemical composition of M67. (author)

  12. IN VITRO INTERACTION OF INFLUENZA VIRUS A(H1N1pdm09 WITH MONOCYTIC MACROPHAGES: INDIVIDUAL RESPONSES OF TLR7 AND RIG1 RECEPTOR GENES

    Directory of Open Access Journals (Sweden)

    T. M. Sokolova

    2017-01-01

    Full Text Available In vitro differentiation of donor blood monocytes to macrophages (Mph following GM-CSF treatment was accompanied by a significant increase in the levels of gene transcription signaling receptors TLR7 or RIG1. The levels of intracellular viral RNA (M1 gene in Mph remained high upon infection by influenza virus A H1N1pdm (Moscow 2009 for 24-96 hours. The innate immunity reactions caused by influenza virus show individual features: they are decreased in Mph from donor 1 which had initially high level of endosomal TLR7 gene activity, and it increased by influenza virus in MPh from donor 2 who had a very low level of TLR7 gene expression. The influenza H1N1pdm virus weakly stimulated expression of gene RIG1 and production of inflammatory cytokines in Mf in donor 1. The differences may be connected with individual sensitivity of the donors to influenza infection.

  13. Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4

    DEFF Research Database (Denmark)

    Watterson, Kenneth R; Hansen, Steffen V F; Hudson, Brian D

    2017-01-01

    High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein-coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential...... of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many...

  14. Disruption of contact inhibition in rat liver epithelial cells by various types of AhR ligands

    Energy Technology Data Exchange (ETDEWEB)

    Vondracek, J.; Chramostova, K.; Kozubik, A. [Institute of Biophysics, Brno (Czech Republic); Krcmar, P.; Machala, M. [Veterinary Research Institute, Brno (Czech Republic)

    2004-09-15

    The maintenance of a balance between cell gain and cell loss is essential for proper liver function. The exact role of aryl hydrocarbon receptor (AhR) in regulating cell proliferation and apoptosis of liver cells remains unclear, since ligand-dependent activation of AhR has been shown to induce cell cycle arrest, proliferation, differentiation or apoptosis, depending on the cellular model used. AhR can directly interact with retinoblastoma protein in hepatic cells, forming protein complexes that can efficiently block cell cycle progression by inducing G1 arrest, or to induce the expression of inhibitors of cyclin-dependent kinases, such as p271. On the other hand, it has been suggested that AhR could play a stimulatory role in cell proliferation, either directly or by mediating a release from contact inhibition. It is now generally accepted that progenitor cells exist in the liver, are activated in various liver diseases and can form a potential target cell population for both tumor initiating and tumor promoting chemicals4. 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) has been found to release rat liver epithelial cells from contact inhibition by upregulating cyclin A expression and cyclin A/cdk2 activity. Our previous studies have shown that a number of AhR ligands5,6 can stimulate proliferation of confluent of rat liver epithelial ''stem-like'' WB-F344 cells. Such mechanism could play a role in liver tumor promotion. In the present study, we used flavonoid compounds that have been reported to act either as pure agonists, such as beta-naphthoflavone (BNF), or as partial/complete antagonists of AhR - alpha-naphthoflavone (ANF) and 3'-methoxy-4'-nitroflavone (3'M4'NF), in order to investigate effects of AhR agonists/antagonists on confluent rat liver epithelial cells. The present study aimed to investigate the effects of model flavonoids on the release of rat liver epithelial cells from contact inhibition, and on inducibility of

  15. In vitro and in silico derived relative effect potencies of ah-receptor-mediated effects by PCDD/Fs and PCBs in rat, mouse, and guinea pig CALUX cell lines.

    Science.gov (United States)

    Ghorbanzadeh, Mehdi; van Ede, Karin I; Larsson, Malin; van Duursen, Majorie B M; Poellinger, Lorenz; Lücke-Johansson, Sandra; Machala, Miroslav; Pěnčíková, Kateřina; Vondráček, Jan; van den Berg, Martin; Denison, Michael S; Ringsted, Tine; Andersson, Patrik L

    2014-07-21

    For a better understanding of species-specific relative effect potencies (REPs), responses of dioxin-like compounds (DLCs) were assessed. REPs were calculated using chemical-activated luciferase gene expression assays (CALUX) derived from guinea pig, rat, and mouse cell lines. Almost all 20 congeners tested in the rodent cell lines were partial agonists and less efficacious than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For this reason, REPs were calculated for each congener using concentrations at which 20% of the maximal TCDD response was reached (REP20TCDD). REP20TCDD values obtained for PCDD/Fs were comparable with their toxic equivalency factors assigned by the World Health Organization (WHO-TEF), while those for PCBs were in general lower than the WHO-TEF values. Moreover, the guinea pig cell line was the most sensitive as indicated by the 20% effect concentrations of TCDD of 1.5, 5.6, and 11.0 pM for guinea pig, rat, and mouse cells, respectively. A similar response pattern was observed using multivariate statistical analysis between the three CALUX assays and the WHO-TEFs. The mouse assay showed minor deviation due to higher relative induction potential for 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,6,7,8-hexachlorodibenzofuran and lower for 1,2,3,4,6,7,8-heptachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl (PCB126). 2,3,7,8-Tetrachlorodibenzofuran was more than two times more potent in the mouse assay as compared with that of rat and guinea pig cells, while measured REP20TCDD for PCB126 was lower in mouse cells (0.05) as compared with that of the guinea pig (0.2) and rat (0.07). In order to provide REP20TCDD values for all WHO-TEF assigned compounds, quantitative structure-activity relationship (QSAR) models were developed. The QSAR models showed that specific electronic properties and molecular surface characteristics play important roles in the AhR-mediated response. In silico derived REP20TCDD values were generally consistent with the WHO

  16. Receptor-mediated gene delivery using chemically modified chitosan

    International Nuclear Information System (INIS)

    Kim, T H; Jiang, H L; Nah, J W; Cho, M H; Akaike, T; Cho, C S

    2007-01-01

    Chitosan has been investigated as a non-viral vector because it has several advantages such as biocompatibility, biodegradability and low toxicity with high cationic potential. However, the low specificity and low transfection efficiency of chitosan need to be solved prior to clinical application. In this paper, we focused on the galactose or mannose ligand modification of chitosan for enhancement of cell specificity and transfection efficiency via receptor-mediated endocytosis in vitro and in vivo

  17. Quantum chemical study of agonist-receptor vibrational interactions for activation of the glutamate receptor.

    Science.gov (United States)

    Kubo, M; Odai, K; Sugimoto, T; Ito, E

    2001-06-01

    To understand the mechanism of activation of a receptor by its agonist, the excitation and relaxation processes of the vibrational states of the receptor should be examined. As a first approach to this problem, we calculated the normal vibrational modes of agonists (glutamate and kainate) and an antagonist (6-cyano-7-nitroquinoxaline-2,3-dione: CNQX) of the glutamate receptor, and then investigated the vibrational interactions between kainate and the binding site of glutamate receptor subunit GluR2 by use of a semiempirical molecular orbital method (MOPAC2000-PM3). We found that two local vibrational modes of kainate, which were also observed in glutamate but not in CNQX, interacted through hydrogen bonds with the vibrational modes of GluR2: (i) the bending vibration of the amine group of kainate, interacting with the stretching vibration of the carboxyl group of Glu705 of GluR2, and (ii) the symmetric stretching vibration of the carboxyl group of kainate, interacting with the bending vibration of the guanidinium group of Arg485. We also found collective modes with low frequency at the binding site of GluR2 in the kainate-bound state. The vibrational energy supplied by an agonist may flow from the high-frequency local modes to the low-frequency collective modes in a receptor, resulting in receptor activation.

  18. Chemical neuroanatomy and in vitro receptor autoradiography: A basis for cerebral positron emission tomography

    International Nuclear Information System (INIS)

    Albin, R.L.; Young, A.B.; Penney, J.B.; Makowiec, R.L.; Gilman, S.

    1991-01-01

    We review chemical neuroanatomy and in vitro receptor (IVG) autoradiography as tools for the development of methods suitable for positron emission tomography (PET) studies. The organizations of monoaminergic, cholinergic, γ-aminobutyric acidergic (GABA), and excitatory amino acidergic (EAA) pathways within the central nervous system are summarized, as is the presently accepted classification of GABA and EAA receptors. We describe the technique of IVG and discuss its unique advantages for the selection of possible PET methods. Finally, we discuss receptor changes in Huntington's disease and olivopontocerebellar atrophy, two human diseases for which IVG has suggested possible targets for PET imaging

  19. Craniofacial form is altered by chronic adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD in Han/Wistar and Long–Evans rats with different aryl hydrocarbon receptor (AhR structures

    Directory of Open Access Journals (Sweden)

    Sabrina B. Sholts

    2015-01-01

    Full Text Available Mammalian bone has shown a variety of responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD exposure in experimental and wildlife studies. Although many responses have been well characterized in the postcranial skeleton, dioxin-induced effects on the cranium are largely unknown. In this study, we investigated the effects of chronic adult exposure to TCDD on cranial size and shape in dioxin-resistant Han/Wistar (H/W and dioxin-sensitive Long–Evans (L–E rat strains. Three-dimensional landmark configurations for the face, vault, and base of the cranium were recorded and analyzed using geometric morphometrics (GM and dose–response modeling. The strongest effects were shown by L–E and H/W rats with daily exposures of 100 and 1000 ng TCDD/kg bw/day, respectively, resulting in significant reductions in centroid size (CS in all three cranial modules for both strains except for the vault in H/W rats. Consistent with previous evidence of intraspecific variation in TCDD resistance, the benchmark doses (CEDs for cranial size reduction in L–E rats were roughly 10-fold lower than those for H/W rats. For both strains, the face showed the greatest size reduction from the highest doses of TCDD (i.e., 3.6 and 6.3% decreases in H/W and L–E rats, respectively, most likely related to dose-dependent reductions in limb bone size and body weight gain. However, intrinsic morphological differences between strains were also observed: although the control groups of H/W and L–E rats had vaults and bases of comparable size, the face was 6.4% larger in L–E rats. Thus, although H/W rats possess an altered aryl hydrocarbon receptor (AhR that appears to mediate and provides some resistance to TCDD exposure, their smaller reductions in facial size may also relate to strain-specific patterns of cranial development and growth. Future research will be aimed at understanding how ontogenetic factors may modulate toxic effects of prenatal and lactational exposure on

  20. Predicting chemical environments of bacteria from receptor signaling.

    Directory of Open Access Journals (Sweden)

    Diana Clausznitzer

    2014-10-01

    Full Text Available Sensory systems have evolved to respond to input stimuli of certain statistical properties, and to reliably transmit this information through biochemical pathways. Hence, for an experimentally well-characterized sensory system, one ought to be able to extract valuable information about the statistics of the stimuli. Based on dose-response curves from in vivo fluorescence resonance energy transfer (FRET experiments of the bacterial chemotaxis sensory system, we predict the chemical gradients chemotactic Escherichia coli cells typically encounter in their natural environment. To predict average gradients cells experience, we revaluate the phenomenological Weber's law and its generalizations to the Weber-Fechner law and fold-change detection. To obtain full distributions of gradients we use information theory and simulations, considering limitations of information transmission from both cell-external and internal noise. We identify broad distributions of exponential gradients, which lead to log-normal stimuli and maximal drift velocity. Our results thus provide a first step towards deciphering the chemical nature of complex, experimentally inaccessible cellular microenvironments, such as the human intestine.

  1. Conservation of lepidopteran ecdysteroid receptor provides evidence for butterfly susceptibility to diacylhydrazine and bisacylhydrazine chemicals

    Science.gov (United States)

    Diacylhydrazine (DAH) and bisacylhydrazine (BAH) chemicals (e.g., methoxyfenozide and tebufenozide, respectively), also known as moulting accelerating compounds, act as agonists of the ecdysteroid receptor (EcR), and have been used as selective insecticides for pests within the o...

  2. Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

    DEFF Research Database (Denmark)

    Hudson, Brian D; Christiansen, Elisabeth; Tikhonova, Irina G

    2012-01-01

    When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL...... on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs.-Hudson, B. D., Christiansen, E., Tikhonova, I. G., Grundmann, M., Kostenis, E., Adams, D. R., Ulven, T., Milligan, G. Chemically engineering...

  3. Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection

    Science.gov (United States)

    Jin, Guang-Bi; Moore, Amanda J.; Head, Jennifer L.; Neumiller, Joshua J.; Lawrence, B. Paige

    2010-01-01

    It has long been known that activation of the aryl hydrocarbon receptor (AhR) by ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses T cell–dependent immune responses; however, the underlying cellular targets and mechanism remain unclear. We have previously shown that AhR activation by TCDD reduces the proliferation and differentiation of influenza virus–specific CD8+ T cells through an indirect mechanism; suggesting that accessory cells are critical AhR targets during infection. Respiratory dendritic cells (DCs) capture antigen, migrate to lymph nodes, and play a key role in activating naive CD8+ T cells during respiratory virus infection. Herein, we report an examination of how AhR activation alters DCs in the lung and affects their trafficking to and function in the mediastinal lymph nodes (MLN) during infection with influenza virus. We show that AhR activation impairs lung DC migration and reduces the ability of DCs isolated from the MLN to activate naive CD8+ T cells. Using novel AhR mutant mice, in which the AhR protein lacks its DNA-binding domain, we show that the suppressive effects of TCDD require that the activated AhR complex binds to DNA. These new findings suggest that AhR activation by chemicals from our environment impacts DC function to stimulate naive CD8+ T cells and that immunoregulatory genes within DCs are critical targets of AhR. Moreover, our results reinforce the idea that environmental signals and AhR ligands may contribute to differential susceptibilities and responses to respiratory infection. PMID:20498003

  4. CDNA CLONING OF FATHEAD MINNOW (PIMEPHALES PROMELAS) ESTROGEN AND ANDROGEN RECEPTORS FOR USE IN STEROID RECEPTOR EXTRAPOLATION STUDIES FOR ENDOCRINE DISRUPTING CHEMICALS

    Science.gov (United States)

    cDNA Cloning of Fathead minnow (Pimephales promelas) Estrogen and Androgen Receptors for Use in Steroid Receptor Extrapolation Studies for Endocrine Disrupting Chemicals. Wilson, V.S.1,, Korte, J.2, Hartig P. 1, Ankley, G.T.2, Gray, L.E., Jr 1, , and Welch, J.E.1. 1U.S...

  5. Rapid, portable detection of endocrine disrupting chemicals through ligand-nuclear hormone receptor interactions.

    Science.gov (United States)

    Hunt, J Porter; Schinn, Song-Min; Jones, Matthew D; Bundy, Bradley C

    2017-12-04

    Endocrine disrupting chemicals (EDC) are structurally diverse compounds that can interact with nuclear hormone receptors, posing significant risk to human and ecological health. Unfortunately, many conventional biosensors have been too structure-specific, labor-intensive or laboratory-oriented to detect broad ranges of EDC effectively. Recently, several technological advances are providing more rapid, portable, and affordable detection of endocrine-disrupting activity through ligand-nuclear hormone receptor interactions. Here, we overview these recent advances applied to EDC biosensors - including cell lyophilization, cell immobilization, cell-free systems, smartphone-based signal detection, and improved competitive binding assays.

  6. Third-Generation Ah Receptor–Responsive Luciferase Reporter Plasmids: Amplification of Dioxin-Responsive Elements Dramatically Increases CALUX Bioassay Sensitivity and Responsiveness

    Science.gov (United States)

    He, Guochun; Tsutsumi, Tomoaki; Zhao, Bin; Baston, David S.; Zhao, Jing; Heath-Pagliuso, Sharon; Denison, Michael S.

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene–based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts. PMID:21775728

  7. AhR Activation Underlies the CYP1A Autoinduction by A-998679 in Rats

    Directory of Open Access Journals (Sweden)

    Michael J. Liguori

    2012-10-01

    Full Text Available Xenobiotic-mediated induction of cytochrome P450 (CYP drug metabolizing enzymes (DMEs is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance. However, autoinduction via CYP1A is encountered less frequently. In this report, an experimental compound, A-998679 (3-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl benzonitrile, was shown to enhance its own clearance via induction of CYP1A1 and CYP1A2. Rats were dosed for 5 days with 30, 100, and 200 mg/kg/day A-998679. During the dosing period, the compound’s plasma AUC decreased at 30 mg/kg (95% and 100 mg/kg (80%. Gene expression analysis and immunohistochemistry of the livers showed a large increase in the mRNA and protein levels of CYP1A, which was involved in the biotransformation of A-998679. Induction of CYP1A was confirmed in primary rat, human, and dog hepatocytes. The compound also weakly inhibited CYP1A2 in human liver microsomes. A-998679 activated the aryl hydrocarbon receptor (AhR in a luciferase gene reporter assay in HepG2 cells, upregulated expression of genes associated with AhR activation in rat liver, and enhanced nuclear migration of AhR in HepG2 cells. Collectively these results demonstrate that A-998679 is an AhR activator that induces CYP1A1 and CYP1A2 expression, resulting in an autoinduction phenomenon. The unique properties of A-998679, along with its novel structure distinct from classical polycyclic aromatic hydrocarbons, may warrant its further evaluation as a tool compound for use in studies involving AhR biology and CYP1A related mechanisms of drug metabolism and toxicity.

  8. Simulation studies for wells AH-4bis/AH-17 and AH-18, Ahuachapan Geothermal Field

    Energy Technology Data Exchange (ETDEWEB)

    Monterrosa, Manuel Ernesto

    1996-01-24

    Well AH-4bis, at the Ahuachapan Geothermal Field is planned to be drilled on the same pad as the former AH-4. A simulation study was carried out for two casing dameters 13 5/8 and 9 5/8” in order to estimate its production and to know its economic feasibility. The simulation results indcate a high probability of production in the range of 7 Mwe, equivalent to 120 kg/s total mass flow rate, 1250 kJ/kg at 6 bar-a for the new well AH-4bis. Well AH- 17 is good producer, during 1991 after ten years of production, the well was shut-in due to silica scaling problems. A wellbore simulation was carried out in order to predict the new production conditions after the work-over, mainly to estimate the water flow rate in order to reduce the silica scaling. The results indicate a very low water flow rate. The match between the simulated and measured production curves after the work-over was successful. The well AH-18 is located at the southern part of the actual bore field. CEL is planning to expand the borefield at this area and it is neccessary to estimate the possible production condtions at that zone. The results indicate a high probabilty of production at that area. The power potential is estimated at 3.5 Mwe per well at WHP 6 bar-a and the wells will not require induction.

  9. AhR transcription serum activity of Inuit´s across Greenlandic districts

    DEFF Research Database (Denmark)

    Long, Manhai; Deutch, Bente; Bonefeld-Jørgensen, Eva Cecilie

    2007-01-01

    . The individual is exposed to a complex mixture of POPs being life-long beginning during critical developmental windows. Exposure to POPs elicits a number of species- and tissue-specific toxic responses, many of which involve the aryl hydrocarbon receptor (AhR). The aim of this study was to compare the actual...... was similar in the different districts. For the combined data the order of the median AhR-TEQ was Tasiilaq > Nuuk > Sisimiut > Qaanaaq possibly being related to the different composition of POPs. In overall, the AhR transactivity was inversely correlated to the levels of sum POPs, age and /or intake of marine......-PCBs; ii) The inverse association between the integrated serum AhR transactivity and sum of POPs might be explained by the higher level of compounds antagonizing the AhR function probably due to selective POP bioaccumulation in the food chain....

  10. Role of the Ah locus in suppression of cytotoxic T lymphocyte activity by halogenated aromatic hydrocarbons (PCBs and TCDD): Structure-activity relationships and effects in C57Bl/6 mice congenic at the Ah locus

    International Nuclear Information System (INIS)

    Kerkvliet, N.I.; Baecher-Steppan, L.; Smith, B.B.; Youngberg, J.A.; Henderson, M.C.; Buhler, D.R.

    1990-01-01

    Previous studies have shown that the generation of cytotoxic T lymphocytes (CTL) following allogeneic tumor challenge is suppressed in Ah-responsive C57Bl/6 mice treated with a single oral dose of the toxic, Ah receptor-binding 3,4,5,3',4',5'-hexachlorobiphenyl (HxCB). The present studies have examined the specific role of the Ah receptor in this immunotoxic response by utilizing HxCB isomers of known, varied affinity for the Ah receptor as well as by comparing effects of high-affinity Ah receptor ligands (3,4,5,3',4',5'-HxCB and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]) on the CTL response of mice that differ only at the Ah locus, that is, Ah-responsive (Ahbb) and Ah-nonresponsive (Ahdd) congenic C57Bl/6 mice. Correlative changes in thymic weight, serum corticosterone (CS) levels, and spleen cellularity were also measured. The potency of HxCB congeners (3,4,5,3',4',5'-; 2,3,4,5,3',4'-; 2,4,5,2',4',5'-) and 2,3,7,8-TCDD to suppress the CTL response, to reduce spleen cellularity, to cause thymic atrophy, and to elevate serum CS levels was directly correlated with the binding affinity of the congener for the Ah receptor. Furthermore, these parameters of immunotoxicity in Ahdd C57Bl/6 mice were significantly more resistant to alterations induced by either 3,4,5,3',4',5'-HxCB or 2,3,7,8-TCDD as compared to Ahbb C57Bl/6 mice. These results strongly support an Ah receptor-dependent immunotoxic mechanism in suppression of the CTL response following acute exposure to halogenated aromatic hydrocarbons

  11. Rainbow trout estrogen receptor (ER) competitive bindng and vitellogenin induction agonism/antagonism data for 94 chemicals

    Data.gov (United States)

    U.S. Environmental Protection Agency — This dataset is from screening 94 diverse chemicals for estrogen receptor (ER) activation in a competitive rainbow trout ER binding assay and a trout liver slice...

  12. Normal mast cell numbers in the tissues of AhR-deficient mice.

    Science.gov (United States)

    Pilz, Caroline; Feyerabend, Thorsten; Sonner, Jana; Redaelli, Chiara; Peter, Katharina; Kunze, Anja; Haas, Katharina; Esser, Charlotte; Schäkel, Knut; Wick, Wolfgang; Rodewald, Hans-Reimer; Lanz, Tobias V; Platten, Michael

    2016-01-01

    The transcription factor aryl hydrocarbon receptor (AhR) acts as an immunomodulatory molecule in several immune cell lineages. Recently, it has been implicated in development and maintenance of immune cells in barrier tissues such as skin and mucosa. To investigate its role on mast cell development and maintenance in skin, peritoneal exudate cells (PECs) and lymph nodes, we studied in depth their phenotype in AhR-deficient mice. Our findings do not provide any evidence for a suspected role of the AhR in mast cell homeostasis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. In vitro nuclear receptor inhibition and cytotoxicity of hydraulic fracturing chemicals and their binary mixtures.

    Science.gov (United States)

    Bain, Peter A; Kumar, Anu

    2018-05-01

    The widespread use of hydraulic fracturing (HF) in oil and gas extraction operations has led to concern over environmental risks posed by chemicals used in HF fluids. Here we employed a suite of stable luciferase reporter gene assays to investigate the potential for selected HF chemicals or geogenics to activate or antagonise nuclear receptor signalling. We screened three biocides (bronopol [BP], glutaraldehyde [GA], and tetrakis(hydroxymethyl)phosphonium sulfate [THPS]), a surfactant (2-butoxyethanol), a friction reducer (polyacrylamide), and a coal seam geogenic (o-cresol) for their potential to act as agonists or antagonists of the estrogen receptor, androgen receptor, progesterone receptor (PR), glucocorticoid receptor or peroxisome proliferator-activated receptor gamma (PPARγ). None of the chemicals induced luciferase activity in any of assays used in the study. In antagonistic mode, BP, GA and THPS caused reductions in luciferase activity in the reporter assays at higher concentrations (50-100 μM), while at low concentrations (2-10 μM) GA and THPS enhanced luciferase activity in some assays relative to controls. None of the other tested chemicals exhibited antagonism in the selected assays. In most cases, altered receptor signalling only occurred at concentrations exhibiting cytotoxicity. However, PPARγ activity, and to a lesser extent PR activity, were inhibited by THPS at sub-cytotoxic concentrations. The majority of binary combinations tested exhibited significantly less-than-additive cytotoxicity, and none of the combinations exhibited synergistic cytotoxicity. In summary, the results of the present study indicate that the selected chemicals are not likely to function as direct agonists of the nuclear receptors tested, and only one chemical, THPS was an apparent partial antagonist of two nuclear receptors. Copyright © 2017. Published by Elsevier Ltd.

  14. Evolutionary trends of A(H1N1 influenza virus hemagglutinin since 1918.

    Directory of Open Access Journals (Sweden)

    Jun Shen

    2009-11-01

    Full Text Available The Pandemic (H1N1 2009 is spreading to numerous countries and causing many human deaths. Although the symptoms in humans are mild at present, fears are that further mutations in the virus could lead to a potentially more dangerous outbreak in subsequent months. As the primary immunity-eliciting antigen, hemagglutinin (HA is the major agent for host-driven antigenic drift in A(H3N2 virus. However, whether and how the evolution of HA is influenced by existing immunity is poorly understood for A(H1N1. Here, by analyzing hundreds of A(H1N1 HA sequences since 1918, we show the first evidence that host selections are indeed present in A(H1N1 HAs. Among a subgroup of human A(H1N1 HAs between 1918 approximately 2008, we found strong diversifying (positive selection at HA(1 156 and 190. We also analyzed the evolutionary trends at HA(1 190 and 225 that are critical determinants for receptor-binding specificity of A(H1N1 HA. Different A(H1N1 viruses appeared to favor one of these two sites in host-driven antigenic drift: epidemic A(H1N1 HAs favor HA(1 190 while the 1918 pandemic and swine HAs favor HA(1 225. Thus, our results highlight the urgency to understand the interplay between antigenic drift and receptor binding in HA evolution, and provide molecular signatures for monitoring future antigenically drifted 2009 pandemic and seasonal A(H1N1 influenza viruses.

  15. Cholera Toxin Induces Sustained Hyperexcitability in Myenteric, but Not Submucosal, AH Neurons in Guinea Pig Jejunum

    Directory of Open Access Journals (Sweden)

    Joel C. Bornstein

    2017-04-01

    Full Text Available Background and Aims: Cholera toxin (CT-induced hypersecretion requires activation of secretomotor pathways in the enteric nervous system (ENS. AH neurons, which have been identified as a population of intrinsic sensory neurons (ISNs, are a source of excitatory input to the secretomotor pathways. We therefore examined effects of CT in the intestinal lumen on myenteric and submucosal AH neurons.Methods: Isolated segments of guinea pig jejunum were incubated for 90 min with saline plus CT (12.5 μg/ml or CT + neurotransmitter antagonist, or CT + tetrodotoxin (TTX in their lumen. After washing CT away, submucosal or myenteric plexus preparations were dissected keeping circumferentially adjacent mucosa intact. Submucosal AH neurons were impaled adjacent to intact mucosa and myenteric AH neurons were impaled adjacent to, more than 5 mm from, and in the absence of intact mucosa. Neuronal excitability was monitored by injecting 500 ms current pulses through the recording electrode.Results: After CT pre-treatment, excitability of myenteric AH neurons adjacent to intact mucosa (n = 29 was greater than that of control neurons (n = 24, but submucosal AH neurons (n = 33, control n = 27 were unaffected. CT also induced excitability increases in myenteric AH neurons impaled distant from the mucosa (n = 6 or in its absence (n = 5. Coincubation with tetrodotoxin or SR142801 (NK3 receptor antagonist, but not SR140333 (NK1 antagonist or granisetron (5-HT3 receptor antagonist prevented the increased excitability induced by CT. Increased excitability was associated with a reduction in the characteristic AHP and an increase in the ADP of these neurons, but not a change in the hyperpolarization-activated inward current, Ih.Conclusions: CT increases excitability of myenteric, but not submucosal, AH neurons. This is neurally mediated and depends on NK3, but not 5-HT3 receptors. Therefore, CT may act to amplify the secretomotor response to CT via an increase in the

  16. Exposure to Gulf War Illness chemicals induces functional muscarinic receptor maladaptations in muscle nociceptors.

    Science.gov (United States)

    Cooper, B Y; Johnson, R D; Nutter, T J

    2016-05-01

    Chronic pain is a component of the multisymptom disease known as Gulf War Illness (GWI). There is evidence that pain symptoms could have been a consequence of prolonged and/or excessive exposure to anticholinesterases and other GW chemicals. We previously reported that rats exposed, for 8 weeks, to a mixture of anticholinesterases (pyridostigmine bromide, chlorpyrifos) and a Nav (voltage activated Na(+) channel) deactivation-inhibiting pyrethroid, permethrin, exhibited a behavior pattern that was consistent with a delayed myalgia. This myalgia-like behavior was accompanied by persistent changes to Kv (voltage activated K(+)) channel physiology in muscle nociceptors (Kv7, KDR). In the present study, we examined how exposure to the above agents altered the reactivity of Kv channels to a muscarinic receptor (mAChR) agonist (oxotremorine-M). Comparisons between muscle nociceptors harvested from vehicle and GW chemical-exposed rats revealed that mAChR suppression of Kv7 activity was enhanced in exposed rats. Yet in these same muscle nociceptors, a Stromatoxin-insensitive component of the KDR (voltage activated delayed rectifier K(+) channel) exhibited decreased sensitivity to activation of mAChR. We have previously shown that a unique mAChR-induced depolarization and burst discharge (MDBD) was exaggerated in muscle nociceptors of rats exposed to GW chemicals. We now provide evidence that both muscle and vascular nociceptors of naïve rats exhibit MDBD. Examination of the molecular basis of the MDBD in naïve animals revealed that while the mAChR depolarization was independent of Kv7, the action potential burst was modulated by Kv7 status. mAChR depolarizations were shown to be dependent, in part, on TRPA1. We argue that dysfunction of the MDBD could be a functional convergence point for maladapted ion channels and receptors consequent to exposure to GW chemicals. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines

    International Nuclear Information System (INIS)

    Dumont, Julie; Josse, Rozenn; Lambert, Carine; Antherieu, Sebastien; Laurent, Veronique; Loyer, Pascal; Robin, Marie-Anne; Guillouzo, Andre

    2010-01-01

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are two of the most common heterocyclic aromatic amines (HAA) produced during cooking of meat, fish and poultry. Both HAA produce different tumor profiles in rodents and are suspected to be carcinogenic in humans. In order to better understand the molecular basis of HAA toxicity, we have analyzed gene expression profiles in the metabolically competent human HepaRG cells using pangenomic oligonucleotide microarrays, after either a single (24-h) or a repeated (28-day) exposure to 10 μM PhIP or MeIQx. The most responsive genes to both HAA were downstream targets of the arylhydrocarbon receptor (AhR): CYP1A1 and CYP1A2 after both time points and CYP1B1 and ALDH3A1 after 28 days. Accordingly, CYP1A1/1A2 induction in HAA-treated HepaRG cells was prevented by chemical inhibition or small interference RNA-mediated down-regulation of the AhR. Consistently, HAA induced activity of the CYP1A1 promoter, which contains a consensus AhR-related xenobiotic-responsive element (XRE). In addition, several other genes exhibited both time-dependent and compound-specific expression changes with, however, a smaller magnitude than previously reported for the prototypical AhR target genes. These changes concerned genes mainly related to cell growth and proliferation, apoptosis, and cancer. In conclusion, these results identify the AhR gene battery as the preferential target of PhIP and MeIQx in HepaRG cells and further support the hypothesis that intake of HAA in diet might increase human cancer risk.

  18. Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation.

    Science.gov (United States)

    Corrada, Dario; Soshilov, Anatoly A; Denison, Michael S; Bonati, Laura

    2016-06-01

    The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the

  19. Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation.

    Directory of Open Access Journals (Sweden)

    Dario Corrada

    2016-06-01

    Full Text Available The Aryl hydrocarbon Receptor (AhR is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT protein, occurring through the Helix-Loop-Helix (HLH and PER-ARNT-SIM (PAS domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms

  20. An in vitro approach for prioritization and evaluation of chemical effects on glucocorticoid receptor mediated adipogenesis.

    Science.gov (United States)

    Hartman, Jessica K; Beames, Tyler; Parks, Bethany; Doheny, Daniel; Song, Gina; Efremenko, Alina; Yoon, Miyoung; Foley, Briana; Deisenroth, Chad; McMullen, Patrick D; Clewell, Rebecca A

    2018-05-18

    Rising obesity rates worldwide have socio-economic ramifications. While genetics, diet, and lack of exercise are major contributors to obesity, environmental factors may enhance susceptibility through disruption of hormone homeostasis and metabolic processes. The obesogen hypothesis contends that chemical exposure early in development may enhance adipocyte differentiation, thereby increasing the number of adipocytes and predisposing for obesity and metabolic disease. We previously developed a primary human adipose stem cell (hASC) assay to evaluate the effect of environmental chemicals on PPARG-dependent adipogenesis. Here, the assay was modified to determine the effects of chemicals on the glucocorticoid receptor (GR) pathway. In differentiation cocktail lacking the glucocorticoid agonist dexamethasone (DEX), hASCs do not differentiate into adipocytes. In the presence of GR agonists, adipocyte maturation was observed using phenotypic makers for lipid accumulation, adipokine secretion, and expression of key genes. To evaluate the role of environmental compounds on adipocyte differentiation, progenitor cells were treated with 19 prioritized compounds previously identified by ToxPi as having GR-dependent bioactivity, and multiplexed assays were used to confirm a GR-dependent mode of action. Five chemicals were found to be strong agonists. The assay was also modified to evaluate GR-antagonists, and 8/10 of the hypothesized antagonists inhibited adipogenesis. The in vitro bioactivity data was put into context with extrapolated human steady state concentrations (Css) and clinical exposure data (Cmax). These data support using a human adipose-derived stem cell differentiation assay to test the potential of chemicals to alter human GR-dependent adipogenesis. Copyright © 2017. Published by Elsevier Inc.

  1. Characterization of AhR agonists reveals antagonistic activity in European herring gull (Larus argentatus) eggs.

    Science.gov (United States)

    Muusse, Martine; Christensen, Guttorm; Gomes, Tânia; Kočan, Anton; Langford, Katherine; Tollefsen, Knut Erik; Vaňková, Lenka; Thomas, Kevin V

    2015-05-01

    European herring gull (Larus argentatus) eggs from two Norwegian islands, Musvær in the south east and Reiaren in Northern Norway, were screened for dioxins, furans, and dioxin-like and selected non-dioxin-like polychlorinated biphenyls (PCBs), and subjected to non-target analysis to try to identify the aryl hydrocarbon receptor (AhR) agonists, responsible for elevated levels measured using the dioxin responsive chemically activated luciferase expression (DR-CALUX) assay. Eggs from Musvær contained chemically calculated toxic equivalent (WHO TEQ) levels of between 109 and 483 pg TEQ/g lw, and between 82 and 337 pg TEQ/g lw was determined in eggs from Reiaren. In particular PCB126 contributed highly to the total TEQ (69-82%). In 19 of the 23 samples the calculated WHO TEQ was higher than the TEQCALUX. Using CALUX specific relative effect potencies (REPs), the levels were lower at between 77 and 292 pg/g lw in eggs from Musvær and between 55 and 223 pg/g lw in eggs from Reiaren, which was higher than the TEQCALUX in 16 of the 23 samples. However, the means of the REP values and the TEQCALUX were not significantly different. This suggests the presence of compounds that can elicit antagonist effects, with a low binding affinity to the AhR. Non-target analysis identified the presence of hexachlorobenzene (HCB) (quantified at 9.6-185 pg/g lw) but neither this compound nor high concentrations of PCB126 and non-dioxin-like PCBs could explain the differences between the calculated TEQ or REP values and the TEQCALUX. Even though, for most AhR agonists, the sensitivity of herring gulls is not known, the reported levels can be considered to represent a risk for biological effects in the developing embryo, compared to LC50 values in chicken embryos. For human consumers of herring gull eggs, these eggs contain TEQ levels up to four times higher than the maximum tolerable weekly intake. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Effects of environmental estrogenic chemicals on AP1 mediated transcription with estrogen receptors alpha and beta.

    Science.gov (United States)

    Fujimoto, Nariaki; Honda, Hiroaki; Kitamura, Shigeyuki

    2004-01-01

    There has been much discussion concerning endocrine disrupting chemicals suspected of exerting adverse effects in both wildlife and humans. Since the majority of these compounds are estrogenic, a large number of in vitro tests for estrogenic characteristics have been developed for screening purpose. One reliable and widely used method is the reporter gene assay employing estrogen receptors (ERs) and a reporter gene with a cis-acting estrogen responsive element (ERE). Other elements such as AP1 also mediate estrogenic signals and the manner of response could be quite different from that of ERE. Since this has yet to be explored, the ER mediated AP1 activity in response to a series of environmental estrogens was investigated in comparison with ERE findings. All the compounds exhibited estrogenic properties with ERE-luc and their AP1 responses were quite similar. These was one exception, however, p,p'-DDT (1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane) did not exert any AP1-luc activity, while it appeared to be estrogenic at 10(-7) to 10(-5)M with the ERE action. None of the compounds demonstrated ER beta:AP1 activity. These data suggest that significant differences can occur in responses through the two estrogen pathways depending on environmental chemicals.

  3. Using novel descriptor accounting for ligand-receptor interactions to define and visually explore biologically relevant chemical space.

    Science.gov (United States)

    Rabal, Obdulia; Oyarzabal, Julen

    2012-05-25

    The definition and pragmatic implementation of biologically relevant chemical space is critical in addressing navigation strategies in the overlapping regions where chemistry and therapeutically relevant targets reside and, therefore, also key to performing an efficient drug discovery project. Here, we describe the development and implementation of a simple and robust method for representing biologically relevant chemical space as a general reference according to current knowledge, independently of any reference space, and analyzing chemical structures accordingly. Underlying our method is the generation of a novel descriptor (LiRIf) that converts structural information into a one-dimensional string accounting for the plausible ligand-receptor interactions as well as for topological information. Capitalizing on ligand-receptor interactions as a descriptor enables the clustering, profiling, and comparison of libraries of compounds from a chemical biology and medicinal chemistry perspective. In addition, as a case study, R-groups analysis is performed to identify the most populated ligand-receptor interactions according to different target families (GPCR, kinases, etc.), as well as to evaluate the coverage of biologically relevant chemical space by structures annotated in different databases (ChEMBL, Glida, etc.).

  4. Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet.

    Science.gov (United States)

    Van Wagoner, Ryan M; Eichner, Amy; Bhasin, Shalender; Deuster, Patricia A; Eichner, Daniel

    2017-11-28

    Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels. Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association-approved analytical procedures. Analytical findings were compared against the label information. Products marketed and sold as selective androgen receptor modulators. Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators. Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products

  5. Receptor visualization and the atomic bomb. A historical account of the development of the chemical neuroanatomy of receptors for neurotransmitters and drugs during the Cold War.

    Science.gov (United States)

    Palacios, J M; Mengod, G

    2018-03-01

    This is a historical account of how receptors for neurotransmitters and drugs got to be seen at the regional, cellular, and subcellular levels in brain, in the years going from the end of the World War II until the collapse of the Soviet Union, the Cold War (1945-1991). The realization in the US of the problem of mental health care, as a consequence of the results of medical evaluation for military service during the war, let the US Government to act creating among other things the National Institute for Mental Health (NIMH). Coincident with that, new drug treatments for these disorders were introduced. War science also created an important number of tools and instruments, such as the radioisotopes, that played a significant role in the development of our story. The scientific context was marked by the development of Biochemistry, Molecular Biology and the introduction in the early 80's of the DNA recombinant technologies. The concepts of chemical neurotransmission in the brain and of receptors for drugs and transmitters, although proposed before the war, where not generally accepted. Neurotransmitters were identified and the mechanisms of biosynthesis, storage, release and termination of action by mechanisms such as reuptake, elucidated. Furthermore, the synapse was seen with the electron microscope and more important for our account, neurons and their processes visualized in the brain first by fluorescence histochemistry, then using radioisotopes and autoradiography, and later by immunohistochemistry (IHC), originating the Chemical Neuroanatomy. The concept of chemical neurotransmission evolved from the amines, expanded to excitatory and inhibitory amino acids, then to neuropeptides and finally to gases and other "atypical" neurotransmitters. In addition, coexpression of more than one transmitter in a neuron, changed the initial ideas of neurotransmission. The concept of receptors for these and other messengers underwent a significant evolution from an abstract

  6. Mechanical and Thermal Properties of the AH of FRW Universe

    International Nuclear Information System (INIS)

    Yi-Huan, Wei

    2010-01-01

    We calculate the work made out by the apparent horizon (AH) of the Friedmann–Robertson–Walker (FRW) universe and the heat flux through the AH from the first law of thermodynamics. We discuss the mechanical properties of the AH and analyze the universe model for which the mechanical properties can change. Finally, the thermal properties of the AH of FRW universe are discussed

  7. A single sex pheromone receptor determines chemical response specificity of sexual behavior in the silkmoth Bombyx mori.

    Science.gov (United States)

    Sakurai, Takeshi; Mitsuno, Hidefumi; Haupt, Stephan Shuichi; Uchino, Keiro; Yokohari, Fumio; Nishioka, Takaaki; Kobayashi, Isao; Sezutsu, Hideki; Tamura, Toshiki; Kanzaki, Ryohei

    2011-06-01

    In insects and other animals, intraspecific communication between individuals of the opposite sex is mediated in part by chemical signals called sex pheromones. In most moth species, male moths rely heavily on species-specific sex pheromones emitted by female moths to identify and orient towards an appropriate mating partner among a large number of sympatric insect species. The silkmoth, Bombyx mori, utilizes the simplest possible pheromone system, in which a single pheromone component, (E, Z)-10,12-hexadecadienol (bombykol), is sufficient to elicit full sexual behavior. We have previously shown that the sex pheromone receptor BmOR1 mediates specific detection of bombykol in the antennae of male silkmoths. However, it is unclear whether the sex pheromone receptor is the minimally sufficient determination factor that triggers initiation of orientation behavior towards a potential mate. Using transgenic silkmoths expressing the sex pheromone receptor PxOR1 of the diamondback moth Plutella xylostella in BmOR1-expressing neurons, we show that the selectivity of the sex pheromone receptor determines the chemical response specificity of sexual behavior in the silkmoth. Bombykol receptor neurons expressing PxOR1 responded to its specific ligand, (Z)-11-hexadecenal (Z11-16:Ald), in a dose-dependent manner. Male moths expressing PxOR1 exhibited typical pheromone orientation behavior and copulation attempts in response to Z11-16:Ald and to females of P. xylostella. Transformation of the bombykol receptor neurons had no effect on their projections in the antennal lobe. These results indicate that activation of bombykol receptor neurons alone is sufficient to trigger full sexual behavior. Thus, a single gene defines behavioral selectivity in sex pheromone communication in the silkmoth. Our findings show that a single molecular determinant can not only function as a modulator of behavior but also as an all-or-nothing initiator of a complex species-specific behavioral sequence.

  8. A single sex pheromone receptor determines chemical response specificity of sexual behavior in the silkmoth Bombyx mori.

    Directory of Open Access Journals (Sweden)

    Takeshi Sakurai

    2011-06-01

    Full Text Available In insects and other animals, intraspecific communication between individuals of the opposite sex is mediated in part by chemical signals called sex pheromones. In most moth species, male moths rely heavily on species-specific sex pheromones emitted by female moths to identify and orient towards an appropriate mating partner among a large number of sympatric insect species. The silkmoth, Bombyx mori, utilizes the simplest possible pheromone system, in which a single pheromone component, (E, Z-10,12-hexadecadienol (bombykol, is sufficient to elicit full sexual behavior. We have previously shown that the sex pheromone receptor BmOR1 mediates specific detection of bombykol in the antennae of male silkmoths. However, it is unclear whether the sex pheromone receptor is the minimally sufficient determination factor that triggers initiation of orientation behavior towards a potential mate. Using transgenic silkmoths expressing the sex pheromone receptor PxOR1 of the diamondback moth Plutella xylostella in BmOR1-expressing neurons, we show that the selectivity of the sex pheromone receptor determines the chemical response specificity of sexual behavior in the silkmoth. Bombykol receptor neurons expressing PxOR1 responded to its specific ligand, (Z-11-hexadecenal (Z11-16:Ald, in a dose-dependent manner. Male moths expressing PxOR1 exhibited typical pheromone orientation behavior and copulation attempts in response to Z11-16:Ald and to females of P. xylostella. Transformation of the bombykol receptor neurons had no effect on their projections in the antennal lobe. These results indicate that activation of bombykol receptor neurons alone is sufficient to trigger full sexual behavior. Thus, a single gene defines behavioral selectivity in sex pheromone communication in the silkmoth. Our findings show that a single molecular determinant can not only function as a modulator of behavior but also as an all-or-nothing initiator of a complex species

  9. Calorimetry of 25 Ah lithium/thionyl chloride cells

    Science.gov (United States)

    Johnson, C. J.; Dawson, S.

    1991-01-01

    Heat flow measurements of 25-Ah lithium thionyl chloride cells provided a method to calculate an effective thermal potential, E(TP) of 3.907 V. The calculation is useful to determine specific heat generation of this cell chemistry and design. The E(TP) value includes heat generation by electrochemical cell reactions, competitive chemical reactions, and resistance heating at the tabs, connectors, and leads. Heat flow was measured while applying electrical loads to the cell in an isothermal calorimeter set at 0, 20, and 60 C.

  10. Cloning retinoid and peroxisome proliferator-activated nuclear receptors of the Pacific oyster and in silico binding to environmental chemicals.

    Directory of Open Access Journals (Sweden)

    Susanne Vogeler

    Full Text Available Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor's functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor's ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT. Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l, all-trans retinoic acid (ATRA (0.06 mg/L and perfluorooctanoic acid (20 mg/L showed high effects on development (>74% abnormal developed D-shelled larvae, while rosiglitazone (40 mg/L showed no effect. The results are discussed in relation to a putative direct (TBT disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests

  11. Development of serotonergic and adrenergic receptors in the rat spinal cord: effects of neonatal chemical lesions and hyperthyroidism.

    Science.gov (United States)

    Lau, C; Pylypiw, A; Ross, L L

    1985-03-01

    The sympathetic preganglionic neurons in the spinal cord receive dense serotonergic (5-HT) and catecholaminergic (CA) afferent inputs from the descending supraspinal pathways. In the rat spinal cord, the levels of these biogenic amines and their receptors are low at birth, but undergo rapid ontogenetic increases in the ensuing 2-3 postnatal weeks until the adult levels are reached. In many systems it has been shown that denervation of presynaptic neurons leads to an up-regulation of the number of postsynaptic receptors. To determine whether the 5-HT and CA receptors in the developing spinal cord are also subject to such transsynaptic regulation, we examined the ontogeny of serotonergic receptors and alpha- and beta-adrenergic receptors in thoracolumbar spinal cord of rats given neurotoxins which destroy serotonergic (5,7-dihydroxytryptamine (5,7-DHT)) or noradrenergic (6-hydroxydopamine (6-OHDA)) nerve terminals. Intracisternal administration of 5,7-DHT or 6-OHDA at 1 and 6 days of age prevented, respectively, the development of 5-HT and CA levels in the spinal cord. Rats lesioned with 5,7-DHT displayed a marked elevation of 5-HT receptors with a binding of 50% greater than controls at 1 week and a continuing increase to twice normal by 4 weeks. A similar pattern of up-regulation was also detected with the alpha-adrenergic receptor, as rats lesioned with 6-OHDA exhibited persistent increases in receptor concentration. However, in these same animals ontogeny of the beta-adrenergic receptor in the spinal cord remained virtually unaffected by the chemical lesion. In several other parts of the nervous system, it has been demonstrated that the beta-adrenergic sensitivity can be modulated by hormonal signals, particularly that of the thyroid hormones. This phenomenon was examined in the spinal cord and in confirmation with previous studies neonatal treatment of triiodothyronine (0.1 mg/kg, s.c. daily) was capable of evoking persistent increases in beta

  12. Estrogenic and AhR activities in dissolved phase and suspended solids from wastewater treatment plants.

    Science.gov (United States)

    Dagnino, Sonia; Gomez, Elena; Picot, Bernadette; Cavaillès, Vincent; Casellas, Claude; Balaguer, Patrick; Fenet, Hélène

    2010-05-15

    The distribution of estrogen receptor (ERalpha) and Aryl Hydrocarbon Receptor (AhR) activities between the dissolved phase and suspended solids were investigated during wastewater treatment. Three wastewater treatment plants with different treatment technologies (waste stabilization ponds (WSPs), trickling filters (TFs) and activated sludge supplemented with a biofilter system (ASB)) were sampled. Estrogenic and AhR activities were detected in both phases in influents and effluents. Estrogenic and AhR activities in wastewater influents ranged from 41.8 to 79 ng/L E(2) Eq. and from 37.9 to 115.5 ng/L TCDD Eq. in the dissolved phase and from 5.5 to 88.6 ng/g E(2) Eq. and from 15 to 700 ng/g TCDD Eq. in the suspended solids. For both activities, WSP showed greater or similar removal efficiency than ASB and both were much more efficient than TF which had the lowest removal efficiency. Moreover, our data indicate that the efficiency of removal of ER and AhR activities from the suspended solid phase was mainly due to removal of suspended solids. Indeed, ER and AhR activities were detected in the effluent suspended solid phase indicating that suspended solids, which are usually not considered in these types of studies, contribute to environmental contamination by endocrine disrupting compounds and should therefore be routinely assessed for a better estimation of the ER and AhR activities released in the environment. Copyright 2010 Elsevier B.V. All rights reserved.

  13. Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

    Science.gov (United States)

    Sakkal, Leon A; Rajkowski, Kyle Z; Armen, Roger S

    2017-06-05

    Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A 1 R, A 2A R, A 3 R) and muscarinic acetylcholine (M 1 R, M 5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M 1 R PAMs were predicted to bind in the analogous M 2 R PAM LY2119620 binding site. The M 5 R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  14. ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR.

    Science.gov (United States)

    Li, Yan; Wang, Kai; Zou, Qing-Yun; Jiang, Yi-Zhou; Zhou, Chi; Zheng, Jing

    2017-12-01

    Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor is involved in regulation of many essential biological processes including vascular development and angiogenesis. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an AhR ligand, which regulates immune responses and cancer cell growth. However, the roles of the ITE/AhR pathway in mediating placental angiogenesis remains elusive. Here, we determined if ITE affected placental angiogenic responses via AhR in human umbilical vein (HUVECs) and artery endothelial (HUAECs) cells in vitro. We observed that ITE dose- and time-dependently inhibited proliferation and viability of HUAECs and HUVECs, whereas it inhibited migration of HUAECs, but not HUVECs. While AhR siRNA significantly suppressed AhR protein expression in HUVECs and HUAECs, it attenuated the ITE-inhibited angiogenic responses of HUAECs, but not HUVECs. Collectively, ITE suppressed angiogenic responses of HUAECs and HUVECs, dependent and independent of AhR, respectively. These data suggest that ITE may regulate placental angiogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view.

    Science.gov (United States)

    Helsley, Robert N; Zhou, Changcheng

    2017-10-01

    Despite the major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. While considerable progress has been achieved to identify gene variations and environmental factors that contribute to CVD, much less is known about the role of "gene-environment interactions" in predisposing individuals to CVD. Our chemical environment has significantly changed in the last few decades, and there are more than 100,000 synthetic chemicals in the market. Recent large-scale human population studies have associated exposure to certain chemicals including many endocrine disrupting chemicals (EDCs) with increased CVD risk, and animal studies have also confirmed that some EDCs can cause aberrant lipid homeostasis and increase atherosclerosis. However, the underlying mechanisms of how exposure to those EDCs influences CVD risk remain elusive. Numerous EDCs can activate the nuclear receptor pregnane X receptor (PXR) that functions as a xenobiotic sensor to regulate host xenobiotic metabolism. Recent studies have demonstrated the novel functions of PXR in lipid homeostasis and atherosclerosis. In addition to directly regulating transcription, PXR has been implicated in the epigenetic regulation of gene transcription. Exposure to many EDCs can also induce epigenetic modifications, but little is known about how the changes relate to the onset or progression of CVD. In this review, we will discuss recent research on PXR and EDCs in the context of CVD and propose that PXR may play a previously unrealized role in EDC-mediated epigenetic modifications that affect lipid homeostasis and atherosclerosis.

  16. AhV_aPA-induced vasoconstriction involves the IP₃Rs-mediated Ca²⁺ releasing.

    Science.gov (United States)

    Zeng, Fuxing; Zou, Zhisong; Niu, Liwen; Li, Xu; Teng, Maikun

    2013-08-01

    AhV_aPA, the acidic PLA₂ purified from Agkistrodon halys pallas venom, was previously reported to possess a strong enzymatic activity and can remarkably induce a further contractile response on the 60 mM K⁺-induced contraction with an EC₅₀ in 369 nM on mouse thoracic aorta rings. In the present study, we found that the p-bromo-phenacyl-bromide (pBPB), which can completely inhibit the enzymatic activity of AhV_aPA, did not significantly reduce the contractile response on vessel rings induced by AhV_aPA, indicating that the vasoconstrictor effects of AhV_aPA are independent of the enzymatic activity. The inhibitor experiments showed that the contractile response induced by AhV_aPA is mainly attributed to the Ca²⁺ releasing from Ca²⁺ store, especially sarcoplasmic reticulum (SR). Detailed studies showed that the Ca²⁺ release from SR is related to the activation of inositol trisphosphate receptors (IP₃Rs) rather than ryanodine receptors (RyRs). Furthermore, the vasoconstrictor effect could be strongly reduced by pre-incubation with heparin, indicating that the basic amino acid residues on the surface of AhV_aPA may be involved in the interaction between AhV_aPA and the molecular receptors. These findings offer new insights into the functions of snake PLA₂ and provide a novel pathogenesis of A. halys pallas venom. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, Ting-Wei; Chang, Ying-Hsu; Kuo, Yung-Chia; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Lee, Li-Yu; Ma, Wen-Lung; Lin, Chun-Cheng; Wu, Wen-Guey

    2017-09-19

    Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

  18. Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

    Science.gov (United States)

    Zorrilla, Eric P.; Heilig, Markus; de Wit, Harriet; Shaham, Yavin

    2013-01-01

    Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence. PMID:23294766

  19. AL-KAFA’AH FI AL-NIKAH

    Directory of Open Access Journals (Sweden)

    Najmah Sayuti

    2015-11-01

    Full Text Available Kafa'ah in marriage is basically equality, suitability and proportionality between the prospective couples getting married. Humans are required to kafa'ah in religion and religiosity. Non-Muslims can't kafa'ah with Muslims because of inequalities in beliefe. Some kafa'ah that should be considered in marriage is nasab, religion, belief or religiosity, profession, liberty and property.

  20. In vivo stem cell tracking with imageable nanoparticles that bind bioorthogonal chemical receptors on the stem cell surface.

    Science.gov (United States)

    Lee, Sangmin; Yoon, Hwa In; Na, Jin Hee; Jeon, Sangmin; Lim, Seungho; Koo, Heebeom; Han, Sang-Soo; Kang, Sun-Woong; Park, Soon-Jung; Moon, Sung-Hwan; Park, Jae Hyung; Cho, Yong Woo; Kim, Byung-Soo; Kim, Sang Kyoon; Lee, Taekwan; Kim, Dongkyu; Lee, Seulki; Pomper, Martin G; Kwon, Ick Chan; Kim, Kwangmeyung

    2017-09-01

    It is urgently necessary to develop reliable non-invasive stem cell imaging technology for tracking the in vivo fate of transplanted stem cells in living subjects. Herein, we developed a simple and well controlled stem cell imaging method through a combination of metabolic glycoengineering and bioorthogonal copper-free click chemistry. Firstly, the exogenous chemical receptors containing azide (-N 3 ) groups were generated on the surfaces of stem cells through metabolic glycoengineering using metabolic precursor, tetra-acetylated N-azidoacetyl-d-mannosamine(Ac 4 ManNAz). Next, bicyclo[6.1.0]nonyne-modified glycol chitosan nanoparticles (BCN-CNPs) were prepared as imageable nanoparticles to deliver different imaging agents. Cy5.5, iron oxide nanoparticles and gold nanoparticles were conjugated or encapsulated to BCN-CNPs for optical, MR and CT imaging, respectively. These imageable nanoparticles bound chemical receptors on the Ac 4 ManNAz-treated stem cell surface specifically via bioorthogonal copper-free click chemistry. Then they were rapidly taken up by the cell membrane turn-over mechanism resulting in higher endocytic capacity compared non-specific uptake of nanoparticles. During in vivo animal test, BCN-CNP-Cy5.5-labeled stem cells could be continuously tracked by non-invasive optical imaging over 15 days. Furthermore, BCN-CNP-IRON- and BCN-CNP-GOLD-labeled stem cells could be efficiently visualized using in vivo MR and CT imaging demonstrating utility of our stem cell labeling method using chemical receptors. These results conclude that our method based on metabolic glycoengineering and bioorthogonal copper-free click chemistry can stably label stem cells with diverse imageable nanoparticles representing great potential as new stem cell imaging technology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Chemical characterization and receptor modeling of PM10 in the surroundings of the opencast lignite mines of Western Macedonia, Greece.

    Science.gov (United States)

    Samara, Constantini; Argyropoulos, George; Grigoratos, Theodoros; Kouras, Αthanasios; Manoli, Εvangelia; Andreadou, Symela; Pavloudakis, Fragkiskos; Sahanidis, Chariton

    2018-05-01

    The Western Macedonian Lignite Center (WMLC) in northwestern Greece is the major lignite center in the Balkans feeding four major power plants of total power exceeding 4 GW. Concentrations of PM 10 (i.e., particulate matters with diameters ≤10 μm) are the main concern in the region, and the high levels observed are often attributed to the activities related to power generation. In this study, the contribution of fugitive dust emissions from the opencast lignite mines to the ambient levels of PM 10 in the surroundings was estimated by performing chemical mass balance (CMB) receptor modeling. For this purpose, PM 10 samples were concurrently collected at four receptor sites located in the periphery of the mine area during the cold and the warm periods of the year (November-December 2011 and August-September 2012), and analyzed for a total of 26 macro- and trace elements and ionic species (sulfate, nitrate, chloride). The robotic chemical mass balance (RCMB) model was employed for source identification/apportionment of PM 10 at each receptor site using as inputs the ambient concentrations and the chemical profiles of various sources including the major mine operations, the fly ash escaping the electrostatic filters of the power plants, and other primary and secondary sources. Mean measured PM 10 concentrations at the different sites ranged from 38 to 72 μg m -3 . The estimated total contribution of mines ranged between 9 and 22% in the cold period increasing to 36-42% in the dry warm period. Other significant sources were vehicular traffic, biomass burning, and secondary sulfate and nitrate aerosol. These results imply that more efficient measures to prevent and suppress fugitive dust emissions from the mines are needed.

  2. Macrocyclic receptors immobilized to monodisperse porous polymer particles by chemical grafting and physical impregnation for strontium capture: A comparative study

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yang [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing (China); Du, Yi [Department of Chemical Engineering, Laboratory for Advanced Materials, Tsinghua University, Beijing (China); Lv, Dachao [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing (China); Ye, Gang, E-mail: yegang@tsinghua.edu.cn [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing (China); Wang, Jianchen [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing (China)

    2014-06-01

    Graphical abstract: Macrocyclic receptors grafted to monodisperse porous polymer particles for Sr(II) capture. - Highlights: • Synthesis of novel selective Sr adsorbent grafted with macrocyclic receptors. • New monodisperse porous polymer particles used to promote Sr adsorption. • Comparative study and discussion on adsorption behaviour and mechanism. • A chromatographic process proposed for Sr separation in simulated HLLW. - Abstract: Separation of strontium is of great significance for radioactive waste treatment and environmental remediation after nuclear accidents. In this work, a novel class of adsorbent (Crown-g-MPPPs) was synthesized by chemical grafting a macrocyclic ether receptor to monodisperse porous polymer particles (MPPPs) for strontium adsorption. Meanwhile, a counterpart material (Crown@MPPPs) with the receptor molecules immobilized to the MPPPs substrate by physical impregnation was prepared. To investigate how the immobilization manner and distribution of the receptors influence the adsorption ability, a comparative study on the adsorption behaviour of the two materials towards Sr(II) in HNO{sub 3} media was accomplished. Due to the shorter diffusion path and covalently-bonded structure, Crown-g-MPPPs showed faster adsorption kinetics and better stability for cycle use. While Crown@MPPPs had the advantages of facile synthesis and higher adsorption capacity, owing to the absence of conformational constraint to form complexation with Sr(II). Kinetic functions (Lagergren pseudo-first-order/pseudo-second-order functions) and adsorption isotherm models (Langmuir/Freundlich models) were used to fit the experimental data and examine the adsorption mechanism. On this basis, a chromatographic process was proposed by using Crown@MPPPs for an effective separation of Sr(II) (91%) in simulated high level liquid waste (HLLW)

  3. Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

    Science.gov (United States)

    Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

    2016-11-01

    Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

  4. A chemically inert drug can stimulate T cells in vitro by their T cell receptor in non-sensitised individuals

    International Nuclear Information System (INIS)

    Engler, Olivier B.; Strasser, Ingrid; Naisbitt, Dean J.; Cerny, Andreas; Pichler, Werner J.

    2004-01-01

    Drugs can interact with T cell receptors (TCR) after binding to peptide-MHC structures. This binding may involve the formation of a stable, covalent bond between a chemically reactive drug and MHC or the peptide embedded within. Alternatively, if the drug is chemically inert, the binding may be non-covalent and readily reversible. Both types of drug presentation account for a substantial number of adverse side effects to drugs. Presently no tests are available to predict the ability of chemically inert drugs to stimulate an immune response. Here we present data on the successful induction of a primary T cell immune response in vitro against a chemically inert drug using blood from healthy individuals, previously not exposed to the drug. Blood lymphocytes were stimulated by the chemically inert drug sulfamethoxazole and the protein-reactive drug-metabolite sulfamethoxazole-nitroso in the presence of IL-2. 9/10 individuals reacted in response to sulfamethoxazole-nitroso, but only three reacted to the chemically inert compound sulfamethoxazole. Drug reactive T cells could be detected after 14-35 days of cell culture by drug-specific proliferation or cytotoxicity, which was MHC-restricted. These cells were CD4, CD8 positive or CD4/CD8 double positive and T cell clones generated secreted Th0 type cytokines. Drug interaction lead to down-regulation of specific TCR. These data confirm the ability of chemically inert drugs to stimulate certain T cells by their TCR and may provide the opportunity to screen new drugs for their ability to interact with TCRs

  5. SMM-chemokines: a class of unnatural synthetic molecules as chemical probes of chemokine receptor biology and leads for therapeutic development.

    Science.gov (United States)

    Kumar, Santosh; Choi, Won-Tak; Dong, Chang-Zhi; Madani, Navid; Tian, Shaomin; Liu, Dongxiang; Wang, Youli; Pesavento, James; Wang, Jun; Fan, Xuejun; Yuan, Jian; Fritzsche, Wayne R; An, Jing; Sodroski, Joseph G; Richman, Douglas D; Huang, Ziwei

    2006-01-01

    Chemokines and their receptors play important roles in numerous physiological and pathological processes. To develop natural chemokines into receptor probes and inhibitors of pathological processes, the lack of chemokine-receptor selectivity must be overcome. Here, we apply chemical synthesis and the concept of modular modifications to generate unnatural synthetically and modularly modified (SMM)-chemokines that have high receptor selectivity and affinity, and reduced toxicity. A proof of the concept was shown by transforming the nonselective viral macrophage inflammatory protein-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for human immunodeficiency virus (HIV)-1 entry. These new analogs provided insights into receptor binding and signaling mechanisms and acted as potent HIV-1 inhibitors. These results support the concept of SMM-chemokines for studying and controlling the function of other chemokine receptors.

  6. No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals.

    Science.gov (United States)

    Bannister, Richard; Beresford, Nicola; Granger, David W; Pounds, Nadine A; Rand-Weaver, Mariann; White, Roger; Jobling, Susan; Routledge, Edwin J

    2013-09-15

    Estrogen receptor orthologues in molluscs may be targets for endocrine disruptors, although mechanistic evidence is lacking. Molluscs are reported to be highly susceptible to effects caused by very low concentrations of environmental estrogens which, if substantiated, would have a major impact on the risk assessment of many chemicals. The present paper describes the most thorough evaluation to-date of the susceptibility of Marisa cornuarietis ER and ERR gene transcription to modulation by vertebrate estrogens in vivo and in vitro. We investigated the effects of estradiol-17β and 4-tert-Octylphenol exposure on in vivo estrogen receptor (ER) and estrogen-related receptor (ERR) gene transcription in the reproductive and neural tissues of the gastropod snail M. cornuarietis over a 12-week period. There was no significant effect (p>0.05) of treatment on gene transcription levels between exposed and non-exposed snails. Absence of a direct interaction of estradiol-17β and 4-tert-Octylphenol with mollusc ER and ERR protein was also supported by in vitro studies in transfected HEK-293 cells. Additional in vitro studies with a selection of other potential ligands (including methyl-testosterone, 17α-ethinylestradiol, 4-hydroxytamoxifen, diethylstilbestrol, cyproterone acetate and ICI182780) showed no interaction when tested using this assay. In repeated in vitro tests, however, genistein (with mcER-like) and bisphenol-A (with mcERR) increased reporter gene expression at high concentrations only (>10(-6)M for Gen and >10(-5)M for BPA, respectively). Like vertebrate estrogen receptors, the mollusc ER protein bound to the consensus vertebrate estrogen-response element (ERE). Together, these data provide no substantial evidence that mcER-like and mcERR activation and transcript levels in tissues are modulated by the vertebrate estrogen estradiol-17β or 4-tert-Octylphenol in vivo, or that other ligands of vertebrate ERs and ERRs (with the possible exception of genistein and

  7. Association of aryl hydrocarbon receptor-related gene variants with the severity of autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Takashi X. Fujisawa

    2016-11-01

    Full Text Available Exposure to environmental chemicals, such as dioxin, is known to have adverse effects on the homeostasis of gonadal steroids, thereby potentially altering the sexual differentiation of the brain to express autistic traits. Dioxin-like chemicals act on the aryl hydrocarbon receptor (AhR, polymorphisms and mutations of AhR-related gene may exert pathological influences on sexual differentiation of the brain, causing autistic traits. To ascertain the relationship between AhR-related gene polymorphisms and autism susceptibility, we identified genotypes of them in patients and controls and determined whether there are different gene and genotype distributions between both groups. In addition, to clarify the relationships between the polymorphisms and the severity of autism, we compared the two genotypes of AhR-related genes (rs2066853, rs2228099 with the severity of autistic symptoms. Although no statistically significant difference was found between autism spectrum disorder (ASD patients and control individuals for the genotypic distribution of any of the polymorphisms studied herein, a significant difference in the total score of severity was observed in rs2228099 polymorphism, suggesting that the polymorphism modifies the severity of ASD symptoms but not ASD susceptibility. Moreover, we found that a significant difference in the social communication score of severity was observed. These results suggest that the rs2228099 polymorphism is possibly associated with the severity of social communication impairment among the diverse ASD symptoms.

  8. Macrocyclic receptors immobilized to monodisperse porous polymer particles by chemical grafting and physical impregnation for strontium capture: a comparative study.

    Science.gov (United States)

    Song, Yang; Du, Yi; Lv, Dachao; Ye, Gang; Wang, Jianchen

    2014-06-15

    Separation of strontium is of great significance for radioactive waste treatment and environmental remediation after nuclear accidents. In this work, a novel class of adsorbent (Crown-g-MPPPs) was synthesized by chemical grafting a macrocyclic ether receptor to monodisperse porous polymer particles (MPPPs) for strontium adsorption. Meanwhile, a counterpart material (Crown@MPPPs) with the receptor molecules immobilized to the MPPPs substrate by physical impregnation was prepared. To investigate how the immobilization manner and distribution of the receptors influence the adsorption ability, a comparative study on the adsorption behaviour of the two materials towards Sr(II) in HNO3 media was accomplished. Due to the shorter diffusion path and covalently-bonded structure, Crown-g-MPPPs showed faster adsorption kinetics and better stability for cycle use. While Crown@MPPPs had the advantages of facile synthesis and higher adsorption capacity, owing to the absence of conformational constraint to form complexation with Sr(II). Kinetic functions (Lagergren pseudo-first-order/pseudo-second-order functions) and adsorption isotherm models (Langmuir/Freundlich models) were used to fit the experimental data and examine the adsorption mechanism. On this basis, a chromatographic process was proposed by using Crown@MPPPs for an effective separation of Sr(II) (91%) in simulated high level liquid waste (HLLW). Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Water exposure assessment of aryl hydrocarbon receptor agonists in Three Gorges Reservoir, China using SPMD-based virtual organisms.

    Science.gov (United States)

    Wang, Jingxian; Bernhöft, Silke; Pfister, Gerd; Schramm, Karl-Werner

    2014-10-15

    SPMD-based virtual organisms (VOs) were deployed at five to eight sites in the Three Gorges Reservoir (TGR), China for five periods in 2008, 2009 and 2011. The water exposure of aryl hydrocarbon receptor (AhR) agonists was assessed by the VOs. The chosen bioassay response for the extracts of the VOs, the induction of 7-ethoxyresorufin-O-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The results show that the extracts from the VOs could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) accounted for water level reached a maximum of 175 m. Although the aqueous concentration of AhR agonists of 0.8-4.8 pg TCDDL(-1) in TGR was not alarming, the tendency of accumulating high concentration of AhR agonists in VO lipid and existence of possible synergism or antagonism in the water may exhibit a potential hazard to local biota being exposed to AhR agonists. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Use of nuclear receptor luciferase-based bioassays to detect endocrine active chemicals in a biosolids-biochar amended soil.

    Science.gov (United States)

    Anderson, Carolyn G; Joshi, Geetika; Bair, Daniel A; Oriol, Charlotte; He, Guochun; Parikh, Sanjai J; Denison, Michael S; Scow, Kate M

    2017-08-01

    Biosolids are a potentially valuable source of carbon and nutrients for agricultural soils; however, potential unintended impacts on human health and the environment must be considered. Virtually all biosolids contain trace amounts endocrine-disrupting chemicals derived from human use of pharmaceuticals and personal care products (PPCPs). One potential way to reduce the bioavailability of PPCPs is to co-apply biosolids with biochar to soil, because biochar's chemical (e.g., aromaticity) and physical properties (e.g., surface area) give it a high affinity to bind many organic chemicals in the environment. We developed a soil-specific extraction method and utilized a luciferase-based bioassay (CALUX) to detect endocrine active chemicals in a biosolids-biochar co-amendment soil greenhouse study. Both biochar (walnut shell, 900 °C) and biosolids had positive impacts on carrot and lettuce biomass accumulation over our study period. However, the walnut shell biochar stimulated aryl hydrocarbon receptor activity, suggesting the presence of potential endocrine active chemicals in the biochar. Since the biochar rate tested (100 t ha -1 ) is above the average agronomic rate (10-20 t ha -1 ), endocrine effects would not be expected in most environmental applications. The effect of high temperature biochars on endocrine system pathways must be explored further, using both quantitative analytical tools to identify potential endocrine active chemicals and highly sensitive bioanalytical assays such as CALUX to measure the resulting biological activity of such compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  12. Development of estrogen receptor beta binding prediction model using large sets of chemicals.

    Science.gov (United States)

    Sakkiah, Sugunadevi; Selvaraj, Chandrabose; Gong, Ping; Zhang, Chaoyang; Tong, Weida; Hong, Huixiao

    2017-11-03

    We developed an ER β binding prediction model to facilitate identification of chemicals specifically bind ER β or ER α together with our previously developed ER α binding model. Decision Forest was used to train ER β binding prediction model based on a large set of compounds obtained from EADB. Model performance was estimated through 1000 iterations of 5-fold cross validations. Prediction confidence was analyzed using predictions from the cross validations. Informative chemical features for ER β binding were identified through analysis of the frequency data of chemical descriptors used in the models in the 5-fold cross validations. 1000 permutations were conducted to assess the chance correlation. The average accuracy of 5-fold cross validations was 93.14% with a standard deviation of 0.64%. Prediction confidence analysis indicated that the higher the prediction confidence the more accurate the predictions. Permutation testing results revealed that the prediction model is unlikely generated by chance. Eighteen informative descriptors were identified to be important to ER β binding prediction. Application of the prediction model to the data from ToxCast project yielded very high sensitivity of 90-92%. Our results demonstrated ER β binding of chemicals could be accurately predicted using the developed model. Coupling with our previously developed ER α prediction model, this model could be expected to facilitate drug development through identification of chemicals that specifically bind ER β or ER α .

  13. Antagonism of ionotropic glutamate receptors attenuates chemical ischemia-induced injury in rat primary cultured myenteric ganglia.

    Directory of Open Access Journals (Sweden)

    Elisa Carpanese

    Full Text Available Alterations of the enteric glutamatergic transmission may underlay changes in the function of myenteric neurons following intestinal ischemia and reperfusion (I/R contributing to impairment of gastrointestinal motility occurring in these pathological conditions. The aim of the present study was to evaluate whether glutamate receptors of the NMDA and AMPA/kainate type are involved in myenteric neuron cell damage induced by I/R. Primary cultured rat myenteric ganglia were exposed to sodium azide and glucose deprivation (in vitro chemical ischemia. After 6 days of culture, immunoreactivity for NMDA, AMPA and kainate receptors subunits, GluN(1 and GluA(1-3, GluK(1-3 respectively, was found in myenteric neurons. In myenteric cultured ganglia, in normal metabolic conditions, -AP5, an NMDA antagonist, decreased myenteric neuron number and viability, determined by calcein AM/ethidium homodimer-1 assay, and increased reactive oxygen species (ROS levels, measured with hydroxyphenyl fluorescein. CNQX, an AMPA/kainate antagonist exerted an opposite action on the same parameters. The total number and viability of myenteric neurons significantly decreased after I/R. In these conditions, the number of neurons staining for GluN1 and GluA(1-3 subunits remained unchanged, while, the number of GluK(1-3-immunopositive neurons increased. After I/R, -AP5 and CNQX, concentration-dependently increased myenteric neuron number and significantly increased the number of living neurons. Both -AP5 and CNQX (100-500 µM decreased I/R-induced increase of ROS levels in myenteric ganglia. On the whole, the present data provide evidence that, under normal metabolic conditions, the enteric glutamatergic system exerts a dualistic effect on cultured myenteric ganglia, either by improving or reducing neuron survival via NMDA or AMPA/kainate receptor activation, respectively. However, blockade of both receptor pathways may exert a protective role on myenteric neurons following and I

  14. Atrazine affects kidney and adrenal hormones (AHs) related genes expressions of rare minnow (Gobiocypris rarus).

    Science.gov (United States)

    Yang, Lihua; Zha, Jinmiao; Li, Wei; Li, Zhaoli; Wang, Zijian

    2010-05-05

    Atrazine, one of the most widely used herbicides, has been proved to interfere with sexual hormones. However few studies have considered the effects of atrazine on adrenal hormones (AH). In this study, rare minnow (Gobiocypris rarus) was exposed to 0, 3, 10, 33, 100 and 333microg/l atrazine for 28 days. The histopathology of kidney and gill was examined and the expressions of AHs-related genes including Na(+),K(+)-ATPase, glucocorticoid receptor (gr), heat shock protein 70 (hsp70), and heat shock protein 90 (hsp90) in kidney and gill were quantitatively determined. Histopathological observation revealed obvious lesions in gill including hyperplasia, necrosis in epithelium region, aneurysm and lamellar fusion at concentrations as low as 10microg/l. The observed lesions in kidney included extensive expansion in the lumen, degenerative and necrotic changes of the tubular epithelia, shrinkage of the glomerulus as well as increase of the Bowman's space at concentrations as low as 10microg/l. The expressions of Na(+),K(+)-ATPase, gr, hsp70 and hsp90 in the kidney of females were significantly decreased at all concentrations. For males, the expressions of hsp90 in the kidney of all treated groups were significantly down-regulated, while gr at all concentrations and hsp70 at 10, 33, 100microg/l were significantly up-regulated. However in the gill, the expressions of these genes were not significantly different from the control. These results indicated that exposure to atrazine caused impairments of kidney and gill of fish at environmental related concentrations. Histopathological lesions could partly attribute to the changes of the expressions of AHs-related genes in kidney. We concluded also that atrazine is a potential AHs-disruptor and AHs-related genes in kidney of fish could be used as sensitive molecular biomarkers.

  15. Atrazine affects kidney and adrenal hormones (AHs) related genes expressions of rare minnow (Gobiocypris rarus)

    Energy Technology Data Exchange (ETDEWEB)

    Yang Lihua; Zha Jinmiao; Li Wei; Li Zhaoli [State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing Road 18, P.O. Box 2871, Beijing 100085 (China); Wang Zijian, E-mail: wangzj@rcees.ac.cn [State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Shuangqing Road 18, P.O. Box 2871, Beijing 100085 (China)

    2010-05-05

    Atrazine, one of the most widely used herbicides, has been proved to interfere with sexual hormones. However few studies have considered the effects of atrazine on adrenal hormones (AH). In this study, rare minnow (Gobiocypris rarus) was exposed to 0, 3, 10, 33, 100 and 333 {mu}g/l atrazine for 28 days. The histopathology of kidney and gill was examined and the expressions of AHs-related genes including Na{sup +},K{sup +}-ATPase, glucocorticoid receptor (gr), heat shock protein 70 (hsp70), and heat shock protein 90 (hsp90) in kidney and gill were quantitatively determined. Histopathological observation revealed obvious lesions in gill including hyperplasia, necrosis in epithelium region, aneurysm and lamellar fusion at concentrations as low as 10 {mu}g/l. The observed lesions in kidney included extensive expansion in the lumen, degenerative and necrotic changes of the tubular epithelia, shrinkage of the glomerulus as well as increase of the Bowman's space at concentrations as low as 10 {mu}g/l. The expressions of Na{sup +},K{sup +}-ATPase, gr, hsp70 and hsp90 in the kidney of females were significantly decreased at all concentrations. For males, the expressions of hsp90 in the kidney of all treated groups were significantly down-regulated, while gr at all concentrations and hsp70 at 10, 33, 100 {mu}g/l were significantly up-regulated. However in the gill, the expressions of these genes were not significantly different from the control. These results indicated that exposure to atrazine caused impairments of kidney and gill of fish at environmental related concentrations. Histopathological lesions could partly attribute to the changes of the expressions of AHs-related genes in kidney. We concluded also that atrazine is a potential AHs-disruptor and AHs-related genes in kidney of fish could be used as sensitive molecular biomarkers.

  16. Atrazine affects kidney and adrenal hormones (AHs) related genes expressions of rare minnow (Gobiocypris rarus)

    International Nuclear Information System (INIS)

    Yang Lihua; Zha Jinmiao; Li Wei; Li Zhaoli; Wang Zijian

    2010-01-01

    Atrazine, one of the most widely used herbicides, has been proved to interfere with sexual hormones. However few studies have considered the effects of atrazine on adrenal hormones (AH). In this study, rare minnow (Gobiocypris rarus) was exposed to 0, 3, 10, 33, 100 and 333 μg/l atrazine for 28 days. The histopathology of kidney and gill was examined and the expressions of AHs-related genes including Na + ,K + -ATPase, glucocorticoid receptor (gr), heat shock protein 70 (hsp70), and heat shock protein 90 (hsp90) in kidney and gill were quantitatively determined. Histopathological observation revealed obvious lesions in gill including hyperplasia, necrosis in epithelium region, aneurysm and lamellar fusion at concentrations as low as 10 μg/l. The observed lesions in kidney included extensive expansion in the lumen, degenerative and necrotic changes of the tubular epithelia, shrinkage of the glomerulus as well as increase of the Bowman's space at concentrations as low as 10 μg/l. The expressions of Na + ,K + -ATPase, gr, hsp70 and hsp90 in the kidney of females were significantly decreased at all concentrations. For males, the expressions of hsp90 in the kidney of all treated groups were significantly down-regulated, while gr at all concentrations and hsp70 at 10, 33, 100 μg/l were significantly up-regulated. However in the gill, the expressions of these genes were not significantly different from the control. These results indicated that exposure to atrazine caused impairments of kidney and gill of fish at environmental related concentrations. Histopathological lesions could partly attribute to the changes of the expressions of AHs-related genes in kidney. We concluded also that atrazine is a potential AHs-disruptor and AHs-related genes in kidney of fish could be used as sensitive molecular biomarkers.

  17. Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability.

    Science.gov (United States)

    Zago, Michela; Sheridan, Jared A; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H; Hamid, Qutayba; Baglole, Carolyn J

    2017-01-01

    Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients.

  18. INDONESIA SHARI'AH COMPLIANCE STOCK RETURN BEHAVIOUR

    Directory of Open Access Journals (Sweden)

    Helma Malini

    2017-04-01

    Full Text Available This study aims to measures the behaviour of Indonesia Shari'ah compliance stock return. The measurement of return behaviour toward volatility will proved the capability of Indonesia Shari'ah compliance toward volatility that happened in Indonesia during the period of observation. Investing in Shari'ah compliance is quite different than investing in conventional stock which followed the capital market set of rules and law, Shari'ah compliance follows not only the capital market set of laws and but also the Islamic principles of principles. Most of the previous studies examine issues related to the conventional stocks and market. The present study take one step further by investigating issue related to Shari'ah compliance instrument. In the case of Shari'ah stock price in Indonesia, the dynamics volatility of the stock price can be minimized by taking an integrated screening process to the listed company, as precautions steps toward volatility

  19. Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library.

    Science.gov (United States)

    Männel, Barbara; Jaiteh, Mariama; Zeifman, Alexey; Randakova, Alena; Möller, Dorothee; Hübner, Harald; Gmeiner, Peter; Carlsson, Jens

    2017-10-20

    Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D 2 dopamine receptor (D 2 R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D 2 R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D 2 R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D 2 R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and β-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated β-arrestin recruitment (EC 50 = 320 nM, E max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

  20. P2X7 receptor mediates activation of microglial cells in prostate of chemically irritated rats

    Directory of Open Access Journals (Sweden)

    Heng Zhang

    2013-04-01

    Full Text Available Purpose Evidence shows that adenosine triphosphate (ATP is involved in the transmission of multiple chronic pain via P2X7 receptor. This study was to investigate the P2X7 and microglial cells in the chronic prostatitis pain. Materials and Methods Rats were divided into control group and chronic prostatitis group (n = 24 per group. A chronic prostatitis animal model was established by injecting complete Freund's adjuvant (CFA to the prostate of rats, and the thermal withdrawal latency (TWL was detected on days 0, 4, 12 and 24 (n = 6 at each time point in each group. Animals were sacrificed and the pathological examination of the prostate, detection of mRNA expression of P2X7 and ionized calcium binding adaptor molecule 1 (IBA-1 and measurement of content of tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β in the dorsal horn of L5-S2 spinal cord were performed on days 0, 4, 12 and 24. In addition, the content of TNF-α and IL-1β in the dorsal horn of L5-S2 spinal cord was measured after intrathecal injection of inhibitors of microglial cells and/or P2X7 for 5 days. Results The chronic prostatitis was confirmed by pathological examination. The expression of P2X7 and IBA-1 and the content of TNF-α and IL-1β in rats with chronic prostatitis were significantly higher than those in the control group. On day 4, the expressions of pro-inflammatory cytokines became to increase, reaching a maximal level on day 12 and started to reduce on day 24, but remained higher than that in the control group. Following suppression of microglial cells and P2X7 receptor, the secretion of TNF-α and IL-1β was markedly reduced. Conclusion In chronic prostatitis pain, the microglial cells and P2X7 receptor are activated resulting in the increased expression of TNF-α and IL-1β in the L5-S2 spinal cord, which might attribute to the maintenance and intensification of pain in chronic prostatitis.

  1. Transient receptor potential channels encode volatile chemicals sensed by rat trigeminal ganglion neurons.

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    Matthias Lübbert

    Full Text Available Primary sensory afferents of the dorsal root and trigeminal ganglia constantly transmit sensory information depicting the individual's physical and chemical environment to higher brain regions. Beyond the typical trigeminal stimuli (e.g. irritants, environmental stimuli comprise a plethora of volatile chemicals with olfactory components (odorants. In spite of a complete loss of their sense of smell, anosmic patients may retain the ability to roughly discriminate between different volatile compounds. While the detailed mechanisms remain elusive, sensory structures belonging to the trigeminal system seem to be responsible for this phenomenon. In order to gain a better understanding of the mechanisms underlying the activation of the trigeminal system by volatile chemicals, we investigated odorant-induced membrane potential changes in cultured rat trigeminal neurons induced by the odorants vanillin, heliotropyl acetone, helional, and geraniol. We observed the dose-dependent depolarization of trigeminal neurons upon application of these substances occurring in a stimulus-specific manner and could show that distinct neuronal populations respond to different odorants. Using specific antagonists, we found evidence that TRPA1, TRPM8, and/or TRPV1 contribute to the activation. In order to further test this hypothesis, we used recombinantly expressed rat and human variants of these channels to investigate whether they are indeed activated by the odorants tested. We additionally found that the odorants dose-dependently inhibit two-pore potassium channels TASK1 and TASK3 heterologously expressed In Xenopus laevis oocytes. We suggest that the capability of various odorants to activate different TRP channels and to inhibit potassium channels causes neuronal depolarization and activation of distinct subpopulations of trigeminal sensory neurons, forming the basis for a specific representation of volatile chemicals in the trigeminal ganglia.

  2. Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction.

    Science.gov (United States)

    Park, Wook-Ha; Jun, Dae Won; Kim, Jin Taek; Jeong, Jae Hoon; Park, Hyokeun; Chang, Yoon-Seok; Park, Kyong Soo; Lee, Hong Kyu; Pak, Youngmi Kim

    2013-01-01

    Serum concentrations of environmental pollutants have been positively correlated with diabetes and metabolic syndrome in epidemiologic studies. In turn, abnormal mitochondrial function has been associated with the diseases. The relationships between these variables, however, have not been studied. We developed novel cell-based aryl hydrocarbon receptor (AhR) agonist bioassay system without solvent extraction process and analyzed whether low-dose circulating AhR ligands in human serum are associated with parameters of metabolic syndrome and mitochondrial function. Serum AhR ligand activities were measured as serum 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent (sTCDDeq) in pM using 10 μL human sera from 97 Korean participants (47 with glucose intolerance and 50 matched controls, average age of 46.6 ± 9.9 years, 53 male and 45 female). sTCDDeq were higher in participants with glucose intolerance than normal controls and were positively associated (P fasting glucose, but not with HDL-cholesterol. Body mass index was in a positive linear relationship with serum AhR ligands in healthy participants. When myoblast cells were incubated with human sera, ATP generating power of mitochondria became impaired in an AhR ligand concentration-dependent manner. Our results support that circulating AhR ligands may directly reduce mitochondrial function in tissues, leading to weight gain, glucose intolerance, and metabolic syndrome. Our rapid cell-based assay using minute volume of human serum may provide one of the best monitoring systems for circulating AhR ligands, good clinical biomarkers for the progress of disease and therapeutic efficacy. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.

  3. TCDD-induced transcriptional profiles in different mouse strains that have an identical AhR genotype

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Qing; Suzuki, Junko S.; Tohyama, Chiharu; Ohsako, Seiichiroh [Environmental Health Sciences Division, National Institute for Environmental Studies, Onogawa, Tsukuba (Japan); Takei, Teiji [Environmental Health and Safety Division, Ministry of the Environment, Kasumigaseki, Tokyo (Japan); Lin, Tinmin; Peterson, R.E. [Wisconsin Univ., Wisconsin, MA (United States). School of Pharmacy and Molecular and Environmental Toxicology Center

    2004-09-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that is known to cause hepatotoxicity, teratogenicity and carcinogenicity. A characteristic feature in the toxicity of TCDD is exceptionally large differences in susceptibility among animal species or even strains belonging to the same species. These strain differences in susceptibility to TCDD have now been elucidated to be due to the difference in ligand binding affinity or transcriptional activity of the aryl hydrocarbon receptor (AhR). Actually the C57BL/6 type AhR (AhR{sup b}) showed 6-fold higher ligand binding affinity than the DBA/2 type AhR (AhR{sup d}). The H/W rat AhR has a C-terminal truncation of the transactivating domain compared to the L-E rat AhR. On the other hand, there is considerable species variability in response sensitivity to TCDD that cannot be ascribed simply to polymorphisms of the AhR gene. A non-AhR gene susceptibility loci for hepatic porphyria has been observed in mice treated with iron compounds prior to TCDD injection by using a quantitative trait locus analysis of an F2 intercross between susceptible C57BL/6 and resistant DBA/2 stains. In the rat, a gene B with Han/Wistar type AhR is likely to be involved in resistance to TCDD lethality. These observations suggest that other modulating genes, so-called ''modifier genes'', have profound effects on the AhR-mediated gene expression phenotype. Based on the nucleotide sequence of the AhR coding region, the BALB/c, CBA/J, and C3H/He mouse strains are clustered together on a single branch. In the present study, we try to confirm the existence of modifiers by using microarray analysis to examine hepatic gene expression after TCDD exposure in BALB/c, CBA/J, and C3H/He mice. To recognize the existence of a modifier besides the AhR, it is a prerequisite experimental condition that the analyzed strains have an identical AhR genotype. Therefore, we selected BALB/c, CBA/J, and C3H/He mice as the model

  4. Targeting the Immune System to Fight Cancer Using Chemical Receptor Homing Vectors Carrying Polyinosine/Cytosine (PolyIC)

    International Nuclear Information System (INIS)

    Levitzki, Alexander

    2012-01-01

    Cancer researchers have been looking for ways to harness the immune system and to reinstate immune surveillance, to kill cancer cells without collateral damage. Here we scan current approaches to targeting the immune system against cancer, and emphasize our own approach. We are using chemical vectors attached to a specific ligand, to introduce synthetic dsRNA, polyinosine/cytosine (polyIC), into tumors. The ligand binds to a receptor protein that is overexpressed on the surface of the tumor cells. Upon ligand binding, the receptor complex is internalized, introducing the polyIC into the cell. In this fashion a large amount of synthetic dsRNA can be internalized, leading to the activation of dsRNA-binding proteins, such as dsRNA dependent protein kinase (PKR), Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-1), and melanoma differentiation-associated gene 5 (MDA5). The simultaneous activation of these signaling proteins leads to the rapid demise of the targeted cell and to cytokine secretion. The cytokines lead to a strong bystander effect and to the recruitment of immune cells that converge upon the targeted cells. The bystander effects lead to the destruction of neighboring tumor cells not targeted themselves by the vector. Normal cells, being more robust than tumor cells, survive. This strategy has several advantages: (1) recruitment of the immune system is localized to the tumor. (2) The response is rapid, leading to fast tumor eradication. (3) The bystander effects lead to the eradication of tumor cells not harboring the target. (4) The multiplicity of pro-death signaling pathways elicited by PolyIC minimizes the likelihood of the emergence of resistance. In this chapter we focus on EGFR as the targeted receptor, which is overexpressed in many tumors. In principle, the strategy can be extended to other tumors that overexpress a protein that can be internalized by a ligand, which can be a small molecule, a single chain antibody, or an affibody.

  5. Targeting the immune system to fight cancer using chemical receptor homing vectors carrying Poly Inosine/Cytosine (PolyIC

    Directory of Open Access Journals (Sweden)

    Alexander eLevitzki

    2012-02-01

    Full Text Available Cancer researchers have been looking for ways to harness the immune system and to reinstate immune surveillance, to kill cancer cells without collateral damage. Here we scan current approaches to targeting the immune system against cancer, and emphasize our own approach. We are using chemical vectors attached to a specific ligand, to introduce synthetic dsRNA, poly Inosine/Cytosine (polyIC, into tumors. The ligand binds to a receptor protein that is overexpressed on the surface of the tumor cells. Upon ligand binding, the receptor complex is internalized, introducing the polyIC into the cell. In this fashion a large amount of synthetic dsRNA can be internalized, leading to the activation of dsRNA binding proteins, such as dsRNA dependent protein kinase (PKR, Toll-3 receptor (TLR3, retinoic acid–inducible gene I (RIG-1 and melanoma differentiation–associated gene 5 (MDA5. The simultaneous activation of these signaling proteins leads to the rapid demise of the targeted cell and to cytokine secretion. The cytokines lead to a strong bystander effect and to the recruitment of immune cells that converge upon the targeted cells. The bystander effects lead to the destruction of neighboring tumor cells not targeted themselves by the vector. Normal cells, being more robust than tumor cells, survive. This strategy has several advantages: (1 Recruitment of the immune system is localized to the tumor. (2 The response is rapid, leading to fast tumor eradication. (3 The bystander effects lead to the eradication of tumor cells not harboring the target. (4 The multiplicity of pro-death signaling pathways elicited by PolyIC minimizes the likelihood of the emergence of resistance. In this chapter we focus on EGFR as the targeted receptor, which is overexpressed in many tumors. In principle, the strategy can be extended to other tumors that overexpress a protein that can be internalized by a ligand, which be a small molecule, a single chain antibody or an

  6. Nutrient Induced Type 2 and Chemical Induced Type 1 Experimental Diabetes Differently Modulate Gastric GLP-1 Receptor Expression

    Directory of Open Access Journals (Sweden)

    Olga Bloch

    2015-01-01

    Full Text Available T2DM patients demonstrate reduced GLP-1 receptor (GLP-1R expression in their gastric glands. Whether induced T2DM and T1DM differently affect the gastric GLP-1R expression is not known. This study assessed extrapancreatic GLP-1R system in glandular stomach of rodents with different types of experimental diabetes. T2DM and T1DM were induced in Psammomys obesus (PO by high-energy (HE diet and by streptozotocin (STZ in Sprague Dawly (SD rats, respectively. GLP-1R expression was determined in glandular stomach by RT PCR and immunohistomorphological analysis. The mRNA expression and cellular association of the GLP-1R in principal glands were similar in control PO and SD rats. However, nutrient and chemical induced diabetes resulted in opposite alterations of glandular GLP-1R expression. Diabetic PO demonstrated increased GLP-1R mRNA expression, intensity of cellular GLP-1R immunostaining, and frequency of GLP-1R positive cells in the neck area of principal glands compared with controls. In contrast, SD diabetic rats demonstrated decreased GLP-1 mRNA, cellular GLP-1R immunoreactivity, and frequency of GLP-1R immunoreactive cells in the neck area compared with controls. In conclusion, nutrient and chemical induced experimental diabetes result in distinct opposite alterations of GLP-1R expression in glandular stomach. These results suggest that induced T1DM and T2DM may differently modulate GLP-1R system in enteropancreatic axis.

  7. Shari’ah concepts in Islamic banking

    Directory of Open Access Journals (Sweden)

    Botis, S.

    2013-12-01

    Full Text Available The paper analyses the main Shari’ah concepts in Islamic banking, a system which operates in accordance with the Islamic law principles, the most important being the prohibition against the payment or acceptance of interest charges (riba, replaced by profit-and-loss-sharing arrangements(PLS, Mudharabah. Also, the paper presents a survey of the historical evolution of the Islamic banking system in Muslim countries, starting with the first Islamic bank, early in the 60’s, Mit Ghamr Local Savings Bank in Egypt. In conclusion, the Islamic banking system is a rapid growth one. It is expected that this presentation will be helpful in increasing the interest in the Islamic principles of banking and financing.

  8. QSAR Classification of ToxCast and Tox21 Chemicals on the Basis of Estrogen Receptor Assays (FutureToxII)

    Science.gov (United States)

    The ToxCast and Tox21 programs have tested ~8,200 chemicals in a broad screening panel of in vitro high-throughput screening (HTS) assays for estrogen receptor (ER) agonist and antagonist activity. The present work uses this large in vitro data set to develop in silico QSAR model...

  9. Development of a platoon driving AHS; AHS jikkensha ni okeru gunsoko seigyo no kaihatsu

    Energy Technology Data Exchange (ETDEWEB)

    Seto, Y; Inoue, H [Nissan Motor Co. Ltd., Tokyo (Japan)

    1997-10-01

    Nissan and the Public Work Research Institute of the Ministry of Construction are developing an Automated Highway System. We are investigating a longitudinal control system in AHS. In this paper, a vehicle control method using two actuators an engine and a brake, is described. Experimental and simulated results are shown. A Platoon driving control method using road-to-vehicle and vehicle-to-vehicle communication is described. And the influence of the communication on the control performance is shown by experiments and simulation. The effects of the communication device and control device mentioned above are verified by experimental results in an AHS field test conducted in September 1996 on a dosed highway. 5 refs., 8 figs.

  10. TABUNGAN: IMPLEMENTASI AKAD WADI’AH ATAU QARD? (Kajian Praktik Wadi’ah di Perbankan Indonesia

    Directory of Open Access Journals (Sweden)

    Mufti Afif

    2016-02-01

    Full Text Available There are no discussion about banking usury in classic Fikh books, because there were no banks, which nowadays they are needed by society to save their worth. As the research of classic Fiqh, there are differences in ulamas’ instructions, based on their understanding. However, they agree to state that bank interest is a usury or forbidden in Islam. Qardul Hasan is another term of qard, that is interpreted by the most of Indonesian people as social engagement, or bequest. Financial department must be careful in understanding the instructions, related to the implementation in the real life. Banks and financial departments claim that money saving is as akad wadi’ah yad dhamanah, whereas the meaning of dhomanah is responsibility. Fiqh ulamas decide that actually, wadi’ah is responsible. Yad dhamanah is irresponsible.

  11. CHEMICALS

    CERN Multimedia

    Medical Service

    2002-01-01

    It is reminded that all persons who use chemicals must inform CERN's Chemistry Service (TIS-GS-GC) and the CERN Medical Service (TIS-ME). Information concerning their toxicity or other hazards as well as the necessary individual and collective protection measures will be provided by these two services. Users must be in possession of a material safety data sheet (MSDS) for each chemical used. These can be obtained by one of several means : the manufacturer of the chemical (legally obliged to supply an MSDS for each chemical delivered) ; CERN's Chemistry Service of the General Safety Group of TIS ; for chemicals and gases available in the CERN Stores the MSDS has been made available via EDH either in pdf format or else via a link to the supplier's web site. Training courses in chemical safety are available for registration via HR-TD. CERN Medical Service : TIS-ME :73186 or service.medical@cern.ch Chemistry Service : TIS-GS-GC : 78546

  12. Chemical crosslinking and mass spectrometry studies of the structure and dynamics of membrane proteins and receptors.

    Energy Technology Data Exchange (ETDEWEB)

    Haskins, William E.; Leavell, Michael D.; Lane, Pamela; Jacobsen, Richard B.; Hong, Joohee; Ayson, Marites J.; Wood, Nichole L.; Schoeniger, Joseph S.; Kruppa, Gary Hermann; Sale, Kenneth L.; Young, Malin M.; Novak, Petr

    2005-03-01

    Membrane proteins make up a diverse and important subset of proteins for which structural information is limited. In this study, chemical cross-linking and mass spectrometry were used to explore the structure of the G-protein-coupled photoreceptor bovine rhodopsin in the dark-state conformation. All experiments were performed in rod outer segment membranes using amino acid 'handles' in the native protein sequence and thus minimizing perturbations to the native protein structure. Cysteine and lysine residues were covalently cross-linked using commercially available reagents with a range of linker arm lengths. Following chemical digestion of cross-linked protein, cross-linked peptides were identified by accurate mass measurement using liquid chromatography-fourier transform mass spectrometry and an automated data analysis pipeline. Assignments were confirmed and, if necessary, resolved, by tandem MS. The relative reactivity of lysine residues participating in cross-links was evaluated by labeling with NHS-esters. A distinct pattern of cross-link formation within the C-terminal domain, and between loop I and the C-terminal domain, emerged. Theoretical distances based on cross-linking were compared to inter-atomic distances determined from the energy-minimized X-ray crystal structure and Monte Carlo conformational search procedures. In general, the observed cross-links can be explained by re-positioning participating side-chains without significantly altering backbone structure. One exception, between C3 16 and K325, requires backbone motion to bring the reactive atoms into sufficient proximity for cross-linking. Evidence from other studies suggests that residues around K325 for a region of high backbone mobility. These findings show that cross-linking studies can provide insight into the structural dynamics of membrane proteins in their native environment.

  13. Bioassay directed identification of natural aryl hydrocarbon-receptor agonists in marmalade

    NARCIS (Netherlands)

    Ede, van K.I.; Li, A.; Antunes Fernandes, E.C.; Mulder, P.P.J.; Peijnenburg, A.A.C.M.; Hoogenboom, L.A.P.

    2008-01-01

    Citrus fruit and citrus fruit products, like grapefruit, lemon and marmalade were shown to contain aryl hydrocarbon receptor (AhR) agonists, as detected with the DR CALUX® bioassay. This is of interest regarding the role of the Ah-receptor pathway in the adverse effects of dioxins, PCBs and other

  14. RASIONALITAS KONVERSI BANK KONVENSIONAL KE BANK SYARI’AH

    Directory of Open Access Journals (Sweden)

    Aji Damanuri

    2016-02-01

    Aji Damanuri   Abstract: Shari>’ah banking, for the last ten years, has increased in prosperity not only at the quantity of conventional banks but also at the count of assets and customers. This economical opportunity drives amount of conventional banks both to convert their institutions to be shari>’ah banks and to open officially shari>’ah platform units with their own assets. This system takes a significant question, is the conversion effected by both banker ideological factor and capitalists or pure economical rational calculation? Is a religious consideration linked to economical rationality? This paper is to elaborate the conversion using not only ‘choice theory’ (teori pilihan but also ‘rational action’ (tindakan rasional to seek religious action possibility in a reasonable way of shari>’ah banking.   Keywords: shari>’ah bank, conversion, rational action, religiosity.

  15. Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States); Zhu, Hao [The Rutgers Center for Computational and Integrative Biology, Rutgers University, Camden, NJ (United States); Department of Chemistry, Rutgers University, Camden, NJ (United States); Afantitis, Antreas; Mouchlis, Varnavas D.; Melagraki, Georgia [NovaMechanics Ltd., Nicosia (Cyprus); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Tropsha, Alexander, E-mail: alex_tropsha@unc.edu [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States)

    2013-10-01

    Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous quantitative structure–activity relationship (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R{sup 2} = 0.71, STL R{sup 2} = 0.73). For ERβ binding affinity, MTL models were significantly more predictive (R{sup 2} = 0.53, p < 0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), and ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation. - Highlights: • This is the largest curated dataset inclusive of ERα and β (the latter is unique). • New methodology that for the first time affords acceptable ERβ models. • A combination of QSAR and docking enables prediction of affinity and function.

  16. Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches

    International Nuclear Information System (INIS)

    Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh; Zhu, Hao; Afantitis, Antreas; Mouchlis, Varnavas D.; Melagraki, Georgia; Rusyn, Ivan; Tropsha, Alexander

    2013-01-01

    Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous quantitative structure–activity relationship (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R 2 = 0.71, STL R 2 = 0.73). For ERβ binding affinity, MTL models were significantly more predictive (R 2 = 0.53, p < 0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), and ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation. - Highlights: • This is the largest curated dataset inclusive of ERα and β (the latter is unique). • New methodology that for the first time affords acceptable ERβ models. • A combination of QSAR and docking enables prediction of affinity and function. • The results

  17. Chronic changes in pituitary adenylate cyclase-activating polypeptide and related receptors in response to repeated chemical dural stimulation in rats.

    Science.gov (United States)

    Han, Xun; Ran, Ye; Su, Min; Liu, Yinglu; Tang, Wenjing; Dong, Zhao; Yu, Shengyuan

    2017-01-01

    Background Preclinical experimental studies revealed an acute alteration of pituitary adenylate cyclase-activating polypeptide in response to a single activation of the trigeminovascular system, which suggests a potential role of pituitary adenylate cyclase-activating polypeptide in the pathogenesis of migraine. However, changes in pituitary adenylate cyclase-activating polypeptide after repeated migraine-like attacks in chronic migraine are not clear. Therefore, the present study investigated chronic changes in pituitary adenylate cyclase-activating polypeptide and related receptors in response to repeated chemical dural stimulations in the rat. Methods A rat model of chronic migraine was established by repeated chemical dural stimulations using an inflammatory soup for a different numbers of days. The pituitary adenylate cyclase-activating polypeptide levels were quantified in plasma, the trigeminal ganglia, and the trigeminal nucleus caudalis using radioimmunoassay and Western blotting in trigeminal ganglia and trigeminal nucleus caudalis tissues. Western blot analysis and real-time polymerase chain reaction were used to measure the protein and mRNA expression of pituitary adenylate cyclase-activating polypeptide-related receptors (PAC1, VPAC1, and VPAC2) in the trigeminal ganglia and trigeminal nucleus caudalis to identify changes associated with repetitive applications of chemical dural stimulations. Results All rats exhibited significantly decreased periorbital nociceptive thresholds to repeated inflammatory soup stimulations. Radioimmunoassay and Western blot analysis demonstrated significantly decreased pituitary adenylate cyclase-activating polypeptide levels in plasma and trigeminal ganglia after repetitive chronic inflammatory soup stimulation. Protein and mRNA analyses of pituitary adenylate cyclase-activating polypeptide-related receptors demonstrated significantly increased PAC1 receptor protein and mRNA expression in the trigeminal ganglia, but not

  18. Activation of the aryl hydrocarbon receptor reduces the number of precursor and effector T cells, but preserves thymic CD4(+)CD25(+)Foxp3(+) regulatory T cells

    NARCIS (Netherlands)

    Schulz, V.J.; Smit, J.J.; Bol-Schoenmakers, M.; van Duursen, M.B.M.; van den Berg, M.; Pieters, R.H.H.

    2012-01-01

    Aryl hydrocarbon receptor (AhR) activation suppresses immune responses, including allergic sensitization, by increasing the percentage of regulatory (Treg) cells. Furthermore, AhR activation is known to affect thymic precursor T cells. However, the effect of AhR activation on intrathymic

  19. Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis.

    Science.gov (United States)

    Le Cann, Fabienne; Delehouzé, Claire; Leverrier-Penna, Sabrina; Filliol, Aveline; Comte, Arnaud; Delalande, Olivier; Desban, Nathalie; Baratte, Blandine; Gallais, Isabelle; Piquet-Pellorce, Claire; Faurez, Florence; Bonnet, Marion; Mettey, Yvette; Goekjian, Peter; Samson, Michel; Vandenabeele, Peter; Bach, Stéphane; Dimanche-Boitrel, Marie-Thérèse

    2017-09-01

    Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-interacting protein kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a noncommercial, kinase-focused chemical library which allowed us to identify Sibiriline as a new inhibitor of necroptosis induced by tumor necrosis factor (TNF) in Fas-associated protein with death domain (FADD)-deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase-dependent apoptosis. By using competition binding assay and recombinant kinase assays, we demonstrated that Sib is a rather specific competitive RIPK1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK1 adenosine triphosphate-binding site in a relatively hydrophobic pocket locking RIPK1 in an inactive conformation. In agreement with its RIPK1 inhibitory property, Sib inhibits both TNF-induced RIPK1-dependent necroptosis and RIPK1-dependent apoptosis. Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis. © 2017 Federation of European Biochemical Societies.

  20. In silico tools to aid risk assessment of endocrine disrupting chemicals

    International Nuclear Information System (INIS)

    Jacobs, M.N.

    2004-01-01

    In silico or computational tools could be used more effectively in endocrine disruptor risk assessment for prescreening potential endocrine disruptors, improving experimental in vitro screening assay design and facilitating more thorough data analyses. The in silico tools reviewed here are three-fold and include the use of: (1) nuclear receptor (NR) crystal structures and homology models to examine potential modes of ligand binding by different representative compounds; (2) multivariate principal component analyses (PCA) techniques to select best predicted cell lines for endocrine disrupting chemicals (EDC) risk assessment purposes; (3) NR quantitative structure-activity relationships (QSARs) that can be constructed from varied biological data sources, using multivariate partial least squares (PLS) techniques and specific descriptors. The cytosolic and NR examples discussed here include the Ah receptor (AhR), the human oestrogen receptor α (hERα) and the human pregnane X receptor (PXR). The varied biological data sets can be compared to give a more integrated dimension to receptor cross talk mechanisms, with further support from molecular modelling studies

  1. EDUKASI MARKETING BANK SYARÎ’AH

    Directory of Open Access Journals (Sweden)

    Wadhan Wadhan

    2013-08-01

    Full Text Available Abstract: Marketing is a significant aspect to increase consumer trust. Hence, it is essential to educate the consumer with the lesson of the importance of syarî’ah products concerning the marketing aspects. In fact, many banks serves the customer with syariah service in Indonesia.  The basic concept of spiritual marketing is the managements of creation, taste, heart and work (the implementation. Those concepts are under the guidence of faith integrity, obidience, and loyality to Allâh swt. The key of ethics and moral of business is truly placed on the doers. A Muslim busines manager must hold tightly the ethic and moral of business that cope –khusn al-huluq, trusty, dan tolerant. There are three marketing strategies of syariah banking; marker driven strategic, viral marketing way, and fish net strategy. Element of  mega marketing that had been intruduced by Rasûlullâh since the fifteenth century, and now can be adopted to any kinds of businesses including syariah banking. Key Words: Marketing, Marketer, dan Mega Marketing  

  2. Shari’ah Auditing: A Review of Shari’ah Audit Practices in Islamic Financial Institution (IFIs

    Directory of Open Access Journals (Sweden)

    Abdul Rashid Azwan

    2017-01-01

    Full Text Available With its increasing number of Islamic Financial Institutions (IFIs in the country, Malaysia has emerged as a leading hub when benchmarked against the other Islamic countries of the world. Unlike its conventional counterpart, the Islamic financial system focuses on the achievement of societal justice as evaluated within its own framework and uses its own criteria in order to achieve the objective of the Maqasid Ash-Shari’ah. To help achieve this objective, the Islamic finance industry is in need of Shari’ah auditors who are not only knowledgeable and competent in ensuring that the IFIs operate in accordance with Shari’ah principles, but also adequate in supply, in order to cater for the increasing number of IFIs in the country. Therefore, a major aim of this study is to conduct a comprehensive review of the auditing process performed by Shari’ah auditors in determining the achievement of the Maqasid Ash-Shari’ah by the IFIs. Another aim of this study is to assess the existing Shari’ah auditing framework and standards practiced by IFIs in Malaysia. The results of this study could serve as a reference point for the regulatory and professional bodies in assessing the implementation of a comprehensive Shari’ah auditing framework.

  3. In vitro screening for aryl hydrocarbon receptor agonistic activity in 200 pesticides using a highly sensitive reporter cell line, DR-EcoScreen cells, and in vivo mouse liver cytochrome P450-1A induction by propanil, diuron and linuron.

    Science.gov (United States)

    Takeuchi, Shinji; Iida, Mitsuru; Yabushita, Hisatoshi; Matsuda, Tadashi; Kojima, Hiroyuki

    2008-12-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism, cellular proliferation and differentiation. In this study, we have developed a highly sensitive AhR-mediated reporter cell line, DR-EcoScreen cells, which are mouse hepatoma Hepa1c1c7 cells stably transfected with a reporter plasmid containing seven copies of dioxin-responsive element. Using these DR-EcoScreen cells, we performed the reporter gene assay and characterized the AhR agonistic activities of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 12 acid amides, 7 triazines, 6 ureas, and 45 others). Eleven of the 200 pesticides (acifluorfen-methyl, bifenox, chlorpyrifos, isoxathion, quinalphos, chlorpropham, diethofencarb, propanil, diuron, linuron, and prochloraz) showed AhR-mediated transcriptional activity. In particular, three herbicides (propanil, diuron, and linuron) have a common chemical structure and showed more potent agonistic activity than other pesticides. To investigate the in vivo effects, we examined the gene expression of AhR-inducible cytochrome P450 1As (CYP1As) in the liver of female C57BL/6 mice intraperitoneally injected with these three herbicides (300 mg kg(-1)) by quantitative RT-PCR, resulting in induction of significant high levels of CYP1A1 and CYP1A2 mRNAs. This indicates that propanil, diuron and linuron possess AhR-mediated transactivation effect in vivo as well as in vitro. Through the present study, we demonstrated that DR-EcoScreen cells are useful for sensitive, rapid and simple identification of AhR agonists among a large number of environmental chemicals.

  4. Antioxidant Functions of the Aryl Hydrocarbon Receptor

    Directory of Open Access Journals (Sweden)

    Cornelia Dietrich

    2016-01-01

    Full Text Available The aryl hydrocarbon receptor (AhR is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

  5. BAY‘ AL-MURABAHAH: Mendudukkan Kembali Posisinya dalam Perbankan Syari’ah

    Directory of Open Access Journals (Sweden)

    Luhur Prasetiyo

    2016-02-01

    Full Text Available BAY‘ AL-MURAbah}ah transaction becomes the most popular product which shari>’ah banking uses to sell its assets for amount of reasons. Total amount of shari>’ah banks store and transact their assets (fund in mura>bah}ah system. The reason is that this product has not only small risk but also ease to manage related to muz}a>rabah and musha>rakah system. In the other hand, Many people don’t understand mura>bah}ah mechanism precisely. They often think that mura>bah}ah mechanism is as credit as well. It is, in fact, that mura>bah}ah system is a cash transaction which shari>’ah banks have. This paper is to elaborate mura>bah}ah system as a product of shari>’ah banking.   Keywords: Perbankan Syariah, mura>bah}ah, margin keuntungan, kredit

  6. Evaluating the interactions of vertebrate receptors with persistent pollutants and antifouling pesticides using recombinant yeast assays

    Energy Technology Data Exchange (ETDEWEB)

    Noguerol, Tania-Noelia; Boronat, Susanna; Casado, Marta; Pina, Benjamin [Institut de Biologia Molecular de Barcelona, CSIC, Department of Molecular Biology, Barcelona (Spain); Raldua, Demetrio [Laboratory of Environmental Toxicology, INTEXTER -UP, Terrassa (Spain); Barcelo, Damia [IIQAB-CSIC, Department of Environmental Chemistry, Barcelona (Spain)

    2006-07-15

    The development of in vitro methods for screening potentially harmful biological activities of new compounds is an extremely important way to increase not only their intrinsic environmental safety, but also the public perception of the safety standards associated with them. In this work we use two yeast systems to test the ability of different chemicals to bind and activate two vertebrate receptors which are intimately related to adverse biological effects of pollution in exposed fauna: the estrogen receptor (ER) and the aryl hydrocarbon receptor (AhR). The panel of compounds analysed here includes well-known pollutants, like PCBs, pp'-DDT and hexachlorobenzene, together with the less-known, emerging putative pollutants, such as Sea-Nine, Irgarol and diuron. Results show the ability of some of these compounds to interact with one or both receptors, provide hints about the relationship between structure and activity, and suggest mechanistic explanations for the biological activities already described in whole-animal experiments. In addition, we show that AhR may have an intrinsic ligand promiscuity comparable to that of ER, a feature not fully appreciated in the past due to the technical difficulties involved with testing highly lipophilic substances in yeast-based assays. (orig.)

  7. Assessment of potential biological activities and distributions of endocrine-disrupting chemicals in sediments of the west coast of South Korea.

    Science.gov (United States)

    Jeon, Seungyeon; Hong, Seongjin; Kwon, Bong-Oh; Park, Jinsoon; Song, Sung Joon; Giesy, John P; Khim, Jong Seong

    2017-02-01

    The west coast of Korea has experienced environmental deterioration for more than half a century. In the present study, we specifically aimed to: i) evaluate potential toxicities of contaminants in sediments that cause effects mediated through the aryl hydrocarbon receptor (AhR) and estrogen receptor (ER); ii) determine spatio-temporal distributions of polycyclic aromatic hydrocarbons (PAHs) and alkylphenols (APs); and iii) identify causes of greater potencies of samples. From 2010 to 2014, sediments were collected from 12 major estuarine and coastal regions along the west coast of South Korea. In vitro cell bioassays were performed to determine AhR- and ER-mediated potencies using H4IIE-luc and MVLN cells, respectively. Fifteen PAHs and six APs in sediments were identified by GC/MSD. Results of bioassays generally showed a low-to-moderate degree of contamination, however, greater AhR- and ER-mediated potencies were measured at some locations. Concentrations of PAHs and APs varied among locations, which indicated that sources were independently affected by the surrounding environment (e.g., industrial complex and cities). Results of bioassays were generally well correlated with concentrations of putative causative chemicals. Benzo[k]fluoranthene, dibenz[a,h]anthracene, and benzo[b]fluoranthene were the major AhR agonists, explaining approximately 30% of the bioassay-derived benzo[a]pyrene equivalent concentration (BaP-EQ). Unknown AhR and ER agonists and potential mixture effects remain in question. Overall, the present study provides baseline information on chemical contaminations and potential toxicity of sediments in a fairly wide geographical region of the west coast of South Korea. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. NIKAH WISATA; PENDEKATAN MAQASHID AL-SYARI’AH

    Directory of Open Access Journals (Sweden)

    Bakhtiar Bakhtiar

    2012-07-01

    Full Text Available The tour marriage as is done in a certain time basically it seems nothing wrong and there is no terms of harmonious violated from the fulfillment side of harmonious and requirements. However, in terms of the purpose of marriage, the law and maqasid al-syari'ah contain marriage problem. In addition, there can also be equated with  mut'ah marriage that is allowed by syi'i. The type of this marriage is not appropriate with the maqasid al-syariah, not only ashliyah but also tabi'iyah. Then the impact could be on the implications of the worst  neglect.Keywords : The tour marriage, maqasid al-Syari'ah and mudharatCopyright © 2012 by Kafa`ah All right reservedDOI : 10.15548/jk.v2i2.56

  9. Novel estrogen receptor-related Transcripts in Marisa cornuarietis; a freshwater snail with reported sensitivity to estrogenic chemicals.

    Science.gov (United States)

    Bannister, Richard; Beresford, Nicola; May, Denise; Routledge, Edwin J; Jobling, Susan; Rand-Weaver, Mariann

    2007-04-01

    We have isolated novel molluskan steroid receptor transcripts orthologous to vertebrate estrogen receptors (ERs) and estrogen receptor-related receptors (ERRs) from the freshwater snail Marisa cornuarietis. Radiolabeled ligand binding analyses showed that neither recombinant receptor protein specifically bound 17beta-estradiol over the range applied (0.3-9.6 nM). These novel receptor transcripts have thus been designated mcER-like and mcERR respectively. Quantitative PCR revealed mcER-like to be expressed ubiquitously throughout a range of male and female structures studied, including neural and reproductive tissues. Highest absolute levels were seen in the male penis-sheath complex. The mcERR mRNA was also expressed ubiquitously throughout all male and female tissues analyzed here, with very low absolute transcript numbers in female accessory sex structures compared to other tissues.

  10. Identification of biased sectors in emission data using a combination of chemical transport model and receptor model

    Science.gov (United States)

    Uranishi, Katsushige; Ikemori, Fumikazu; Nakatsubo, Ryohei; Shimadera, Hikari; Kondo, Akira; Kikutani, Yuki; Asano, Katsuyoshi; Sugata, Seiji

    2017-10-01

    This study presented a comparison approach with multiple source apportionment methods to identify which sectors of emission data have large biases. The source apportionment methods for the comparison approach included both receptor and chemical transport models, which are widely used to quantify the impacts of emission sources on fine particulate matter of less than 2.5 μm in diameter (PM2.5). We used daily chemical component concentration data in the year 2013, including data for water-soluble ions, elements, and carbonaceous species of PM2.5 at 11 sites in the Kinki-Tokai district in Japan in order to apply the Positive Matrix Factorization (PMF) model for the source apportionment. Seven PMF factors of PM2.5 were identified with the temporal and spatial variation patterns and also retained features of the sites. These factors comprised two types of secondary sulfate, road transportation, heavy oil combustion by ships, biomass burning, secondary nitrate, and soil and industrial dust, accounting for 46%, 17%, 7%, 14%, 13%, and 3% of the PM2.5, respectively. The multiple-site data enabled a comprehensive identification of the PM2.5 sources. For the same period, source contributions were estimated by air quality simulations using the Community Multiscale Air Quality model (CMAQ) with the brute-force method (BFM) for four source categories. Both models provided consistent results for the following three of the four source categories: secondary sulfates, road transportation, and heavy oil combustion sources. For these three target categories, the models' agreement was supported by the small differences and high correlations between the CMAQ/BFM- and PMF-estimated source contributions to the concentrations of PM2.5, SO42-, and EC. In contrast, contributions of the biomass burning sources apportioned by CMAQ/BFM were much lower than and little correlated with those captured by the PMF model, indicating large uncertainties in the biomass burning emissions used in the

  11. Dimensional and chemical characterization of particles at a downwind receptor site of a waste-to-energy plant.

    Science.gov (United States)

    Buonanno, G; Stabile, L; Avino, P; Vanoli, R

    2010-07-01

    In the last years numerous epidemiological studies were carried out to evaluate the effects of particulate matter on human health. In industrialized areas, anthropogenic activities highly contribute to the fine and ultrafine particle concentrations. Then, it is important to characterize the evolution of particle size distribution and chemical composition near these emission points. Waste incineration represents a favorable technique for reducing the waste volume. However, in the past, municipal waste incinerators (MWIs) had a bad reputation due to the emission of toxic combustion byproducts. Consequently, the risk perception of the people living near MWIs is very high even if in Western countries waste incineration has nowadays to be considered a relatively clean process from a technical point of view. The study here presented has an exemplary meaning for developing appropriate management and control strategies for air quality in the surrounding of MWIs and to perform exposure assessment for populations involved. Environment particles were continuously measured through a SMPS/APS system over 12 months. The monitoring site represents a downwind receptor of a typical MWI. Furthermore, elements and organic fractions were measured by means of the Instrumental Neutron Activation Analysis and using dichotomous and high volume samplers. Annual mean values of 8.6 x 10(3)+/-3.7 x 10(2)part.cm(-3) and 31.1+/-9.0 microg m(-3) were found for number and mass concentration, typical of a rural site. Most of the elements can be attributed to long-range transport from other natural and/or anthropogenic sources. Finally, the Polycyclic Aromatic Hydrocarbons present low concentrations with a mean value of 24.6 ng m(-3). Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  12. Relationship between murine Ah phenotype and the hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD)

    International Nuclear Information System (INIS)

    Shen, E.S.; Olson, J.R.

    1986-01-01

    The Ah receptor has been correlated with the toxic effects of TCDD in C57BL/6J (B6) and DBA/2J (D2) mice. The B6 strain, which has a high affinity cytosolic Ah receptor, is more sensitive to TCDD than the D2 strain, which lacks this receptor. The metabolism of TCDD was studied by incubating 14 C-TCDD (2.2 μM) with hepatocytes from control and TCDD-pretreated B6 and D2 mice. Mice were pretreated with TCDD at doses that maximally induce ethoxyresorufin-O-deethylase (EROD) activity, a measure of Ah locus responsiveness to TCDD (B6, 3μg/kg, ip;D2, 30μg/kg, ip). Similar cytochrome P-450 content was detected in control B6 and D2 hepatocytes, however, TCDD pretreatment increased P-450 content 400% in B6 and 300% in D2 mice. No difference in hepatic EROD activity was found between control B6 and D2 mice (81.7 and 101.7 pmol/min/nmol P-450, respectively), but EROD activity was increased 17-fold in B6 and 10-fold in D2 mice after TCDD administration. The average rate of hepatic TCDD metabolism over two hours was similar in control B6 and D2 mice (1.103 and 0.945 pmol/hr/mg cell protein, respectively), although some qualitative differences in the metabolites were detected by HPLC. TCDD pretreatment produced no quantitative or qualitative changes in TCDD metabolism. These results suggest that the rate of hepatic TCDD metabolism does not correlate with genetic differences at the Ah locus

  13. Conservation and divergence of chemical defense system in the tunicate Oikopleura dioica revealed by genome wide response to two xenobiotics

    Directory of Open Access Journals (Sweden)

    Yadetie Fekadu

    2012-02-01

    Full Text Available Abstract Background Animals have developed extensive mechanisms of response to xenobiotic chemical attacks. Although recent genome surveys have suggested a broad conservation of the chemical defensome across metazoans, global gene expression responses to xenobiotics have not been well investigated in most invertebrates. Here, we performed genome survey for key defensome genes in Oikopleura dioica genome, and explored genome-wide gene expression using high density tiling arrays with over 2 million probes, in response to two model xenobiotic chemicals - the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP the pharmaceutical compound Clofibrate (Clo. Results Oikopleura genome surveys for key genes of the chemical defensome suggested a reduced repertoire. Not more than 23 cytochrome P450 (CYP genes could be identified, and neither CYP1 family genes nor their transcriptional activator AhR was detected. These two genes were present in deuterostome ancestors. As in vertebrates, the genotoxic compound BaP induced xenobiotic biotransformation and oxidative stress responsive genes. Notable exceptions were genes of the aryl hydrocarbon receptor (AhR signaling pathway. Clo also affected the expression of many biotransformation genes and markedly repressed genes involved in energy metabolism and muscle contraction pathways. Conclusions Oikopleura has the smallest number of CYP genes among sequenced animal genomes and lacks the AhR signaling pathway. However it appears to have basic xenobiotic inducible biotransformation genes such as a conserved genotoxic stress response gene set. Our genome survey and expression study does not support a role of AhR signaling pathway in the chemical defense of metazoans prior to the emergence of vertebrates.

  14. Introducing the "TCDD-inducible AhR-Nrf2 gene battery".

    Science.gov (United States)

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

    2009-10-01

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

  15. Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ya-Hsin, E-mail: yhcheng@mail.cmu.edu.tw [Department of Physiology, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China); Li, Lih-Ann; Lin, Pinpin; Cheng, Li-Chuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China); Hung, Chein-Hui [Graduate Institute of Clinical Medicine Sciences, Chang Gung University, Puizi City, Chiayi 613, Taiwan, ROC (China); Chang, Nai Wen [Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan, ROC (China); Lin, Chingju [Department of Physiology, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China)

    2012-09-15

    Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. -- Highlights: ► Baicalein causes the G1 phase arrest by decreasing Rb phosphorylation. ► Baicalein modulates AhR-mediated cell proliferation. ► Both AhR activation and cyclin D1 degradation results in hypophosphorylation of Rb. ► Baicalein facilitates cyclin D1 degradation by signalling the GSK-3β pathway.

  16. Identifying Environmental Chemicals as Agonists of the Androgen Receptor by Applying a Quantitative High-throughput Screening Platform

    Science.gov (United States)

    Background: The androgen receptor (AR, NR3C4) is a nuclear receptor whose main function is acting as a transcription factor regulating gene expression for male sexual development and maintaining accessory sexual organ function. It is also a necessary component of female fertility...

  17. Klymollins A-H, bioactive eunicellin-based diterpenoids from the formosan soft coral Klyxum molle.

    Science.gov (United States)

    Hsu, Fang-Jung; Chen, Bo-Wei; Wen, Zhi-Hong; Huang, Chiung-Yao; Dai, Chang-Feng; Su, Jui-Hsin; Wu, Yang-Chang; Sheu, Jyh-Horng

    2011-11-28

    Eight new eunicellin-based diterpenoids, klymollins A-H (1-8), were isolated during the chemical investigation of the soft coral Klyxum molle from Taiwan waters. Their structures were elucidated by extensive spectroscopic analysis. The absolute configuration of 4 was determined by Mosher's method. Bioassays of the new metabolites showed that compounds 3-8 displayed significant in vitro anti-inflammatory activity by inhibiting the expression of the iNOS protein, and compounds 3, 4, and 6-8 also could effectively reduce the accumulation of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.

  18. No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals

    OpenAIRE

    Beresford, N; Granger, DW; Pounds, NA; Rand-Weaver, M; White, R; Jobling, S; Routledge, EJ

    2013-01-01

    This article is made available through the Brunel Open Access Publishing Fund. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. Estrogen receptor orthologues in molluscs may be targets for endocrine disruptors, although mechanistic evidence is lacking. Molluscs ...

  19. RESPON PERBANKAN SYARI’AH DAN LEMBAGA KEUANGAN SYARIAH DI PAMEKASAN TERHADAP PEMBUKAAN PROGRAM STUDI PERBANKAN SYARI’AH DI STAIN PAMEKASAN

    Directory of Open Access Journals (Sweden)

    Rudy Haryanto

    2011-01-01

    Full Text Available There are three focuses becoming study in this research that is: a Response ( appresiation Syari'ah Bangking and Financial Institution of Syari'ah in Pamekasan, b Expectation of Syari'ah Bangking and Financial Institution of Syari'Ah in Pamekasan to grad, c Elementary compentence which must be had by grad. This research uses the approach qualitative trying to watch closely the response of the head Syari'ah Bangking and Financial Institution of Moslem law in Pamekasan to opening of Study Program of Syari’ah Banking in STAIN Pamekasan. Result of this research showing that: Response of Financial Institution and Syari’ah Banking in Pamekasan to opening the Study Program of Syari’ah Banking in STAIN Pamekasan is very good, and they are also ready for cooperating in powering the Study Program of Syari’ah Banking in STAIN Pamekasan. Expectation of Syari’ah Banking and Financial Institution of Syari'ah in Pamekasan to grad of Study Program of Syari’ah Banking in STAIN Pamekasan, that is; the grad of Study Program of Syari’ah Banking STAIN Pamekasan next, absolute mastering the conception of Syari’ah Banking supported with knowledge of conventional banking concept and domination of information Technology Skill. Elementary compentence which must be had by the grad of Study Program of Syari’ah Banking in STAIN Pamekasan, that is; some of responders assess is competent, and some of other assess still many conventional banking payload, less payload of syari’ah banking, and still less subjects which uplift the skill and practice because the next grad have to ready to work in banking area.

  20. Prostate tumor progression in the TRAMP mouse. Protective effects of the aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Fritz, W.; Lin, T.M.; Peterson, R. [Wisconsin Univ., Madison, WI (United States)

    2004-09-15

    The developing male reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD binds to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, to produce sustained alterations in gene expression. Mice lacking the AhR (AhRKO, Ahr{sup -/-}) have permitted further characterization of the role of the AhR in mediating TCDD effects and revealed a physiological role for the AhR in normal development. We previously demonstrated that in utero and lactational TCDD exposure significantly reduced ventral, dorsolateral and anterior prostate weights, and that these effects were dependent on the AhR5. However, reductions in prostate lobe weights in untreated, AhRKO mice compared to wild-type counterparts at various ages demonstrated that the AhR signaling pathway is involved in normal development of the dorsolateral and anterior prostates, but apparently not the ventral prostate. Unaltered serum testosterone concentrations and modest reduction in serum 5{alpha}-androstane-3{alpha},17{beta}a-diol concentrations could not account for reductions in prostate weights in mice lacking AhR (Ahr{sup -/-}). Normal histology and lack of alteration in androgen receptor mRNA levels further indicate that the reduction in prostate weights is not a result of reduced androgen action in AhRKO mice. The observation that regulation of early prostate growth in mice occurs following AhR activation by TCDD, as well as by loss of AhR, suggests that the AhR may also regulate aberrant prostate growth that results from ''reawakening'' of the prostate growth regulatory signals later in life. Our objective was to determine if the AhR signaling pathway has an effect on prostate cancer development.

  1. Influence of physical and chemical characteristics of diesel fuels and exhaust emissions on biological effects of particle extracts: a multivariate statistical analysis of ten diesel fuels.

    Science.gov (United States)

    Sjögren, M; Li, H; Banner, C; Rafter, J; Westerholm, R; Rannug, U

    1996-01-01

    The emission of diesel exhaust particulates is associated with potentially severe biological effects, e.g., cancer. The aim of the present study was to apply multivariate statistical methods to identify factors that affect the biological potency of these exhausts. Ten diesel fuels were analyzed regarding physical and chemical characteristics. Particulate exhaust emissions were sampled after combustion of these fuels on two makes of heavy duty diesel engines. Particle extracts were chemically analyzed and tested for mutagenicity in the Ames test. Also, the potency of the extracts to competitively inhibit the binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor was assessed. Relationships between fuel characteristics and biological effects of the extracts were studied, using partial least squares regression (PLS). The most influential chemical fuel parameters included the contents of sulfur, certain polycyclic aromatic compounds (PAC), and naphthenes. Density and flash point were positively correlated with genotoxic potency. Cetane number and upper distillation curve points were negatively correlated with both mutagenicity and Ah receptor affinity. Between 61% and 70% of the biological response data could be explained by the measured chemical and physical factors of the fuels. By PLS modeling of extract data versus the biological response data, 66% of the genotoxicity could be explained, by 41% of the chemical variation. The most important variables, associated with both mutagenicity and Ah receptor affinity, included 1-nitropyrene, particle bound nitrate, indeno[1,2,3-cd]pyrene, and emitted mass of particles. S9-requiring mutagenicity was highly correlated with certain PAC, whereas S9-independent mutagenicity was better correlated with nitrates and 1-nitropyrene. The emission of sulfates also showed a correlation both with the emission of particles and with the biological effects. The results indicate that fuels with biologically less hazardous

  2. Comparing introduction to Europe of highly pathogenic avian influenza viruses A(H5N8) in 2014 and A(H5N1) in 2005

    NARCIS (Netherlands)

    Adlhoch, C.; Gossner, C.; Koch, G.; Brown, I.; Bouwstra, R.J.; Verdonck, F.; Penttinen, P.; Harder, T.

    2014-01-01

    Since the beginning of November 2014, nine outbreaks of highly pathogenic avian influenza virus (HPAIV) A(H5N8) in poultry have been detected in four European countries. In this report, similarities and differences between the modes of introduction of HPAIV A(H5N1) and A(H5N8) into Europe are

  3. Chemical and bioanalytical characterisation of PAHs in risk assessment of remediated PAH-contaminated soils.

    Science.gov (United States)

    Larsson, Maria; Hagberg, Jessika; Rotander, Anna; van Bavel, Bert; Engwall, Magnus

    2013-12-01

    Polycyclic aromatic hydrocarbons (PAHs) are common contaminants in soil at former industrial areas; and in Sweden, some of the most contaminated sites are being remediated. Generic guideline values for soil use after so-called successful remediation actions of PAH-contaminated soil are based on the 16 EPA priority pollutants, which only constitute a small part of the complex cocktail of toxicants in many contaminated soils. The aim of the study was to elucidate if the actual toxicological risks of soil samples from successful remediation projects could be reflected by chemical determination of these PAHs. We compared chemical analysis (GC-MS) and bioassay analysis (H4IIE-luc) of a number of remediated PAH-contaminated soils. The H4IIE-luc bioassay is an aryl hydrocarbon (Ah) receptor-based assay that detects compounds that activate the Ah receptor, one important mechanism for PAH toxicity. Comparison of the results showed that the bioassay-determined toxicity in the remediated soil samples could only be explained to a minor extent by the concentrations of the 16 priority PAHs. The current risk assessment method for PAH-contaminated soil in use in Sweden along with other countries, based on chemical analysis of selected PAHs, is missing toxicologically relevant PAHs and other similar substances. It is therefore reasonable to include bioassays in risk assessment and in the classification of remediated PAH-contaminated soils. This could minimise environmental and human health risks and enable greater safety in subsequent reuse of remediated soils.

  4. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    International Nuclear Information System (INIS)

    Yu, Hui; Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi; Wang, Zhanli; Liang, Huaping

    2010-01-01

    Research highlights: → Evodiamine interacted with the AhR. → Evodiamine inhibited the specific binding of [ 3 H]-TCDD to the AhR. → Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K i value of 28.4 ± 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  5. Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression

    International Nuclear Information System (INIS)

    Ikuta, Togo; Kurosumi, Masafumi; Yatsuoka, Toshimasa; Nishimura, Yoji

    2016-01-01

    Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc"M"i"n"/"+mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. - Highlights: • In the normal intestine, AhR was mainly localized in stroma containing immune cells. • In the tumor tissue, AhR expression was found in both stromal and tumor cells. • AhR knockdown promoted cell growth in colon cancer cell lines.

  6. Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression

    Energy Technology Data Exchange (ETDEWEB)

    Ikuta, Togo, E-mail: togo@cancer-c.pref.saitama.jp [Department of Cancer Prevention, Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Kurosumi, Masafumi, E-mail: mkurosumi@cancer-c.pref.saitama.jp [Division of Pathology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Yatsuoka, Toshimasa, E-mail: yatsuoka-gi@umin.ac.jp [Division of Gastroenterological Surgery, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Nishimura, Yoji, E-mail: yojinish@cancr-c.pref.saitama.jp [Division of Gastroenterological Surgery, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan)

    2016-05-01

    Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc{sup Min/+}mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. - Highlights: • In the normal intestine, AhR was mainly localized in stroma containing immune cells. • In the tumor tissue, AhR expression was found in both stromal and tumor cells. • AhR knockdown promoted cell growth in colon cancer cell lines.

  7. HIV-1 and its gp120 inhibits the influenza A(H1N1)pdm09 life cycle in an IFITM3-dependent fashion.

    Science.gov (United States)

    Mesquita, Milene; Fintelman-Rodrigues, Natalia; Sacramento, Carolina Q; Abrantes, Juliana L; Costa, Eduardo; Temerozo, Jairo R; Siqueira, Marilda M; Bou-Habib, Dumith Chequer; Souza, Thiago Moreno L

    2014-01-01

    HIV-1-infected patients co-infected with A(H1N1)pdm09 surprisingly presented benign clinical outcome. The knowledge that HIV-1 changes the host homeostatic equilibrium, which may favor the patient resistance to some co-pathogens, prompted us to investigate whether HIV-1 infection could influence A(H1N1)pdm09 life cycle in vitro. We show here that exposure of A(H1N1)pdm09-infected epithelial cells to HIV-1 viral particles or its gp120 enhanced by 25% the IFITM3 content, resulting in a decrease in influenza replication. This event was dependent on toll-like receptor 2 and 4. Moreover, knockdown of IFITM3 prevented HIV-1 ability to inhibit A(H1N1)pdm09 replication. HIV-1 infection also increased IFITM3 levels in human primary macrophages by almost 100%. Consequently, the arrival of influenza ribonucleoproteins (RNPs) to nucleus of macrophages was inhibited, as evaluated by different approaches. Reduction of influenza RNPs entry into the nucleus tolled A(H1N1)pdm09 life cycle in macrophages earlier than usual, limiting influenza's ability to induce TNF-α. As judged by analysis of the influenza hemagglutin (HA) gene from in vitro experiments and from samples of HIV-1/A(H1N1)pdm09 co-infected individuals, the HIV-1-induced reduction of influenza replication resulted in delayed viral evolution. Our results may provide insights on the mechanisms that may have attenuated the clinical course of Influenza in HIV-1/A(H1N1)pdm09 co-infected patients during the recent influenza form 2009/2010.

  8. HIV-1 and its gp120 inhibits the influenza A(H1N1pdm09 life cycle in an IFITM3-dependent fashion.

    Directory of Open Access Journals (Sweden)

    Milene Mesquita

    Full Text Available HIV-1-infected patients co-infected with A(H1N1pdm09 surprisingly presented benign clinical outcome. The knowledge that HIV-1 changes the host homeostatic equilibrium, which may favor the patient resistance to some co-pathogens, prompted us to investigate whether HIV-1 infection could influence A(H1N1pdm09 life cycle in vitro. We show here that exposure of A(H1N1pdm09-infected epithelial cells to HIV-1 viral particles or its gp120 enhanced by 25% the IFITM3 content, resulting in a decrease in influenza replication. This event was dependent on toll-like receptor 2 and 4. Moreover, knockdown of IFITM3 prevented HIV-1 ability to inhibit A(H1N1pdm09 replication. HIV-1 infection also increased IFITM3 levels in human primary macrophages by almost 100%. Consequently, the arrival of influenza ribonucleoproteins (RNPs to nucleus of macrophages was inhibited, as evaluated by different approaches. Reduction of influenza RNPs entry into the nucleus tolled A(H1N1pdm09 life cycle in macrophages earlier than usual, limiting influenza's ability to induce TNF-α. As judged by analysis of the influenza hemagglutin (HA gene from in vitro experiments and from samples of HIV-1/A(H1N1pdm09 co-infected individuals, the HIV-1-induced reduction of influenza replication resulted in delayed viral evolution. Our results may provide insights on the mechanisms that may have attenuated the clinical course of Influenza in HIV-1/A(H1N1pdm09 co-infected patients during the recent influenza form 2009/2010.

  9. OPTIMALISASI BANK SYARI’AH MENUJU GOOD CORPORATE GOVERNANCE

    Directory of Open Access Journals (Sweden)

    Fahrur Ulum Fahrur Ulum

    2013-08-01

    Full Text Available Abstract: Syarî’ah banking must be optimized earnestly to fulfill the stakeholders interest. The effective implementation of cooporate governance would realize the goal of fairness, accountability, and transparancy.  There are several prior focus of this system manager: basic concept and problems of cooperate governance in syarî’ah banking, the pillars of implementation, and the mechanism.  As a result, to create an effective  cooperate governance of syariah banking, the following aspects must be urgently required: a contract clarity, market discipline, moral dimension, socio-political atmosphere,  law enforcement, and institution. Board of directors, senior management, stockholders, and depositors have important roles to establish the  harmony of syariah banking development. The stakeholders  are directly connected to the mechanism of cooperate governance of syariah banking. Key Words: corporate governance, bank syari’ah, stakeholders, dan mudlârabah

  10. Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat.

    Science.gov (United States)

    Haley, Jane E; Dickenson, Anthony H

    2016-08-15

    We used in vivo electrophysiology and a model of more persistent nociceptive inputs to monitor spinal cord neuronal activity in anaesthetised rats to reveal the pharmacology of enhanced pain signalling. The study showed that all responses were blocked by non-selective antagonism of glutamate receptors but a selective and preferential role of the N-methyl-d-aspartate (NMDA) receptor in the prolonged plastic responses was clearly seen. The work lead to many publications, initially preclinical but increasingly from patient studies, showing the importance of the NMDA receptor in central sensitisation within the spinal cord and how this could relate to persistent pain states. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

    International Nuclear Information System (INIS)

    Khan, Shaheen; Liu Shengxi; Stoner, Matthew; Safe, Stephen

    2007-01-01

    The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and mRNA levels and also activates inhibitory AhR-ERα crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AhR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1α or other factors that sequester the AhR nuclear translocation (Arnt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NFκB which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 h, BRCA1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 h, BRCA1 was not decreased, but induction of CYP1A1 by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 h enhanced CYP1A1 expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ah-responsiveness (under normoxia) that are also inhibited by cycloheximide

  12. Synthesis and characterization of N-hydroxysuccinimide ester chemical affinity derivatives of asialoorosomucoid that covalently cross-link to galactosyl receptors on isolated rat hepatocytes

    International Nuclear Information System (INIS)

    Herzig, M.C.S.; Weigel, P.H.

    1989-01-01

    The authors have developed chemical affinity reagents for the hepatic galactosyl receptor. Asialoorosomucoid (ASOR) was derivatized with five homobifunctional N-hydroxysuccinimide (NHS) ester cross-linkers. NHS/ASOR derivatives were synthesized, purified, and applied within 10 min to isolated rat hepatocytes at 4 degree C. Specific binding of these 125 I-labeled derivatives was ∼90% in the presence of either EGTA or excess ASOR. Specific cross-linking assessed by the resistance of specifically bound NHS/ 125 I-ASOR to release by EGTA, was 50-75% of the specifically bound ligand. The extent of specific cross-linking correlated with the average number of NHS groups per ASOR and was controlled by varying the molar ratio of cross-linker to ASOR during the synthesis. After being cross-linked with any of the NHS/ 125 I-ASOR derivatives, cells were washed with EGTA, solubilized in Triton X-100, and analyzed by SDA-PAGE and autoradiography. They conclude that all three receptor subunits can cross-link to ligand. They propose a model in which the native receptor is a heterohexamer composed of four subunits of RHL 1 and two subunits of RHL 2 and/or RHL 3

  13. PEMIKIRAN ISLAM DALAM PERSPEKTIF SUNNI DAN SYI’AH

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    Muh. Shohibul Itmam

    2013-09-01

    Full Text Available THE ISLAMIC THINKING IN SUNNI AND SYI’AH PERSPECTIVES. This paper attempts to describe the problems associated with Islam in particular with regard to Sunni and Syi’ah teachings. The number of  streams that developed in Islam today has resulted Islam got claims from various clerical community, such as terrorism and others, resulting in the ruination image of  Islam in the constellation of  the religions of  man. As the flow and the teachings of  the most dominating civilization of  the world religions, Sunni and Syiah, including the Wahhabi, are necessary to clarify the existence or clarified the diversity in the constellation of  Islam, considering the number of streams that are currently claiming truth on themselves. Iran as the country becoming a reference in the world of  developing Syi’ah should be used as a reference in the study of  understanding associated with Sunni and Syi’ah. From this country, the world of  Islam knows the concept ofgoverning “Wilayatul Faqih”. The concept was pioneered by the government of Imam Khomeini who became known after Islamic Revolution in Iran 1979 and continues to be developed up to now. Every year Iran is celebrated with a huge demonstration with the slogan in Persian, “Islam Pyruz ast, ast Nabud Istikbar”, Islam is victorious, crushed the vanity of the islam enemy. keywords: Islam, Sunni, Syi’ah, Perspective, Differences, Similarities. Tulisan ini mencoba mengurai persoalan yang berhubungan dengan Islam secara khusus yang berkaitan dengan ajaran Sunni dan Syi’ah. Banyaknya aliran yang berkembang dalam Islam dewasa ini telah mengakibatkan Islam mendapat klaim dari berbagai komunitas agamawan, seperti teroris dan lainnya, yang mengakibatkan redupnya citra Islam dalam percaturan agama-agama manusia. Sebagai aliran dan ajaran yang paling mendominasi peradaban agama dunia, Sunni dan  Syi’ah,  termasuk  Wahabi,  perlu  memperjelas  eksistensinya atau diperjelas

  14. Atividade da enzima acetil-hidrolase do fator ativador de plaquetas (PAF-AH em pacientes com diabete melito tipo 1 Platelet-activating factor acetylhydrolase (PAF-AH activity in patients with type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Simone Henriques de Castro

    2007-02-01

    Full Text Available OBJETIVO: Avaliar a atividade da acetil-hidrolase do fator ativador de plaquetas (PAF-AH e sua relação com variáveis clinicodemográficas, com o controle metabólico, os níveis de apolipoproteínas A e B e a suscetibilidade da lipoproteína de baixa densidade (LDL à oxidação in vitro em pacientes com DM tipo 1 (DM 1. MÉTODOS: Foram avaliados 42 pacientes com DM1 (27 mulheres e 48 não-diabéticos (16 mulheres, pareados por sexo, idade e índice de massa corporal (IMC. Os exames realizados foram: glicemia de jejum (GJ e pós-prandial (GPP, lipidograma, ácido úrico (AU, hemoglobina glicosilada (HbA1c e coeficiente de oxidação da lipoproteína de baixa densidade (LDL por espectrofotometria. A análise da atividade da PAF-AH foi realizada por espectrofotometria (Cayman Chemical. RESULTADOS: A análise da atividade da PAF-AH mostrou haver maior atividade enzimática nos pacientes com DM 1 do que nos não-diabéticos (0,0150 ± 0,0051 versus 0,0116 ± 0,0041; p OBJECTIVE: To evaluate platelet-activating factor acetylhydrolase (PAF-AH activity and its relationship with clinical and demographic variables, metabolic control, apolipoprotein A and B levels and the susceptibility of low-density lipoprotein (LDL to in vitro oxidation in patients with type 1 diabetes mellitus (DM 1. METHODS: Forty two patients with DM 1 (27 females and 48 control subjects (16 females matched for gender, age and body mass index (BMI were evaluated. The following tests were performed: fast plasma glucose (FG and postprandial plasma glucose (PPG, lipid profile, uric acid (UA, glycosylated hemoglobin (HbA1c, and low-density lipoprotein (LDL oxidation rate using colorimetric assay. The PAF-AH activity was analyzed using colorimetric assay (Cayman Chemical. RESULTS: The analysis of PAF-AH activity showed a higher enzyme activity in patients with DM 1 than in control subjects (0.0150 ± 0.0051 vs. 0.0116 ± 0.0041; p < 0.001. In patients with DM 1, a direct correlation

  15. AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle.

    Science.gov (United States)

    Kim, Young-Chae; Seok, Sunmi; Byun, Sangwon; Kong, Bo; Zhang, Yang; Guo, Grace; Xie, Wen; Ma, Jian; Kemper, Byron; Kemper, Jongsook Kim

    2018-02-07

    Phosphatidylcholines (PC) and S-adenosylmethionine (SAM) are critical determinants of hepatic lipid levels, but how their levels are regulated is unclear. Here, we show that Pemt and Gnmt, key one-carbon cycle genes regulating PC/SAM levels, are downregulated after feeding, leading to decreased PC and increased SAM levels, but these effects are blunted in small heterodimer partner (SHP)-null or FGF15-null mice. Further, aryl hydrocarbon receptor (AhR) is translocated into the nucleus by insulin/PKB signaling in the early fed state and induces Pemt and Gnmt expression. This induction is blocked by FGF15 signaling-activated SHP in the late fed state. Adenoviral-mediated expression of AhR in obese mice increases PC levels and exacerbates steatosis, effects that are blunted by SHP co-expression or Pemt downregulation. PEMT, AHR, and PC levels are elevated in simple steatosis patients, but PC levels are robustly reduced in steatohepatitis-fibrosis patients. This study identifies AhR and SHP as new physiological regulators of PC/SAM levels.

  16. Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

    International Nuclear Information System (INIS)

    Wei, Kuo-Liang; Chen, Fei-Yun; Lin, Chih-Yi; Gao, Guan-Lun; Kao, Wen-Ya; Yeh, Chi-Hui; Chen, Chang-Rong; Huang, Hao-Chun; Tsai, Wei-Ren; Jong, Koa-Jen; Li, Wan-Jung; Su, Jyan-Gwo Joseph

    2016-01-01

    Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG 0 /G 1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. - Highlights: • Carbendazim induced transcriptional activity of the aryl hydrocarbon response element. • Carbendazim induced nuclear translocation of the aryl hydrocarbon

  17. Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Kuo-Liang [Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC (China); College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, ROC (China); Chen, Fei-Yun; Lin, Chih-Yi [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Gao, Guan-Lun [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC (China); Kao, Wen-Ya [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Yeh, Chi-Hui [Department of Environmental Engineering, College of Engineering, Da-Yeh University, Dacun, Changhua 51591, Taiwan, ROC (China); Chen, Chang-Rong [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Huang, Hao-Chun [Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC (China); Tsai, Wei-Ren [Division of Applied Toxicology, Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung 41358, Taiwan, ROC (China); Jong, Koa-Jen [Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC (China); Li, Wan-Jung [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Su, Jyan-Gwo Joseph, E-mail: jgjsu@mail.ncyu.edu.tw [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China)

    2016-09-01

    Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG{sub 0}/G{sub 1} population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. - Highlights: • Carbendazim induced transcriptional activity of the aryl hydrocarbon response element. • Carbendazim induced nuclear translocation of the aryl

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

    Energy Technology Data Exchange (ETDEWEB)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    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.

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

    International Nuclear Information System (INIS)

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

    2014-01-01

    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

  20. Allantoin ameliorates chemically-induced pancreatic β-cell damage through activation of the imidazoline I3 receptors

    Directory of Open Access Journals (Sweden)

    Marie Amitani

    2015-08-01

    Full Text Available Objective. Allantoin is the primary active compound in yams (Dioscorea spp.. Recently, allantoin has been demonstrated to activate imidazoline 3 (I3 receptors located in pancreatic tissues. Thus, the present study aimed to investigate the role of allantoin in the effect to improve damage induced in pancreatic β-cells by streptozotocin (STZ via the I3 receptors.Research Design and Methods. The effect of allantoin on STZ-induced apoptosis in pancreatic β-cells was examined using the ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and Western blottings. The potential mechanism was investigated using KU14R: an I3 receptor antagonist, and U73122: a phospholipase C (PLC inhibitor. The effects of allantoin on serum glucose and insulin secretion were measured in STZ-treated rats.Results. Allantoin attenuated apoptosis and cytotoxicity and increased the viability of STZ-induced β-cells in a dose-dependent manner; this effect was suppressed by KU14R and U73112. Allantoin decreased the level of caspase-3 and increased the level of phosphorylated B-cell lymphoma 2 (Bcl-2 expression detected by Western blotting. The improvement in β-cells viability was confirmed using flow cytometry analysis. Daily injection of allantoin for 8 days in STZ-treated rats significantly lowered plasma glucose and increased plasma insulin levels. This action was inhibited by treatment with KU14R.Conclusion. Allantoin ameliorates the damage of β-cells induced by STZ. The blockade by pharmacological inhibitors indicated that allantoin can activate the I3 receptors through a PLC-related pathway to decrease this damage. Therefore, allantoin and related analogs may be effective in the therapy for β-cell damage.

  1. Oculomotor deficits in aryl hydrocarbon receptor null mouse.

    Directory of Open Access Journals (Sweden)

    Aline Chevallier

    Full Text Available The Aryl hydrocarbon Receptor or AhR, a ligand-activated transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD. Recent studies in Caenorhabditis elegans and Drosophila melanogaster show that the orthologs of the AhR are expressed exclusively in certain types of neurons and are implicated in the development and the homeostasis of the central nervous system. While physiological roles of the AhR were demonstrated in the mammalian heart, liver and gametogenesis, its ontogenic expression and putative neural functions remain elusive. Here, we report that the constitutive absence of the AhR in adult mice (AhR-/- leads to abnormal eye movements in the form of a spontaneous pendular horizontal nystagmus. To determine if the nystagmus is of vestibular, visual, or cerebellar origin, gaze stabilizing reflexes, namely vestibulo-ocular and optokinetic reflexes (VOR and OKR, were investigated. The OKR is less effective in the AhR-/- mice suggesting a deficit in the visuo-motor circuitry, while the VOR is mildly affected. Furthermore, the AhR is expressed in the retinal ganglion cells during the development, however electroretinograms revealed no impairment of retinal cell function. The structure of the cerebellum of the AhR-/- mice is normal which is compatible with the preserved VOR adaptation, a plastic process dependent on cerebellar integrity. Finally, intoxication with TCDD of control adults did not lead to any abnormality of the oculomotor control. These results demonstrate that the absence of the AhR leads to acquired central nervous system deficits in the adults. Given the many common features between both AhR mouse and human infantile nystagmus syndromes, the AhR-/- mice might give insights into the developmental mechanisms which lead to congenital eye disorders.

  2. Role of the Aryl Hydrocarbon Receptor in Colon Neoplasia

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Guofeng, E-mail: gxie@medicine.umaryland.edu; Raufman, Jean-Pierre [Division of Gastroenterology and Hepatology, Veterans Administration Maryland Health Care System, University of Maryland School of Medicine, Baltimore, MD 21201 (United States)

    2015-07-31

    For both men and women, colorectal cancer (CRC) is the second leading cause of cancer death in the United States, primarily as a consequence of limited therapies for metastatic disease. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor with diverse functions in detoxification of xenobiotics, inflammatory responses, and tissue homeostasis. Emerging evidence indicates that AhR also plays an important role in regulating intestinal cell proliferation and tumorigenesis. Here, we review both the pro- and anti-carcinogenic properties of AhR signaling and its potential role as a therapeutic target in CRC.

  3. Evidence of the aryl hydrocarbon receptor in chemosynthetic mussels from the Gulf of Mexico

    International Nuclear Information System (INIS)

    Willett, K.; Thomsen, J.; Wilson, C.; McDonald, S.; Safe, S.

    1995-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls expression of various genes including cytochrome P450. Polynuclear aromatic and halogenated aromatic hydrocarbons are agonists for the AhR in fish and mammalian species. Previously, a homologous AhR has not been identified in marine invertebrate species. Chemosynthetic mussels were collected from gas and petroleum seeps in the Gulf of Mexico to investigate the presence of the AhR and the induction of the cytochrome P450 system. Aryl hydrocarbon hydroxylase and glutathione S-transferase activities in the gill and hepatopancreas were elevated in the petroleum seep mussels relative to those from the gas seep. A nuclear AhR in the hepatopancreas was detected in both mussel populations after treatment with [ 3 H]-tetrachlorodibenzo-p-dioxin (tcdd) followed by sucrose density gradient analysis. Gel mobility shift assays using a labeled dioxin responsive element (DRE) oligonucleotide and tcdd-transformed mussel cytosol showed a retarded band which could be competed with excess unlabeled DRE. Results from gel shifts indicated specific binding of the tcdd-mussel AhR complex to its responsible element. Finally, PCR primers designed to amplify a 700 base pair region of the human AhR detected AhR mRNA in both mussel populations. The sequence of this PCR product is being determined. The presence of the AhR in marine invertebrates has important implications in the evolutionary age of the AhR

  4. Identification of amino acid residues in the ligand-binding domain of the aryl hydrocarbon receptor causing the species-specific response to omeprazole: possible determinants for binding putative endogenous ligands.

    Science.gov (United States)

    Shiizaki, Kazuhiro; Ohsako, Seiichiroh; Kawanishi, Masanobu; Yagi, Takashi

    2014-02-01

    Omeprazole (OME) induces the expression of genes encoding drug-metabolizing enzymes, such as CYP1A1, via activation of the aryl hydrocarbon receptor (AhR) both in vivo and in vitro. However, the precise mechanism of OME-mediated AhR activation is still under investigation. While elucidating species-specific susceptibility to dioxin, we found that OME-mediated AhR activation was mammalian species specific. Moreover, we previously reported that OME has inhibitory activity toward CYP1A1 enzymes. From these observations, we speculated that OME-mediated AhR target gene transcription is due to AhR activation by increasing amounts of putative AhR ligands in serum by inhibition of CYP1A1 activity. We compared the amino acid sequences of OME-sensitive rabbit AhR and nonsensitive mouse AhR to identify the residues responsible for the species-specific response. Chimeric AhRs were constructed by exchanging domains between mouse and rabbit AhRs to define the region required for the response to OME. OME-mediated transactivation was observed only with the chimeric AhR that included the ligand-binding domain (LBD) of the rabbit AhR. Site-directed mutagenesis revealed three amino acids (M328, T353, and F367) in the rabbit AhR that were responsible for OME-mediated transactivation. Replacing these residues with those of the mouse AhR abolished the response of the rabbit AhR. In contrast, substitutions of these amino acids with those of the rabbit AhR altered nonsensitive mouse AhR to become sensitive to OME. These results suggest that OME-mediated AhR activation requires a specific structure within LBD that is probably essential for binding with enigmatic endogenous ligands.

  5. Cannabinoid Type 1 Receptor (CB1) Ligands with Therapeutic Potential for Withdrawal Syndrome in Chemical Dependents of Cannabis sativa.

    Science.gov (United States)

    Ferreira, Jaderson V; Chaves, Gisele A; Marino, Bianca L B; Sousa, Kessia P A; Souza, Lucilene R; Brito, Maiara F B; Teixeira, Hueldem R C; da Silva, Carlos H T P; Santos, Cleydson B R; Hage-Melim, Lorane I S

    2017-08-22

    Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer.

    Science.gov (United States)

    Koliopanos, Alexander; Kleeff, Jörg; Xiao, Yi; Safe, Stephen; Zimmermann, Arthur; Büchler, Markus W; Friess, Helmut

    2002-09-05

    The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analysed by Northern blotting. The exact site of AhR expression was analysed by in situ hybridization and immunohistochemistry. The effects of TCDD and four selective AhR agonists on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p21. There was strong AhR mRNA expression in 14 out of 15 pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. TCDD and the four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 and was not induced by TCDD and AhR agonists. In contrast, TCDD and AhR agonists induced the expression of the cyclin-dependent kinase inhibitor p21. In conclusion, the relatively non-toxic AhR agonists caused growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. In addition, almost all human pancreatic cancer tissues expressed this receptor at high levels, suggesting that these or related compounds may play a role in the therapy of pancreatic cancer in the future.

  7. Aryl hydrocarbon receptor and intestinal immunity.

    Science.gov (United States)

    Lamas, Bruno; Natividad, Jane M; Sokol, Harry

    2018-04-07

    Aryl hydrocarbon receptor (AhR) is a member of the basic helix-loop-helix-(bHLH) superfamily of transcription factors, which are associated with cellular responses to environmental stimuli, such as xenobiotics and oxygen levels. Unlike other members of bHLH, AhR is the only bHLH transcription factor that is known to be ligand activated. Early AhR studies focused on understanding the role of AhR in mediating the toxicity and carcinogenesis properties of the prototypic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In recent years, however, it has become apparent that, in addition to its toxicological involvement, AhR is highly receptive to a wide array of endogenous and exogenous ligands, and that its activation leads to a myriad of key host physiological functions. In this study, we review the current understanding of the functions of AhR in the mucosal immune system with a focus on its role in intestinal barrier function and intestinal immune cells, as well as in intestinal homeostasis.

  8. Comparing introduction to Europe of highly pathogenic avian influenza viruses A(H5N8) in 2014 and A(H5N1) in 2005.

    Science.gov (United States)

    Adlhoch, C; Gossner, C; Koch, G; Brown, I; Bouwstra, R; Verdonck, F; Penttinen, P; Harder, T

    2014-12-18

    Since the beginning of November 2014, nine outbreaks of highly pathogenic avian influenza virus (HPAIV) A(H5N8) in poultry have been detected in four European countries. In this report, similarities and differences between the modes of introduction of HPAIV A(H5N1) and A(H5N8) into Europe are described. Experiences from outbreaks of A(H5N1) in Europe demonstrated that early detection to control HPAIV in poultry has proven pivotal to minimise the risk of zoonotic transmission and prevention of human cases.

  9. Ah lo previdi - Arien von Mozart, Cocchi, Colla und Paisiello

    Czech Academy of Sciences Publication Activity Database

    Jonášová, Milada

    -, - (2008), s. 75-86. ISBN 9783761821107. ISSN 1861-9053. [Der junge Mozart 1756-1780. Philologie – Analyse – Rezeption. Salzburg, 01.12.2005-4.12.2005] R&D Projects: GA AV ČR 1QS900580552 Institutional research plan: CEZ:AV0Z90580513 Keywords : Ah lo previdi * Wolfgang Amadeus Mozart * G. Cocchi * G. Colla * G. Paisiello Subject RIV: AL - Art, Architecture, Cultural Heritage

  10. Characterization of the functional epitope on the urokinase receptor. Complete alanine scanning mutagenesis supplemented by chemical cross-linking

    DEFF Research Database (Denmark)

    Gårdsvoll, Henrik; Gilquin, Bernard; Le Du, Marie Hélène

    2006-01-01

    a comprehensive alanine scanning mutagenesis of uPAR combined with low resolution distance constraints defined within the complex using chemical cross-linkers as molecular rulers. The kinetic rate constants for the interaction between pro-uPA and 244 purified uPAR mutants with single-site replacements were...

  11. Women with multiple chemical sensitivity have increased harm avoidance and reduced 5-HT(1A receptor binding potential in the anterior cingulate and amygdala.

    Directory of Open Access Journals (Sweden)

    Lena Hillert

    Full Text Available Multiple chemical sensitivity (MCS is a common condition, characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the underlying mechanisms are unknown. Contrary to the expectations it was recently found that persons with MCS activate the odor-processing brain regions less than controls, while their activation of the anterior cingulate cortex (ACC is increased. The present follow-up study was designed to test the hypotheses that MCS subjects have increased harm avoidance and deviations in the serotonin system, which could render them intolerant to environmental odors. Twelve MCS and 11 control subjects, age 22-44, all working or studying females, were included in a PET study where 5-HT(1A receptor binding potential (BP was assessed after bolus injection of [(11C]WAY100635. Psychological profiles were assessed by the Temperament and Character Inventory and the Swedish universities Scales of Personality. All MCS and 12 control subjects were also tested for emotional startle modulation in an acoustic startle test. MCS subjects exhibited significantly increased harm avoidance, and anxiety compared to controls. They also had a reduced 5-HT(1A receptor BP in amygdala (p = 0.029, ACC (p = 0.005 (planned comparisons, significance level 0.05, and insular cortex (p = 0.003; significance level p<0.005 with Bonferroni correction, and showed an inverse correlation between degree of anxiety and the BP in the amygdala (planned comparison. No group by emotional category difference was found in the startle test. Increased harm avoidance and the observed changes in the 5-HT(1A receptor BP in the regions processing harm avoidance provides a plausible pathophysiological ground for the symptoms described in MCS, and yields valuable information for our general understanding of idiopathic environmental intolerances.

  12. Direct chemical synthesis of 1 alpha,25-dihydroxy[26,27-3H] vitamin D3 with high specific activity: its use in receptor studies

    International Nuclear Information System (INIS)

    Napoli, J.L.; Mellon, W.S.; Fivizzani, M.A.; Schnoes, H.K.; DeLuca, H.F.

    1980-01-01

    The first direct chemical synthesis of radiolabeled 1 alpha, 25-dihydroxyvitamin D3 is reported. Unlike all previous syntheses, the new approach does not rely on enzymatic 1 alpha-hydroxylation of radiolabeled precursors. Rather, isotope is introduced in the last synthetic step by reaction of [3H] -methylmagnesium bromide with methyl 1 alpha-hydroxy-26,27-dinorvitamin D3-25-carboxylate to give 1 alpha,25-dihydroxy-[26,27-3H] vitamin D3 with a specific activity of 160 Ci/mmol. Mass spectroscopy confirmed that the radiohormone consists of a single isomer with six tritium atoms bound to carbons 26 and 27. Synthetically produced 1 alpha,25-dihydroxy [26,27-3H] vitamin D3 is indistinguishable from 1 alpha,25-dihydroxy-[26,27-3H] vitamin D3 obtained from the enzymatic 1 alpha-hydroxylation of 25-hydroxy[26,27-3H] vitamin D3 (160 Ci/mmol) by high-pressure liquid chromatography analysis and in the competitive binding assay using chick intestinal cytosol as the receptor source. Equilibrium dissociation constant measurements with the high specific activity radiohormone indicate a Kd of 8.2 x 10(-11) M for the chick intestinal cytosol 1 alpha,25-dihydroxyvitamin D3 receptor--a value considerably lower than the constants in the range of (1-5) x 10(-9) M previously reported

  13. Natural co-infection of influenza A/H3N2 and A/H1N1pdm09 viruses resulting in a reassortant A/H3N2 virus.

    Science.gov (United States)

    Rith, Sareth; Chin, Savuth; Sar, Borann; Y, Phalla; Horm, Srey Viseth; Ly, Sovann; Buchy, Philippe; Dussart, Philippe; Horwood, Paul F

    2015-12-01

    Despite annual co-circulation of different subtypes of seasonal influenza, co-infections between different viruses are rarely detected. These co-infections can result in the emergence of reassortant progeny. We document the detection of an influenza co-infection, between influenza A/H3N2 with A/H1N1pdm09 viruses, which occurred in a 3 year old male in Cambodia during April 2014. Both viruses were detected in the patient at relatively high viral loads (as determined by real-time RT-PCR CT values), which is unusual for influenza co-infections. As reassortment can occur between co-infected influenza A strains we isolated plaque purified clonal viral populations from the clinical material of the patient infected with A/H3N2 and A/H1N1pdm09. Complete genome sequences were completed for 7 clonal viruses to determine if any reassorted viruses were generated during the influenza virus co-infection. Although most of the viral sequences were consistent with wild-type A/H3N2 or A/H1N1pdm09, one reassortant A/H3N2 virus was isolated which contained an A/H1N1pdm09 NS1 gene fragment. The reassortant virus was viable and able to infect cells, as judged by successful passage in MDCK cells, achieving a TCID50 of 10(4)/ml at passage number two. There is no evidence that the reassortant virus was transmitted further. The co-infection occurred during a period when co-circulation of A/H3N2 and A/H1N1pdm09 was detected in Cambodia. It is unclear how often influenza co-infections occur, but laboratories should consider influenza co-infections during routine surveillance activities. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  14. A Single Sex Pheromone Receptor Determines Chemical Response Specificity of Sexual Behavior in the Silkmoth Bombyx mori

    OpenAIRE

    Sakurai, Takeshi; Mitsuno, Hidefumi; Haupt, Stephan Shuichi; Uchino, Keiro; Yokohari, Fumio; Nishioka, Takaaki; Kobayashi, Isao; Sezutsu, Hideki; Tamura, Toshiki; Kanzaki, Ryohei

    2011-01-01

    In insects and other animals, intraspecific communication between individuals of the opposite sex is mediated in part by chemical signals called sex pheromones. In most moth species, male moths rely heavily on species-specific sex pheromones emitted by female moths to identify and orient towards an appropriate mating partner among a large number of sympatric insect species. The silkmoth, Bombyx mori, utilizes the simplest possible pheromone system, in which a single pheromone component, (E, Z...

  15. Interleukin-24 as a target cytokine of environmental aryl hydrocarbon receptor agonist exposure in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Yueh-Hsia; Kuo, Yu-Chun; Tsai, Ming-Hsien; Ho, Chia-Chi; Tsai, Hui-Ti; Hsu, Chin-Yu; Chen, Yu-Cheng; Lin, Pinpin, E-mail: pplin@nhri.org.tw

    2017-06-01

    Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4 weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists. - Graphical abstract: (A) Cytokine and chemokine gene expressions were examined in CL5 cells treated with AhR and non-AhR agonists. Thirteen cytokines and chemokines genes were altered in the AhR agonist-treated cells, but not in the non-AhR agonist-treated cells. IL-24 was the most highly induced gene among the AhR-modulated cytokines. (B

  16. Effect of TBT and PAHs on CYP1A, AhR and Vitellogenin Gene Expression in the Japanese Eel, Anguilla japonica.

    Science.gov (United States)

    Choi, Min Seop; Kwon, Se Ryun; Choi, Seong Hee; Kwon, Hyuk Chu

    2012-12-01

    Gene expressions of cytochrome P4501A (CYP1A), aryl hydrocarbon receptor (AhR) and vitellogenin (Vg) by endocrine disruptors, benzo[α]pyrene (B[a]P) and tributyltin (TBT) were examined in cultured eel hepatocytes which were isolated from eels treated previously with B[a]P (10 mg/kg) or estradiol-17β (20 mg/kg) in vivo, and the relationship between CYP1A, AhR and Vg genes were studied. When the cultured eel hepatocytes were treated with B[a]P (10(-6)-10(-5) M) the gene expressions of CYP1A and AhR were enhanced in a concentration-dependent manner. However, when treated with TBT (10(-9)-10(-5) M) the gene expressions of CYP1A and AhR were suppressed at high concentrations (10(-6)-10(-5) M), while having no effects at low concentrations (10(-9)-10(-7) M). Gene expression of Vg was also suppressed by TBT in a concentration-dependent manner in cultured eel hepatocytes which was previously treated in vivo with estradiol-17β.

  17. Functional conservation and divergence of four ginger AP1/AGL9 MADS-box genes revealed by analysis of their expression and protein-protein interaction, and ectopic expression of AhFUL gene in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Xiumei Li

    Full Text Available Alpinia genus are known generally as ginger-lilies for showy flowers in the ginger family, Zingiberaceae, and their floral morphology diverges from typical monocotyledon flowers. However, little is known about the functions of ginger MADS-box genes in floral identity. In this study, four AP1/AGL9 MADS-box genes were cloned from Alpinia hainanensis, and protein-protein interactions (PPIs and roles of the four genes in floral homeotic conversion and in floral evolution are surveyed for the first time. AhFUL is clustered to the AP1 lineage, AhSEP4 and AhSEP3b to the SEP lineage, and AhAGL6-like to the AGL6 lineage. The four genes showed conserved and divergent expression patterns, and their encoded proteins were localized in the nucleus. Seven combinations of PPI (AhFUL-AhSEP4, AhFUL-AhAGL6-like, AhFUL-AhSEP3b, AhSEP4-AhAGL6-like, AhSEP4-AhSEP3b, AhAGL6-like-AhSEP3b, and AhSEP3b-AhSEP3b were detected, and the PPI patterns in the AP1/AGL9 lineage revealed that five of the 10 possible combinations are conserved and three are variable, while conclusions cannot yet be made regarding the other two. Ectopic expression of AhFUL in Arabidopsis thaliana led to early flowering and floral organ homeotic conversion to sepal-like or leaf-like. Therefore, we conclude that the four A. hainanensis AP1/AGL9 genes show functional conservation and divergence in the floral identity from other MADS-box genes.

  18. Trivalent influenza vaccine in patients on haemodialysis: impaired seroresponse with differences for A-H3N2 and A-H1N1 vaccine components

    NARCIS (Netherlands)

    W.E.Ph. Beyer (Walter); D.J. Versluis; P. Kramer; P.P.N.M. Diderich (Philip); W. Weimar (Willem); N. Masurel (Nic)

    1987-01-01

    textabstractOne hundred and one patients on haemodialysis, 21 patients on peritoneal dialysis and 30 healthy controls received a trivalent split vaccine containing 15 micrograms haemagglutinin of a recent influenza A-H3N2, influenza A-H1N1 and influenza B strain, respectively. Antibody production

  19. Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza

    NARCIS (Netherlands)

    Cheng, Zhongshan; Zhou, Jie; To, Kelvin Kai-Wang; Chu, Hin; Li, Cun; Wang, Dong; Yang, Dong; Zheng, Shufa; Hao, Ke; Bosse, Yohan; Obeidat, Ma'en; Brandsma, Corry-Anke; Song, You-Qiang; Chen, Yu; Zheng, Bo-Jian; Li, Lanjuan; Yuen, Kwok-Yung

    2015-01-01

    The genetic predisposition to severe A(H1N1) 2009 (A[H1N1]pdm09) influenza was evaluated in 409 patients, including 162 cases with severe infection and 247 controls with mild infection. We prioritized candidate variants based on the result of a pilot genome-wide association study and a lung

  20. Hexachlorobenzene modulates the crosstalk between the aryl hydrocarbon receptor and transforming growth factor-β1 signaling, enhancing human breast cancer cell migration and invasion

    International Nuclear Information System (INIS)

    Miret, Noelia; Pontillo, Carolina; Ventura, Clara; Carozzo, Alejandro; Chiappini, Florencia

    2016-01-01

    Highlights: • HCB enhances TGF-β1 expression and activation levels in breast cancer cells. • HCB activates TGF-β1 pathways: Smad3, JNK and p38. • The HCB- induced migration and invasion involves TGF-β1 signaling pathways. • HCB modulates AhR levels and activation. • HCB enhances TGF-β1 mRNA expression in an AhR-dependent manner. - Abstract: Given the number of women affected by breast cancer, considerable interest has been raised in understanding the relationships between environmental chemicals and disease onset. Hexachlorobenzene (HCB) is a dioxin-like compound that is widely distributed in the environment and is a weak ligand of the aryl hydrocarbon receptor (AhR). We previously demonstrated that HCB acts as an endocrine disruptor capable of stimulating cell proliferation, migration, invasion, and metastasis in different breast cancer models. In addition, increasing evidence indicates that transforming growth factor-β1 (TGF-β1) can contribute to tumor maintenance and progression. In this context, this work investigated the effect of HCB (0.005, 0.05, 0.5, and 5 μM) on TGF-β1 signaling and AhR/TGF-β1 crosstalk in the human breast cancer cell line MDA-MB-231 and analyzed whether TGF-β1 pathways are involved in HCB-induced cell migration and invasion. RT-qPCR results indicated that HCB reduces AhR mRNA expression through TGF-β1 signaling but enhances TGF-β1 mRNA levels involving AhR signaling. Western blot analysis demonstrated that HCB could increase TGF-β1 protein levels and activation, as well as Smad3, JNK, and p38 phosphorylation. In addition, low and high doses of HCB were determined to exert differential effects on AhR protein levels, localization, and activation, with a high dose (5 μM) inducing AhR nuclear translocation and AhR-dependent CYP1A1 expression. These findings also revealed that c-Src and AhR are involved in HCB-mediated activation of Smad3. HCB enhances cell migration (scratch motility assay) and invasion (Transwell

  1. Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome.

    Science.gov (United States)

    Boule, Lisbeth A; Burke, Catherine G; Jin, Guang-Bi; Lawrence, B Paige

    2018-01-29

    The aryl hydrocarbon receptor (AHR) offers a compelling target to modulate the immune system. AHR agonists alter adaptive immune responses, but the consequences differ across studies. We report here the comparison of four agents representing different sources of AHR ligands in mice infected with influenza A virus (IAV): TCDD, prototype exogenous AHR agonist; PCB126, pollutant with documented human exposure; ITE, novel pharmaceutical; and FICZ, degradation product of tryptophan. All four compounds diminished virus-specific IgM levels and increased the proportion of regulatory T cells. TCDD, PCB126 and ITE, but not FICZ, reduced virus-specific IgG levels and CD8 + T cell responses. Similarly, ITE, PCB126, and TCDD reduced Th1 and Tfh cells, whereas FICZ increased their frequency. In Cyp1a1-deficient mice, all compounds, including FICZ, reduced the response to IAV. Conditional Ahr knockout mice revealed that all four compounds require AHR within hematopoietic cells. Thus, differences in the immune response to IAV likely reflect variances in quality, magnitude, and duration of AHR signaling. This indicates that binding affinity and metabolism may be stronger predictors of immune effects than a compound's source of origin, and that harnessing AHR will require finding a balance between dampening immune-mediated pathologies and maintaining sufficient host defenses against infection.

  2. Developmental programming: Impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus

    International Nuclear Information System (INIS)

    Mahoney, Megan M.; Padmanabhan, Vasantha

    2010-01-01

    Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC, or BPA (5 mg/kg/day) from day 30 to 90 of gestation (term 147 d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F 2α , just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female.

  3. Investigation and characterization of receptors for pituitary adenylate cyclase-activating polypeptide in human brain by radioligand binding and chemical cross-linking

    International Nuclear Information System (INIS)

    Suda, K.; Smith, D.M.; Ghatei, M.A.; Murphy, J.K.; Bloom, S.R.

    1991-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel peptide of hypothalamic origin which increases adenylate cyclase activity in rat anterior pituitary cell cultures. The 38-amino acid peptide shows a close sequence homology to vasoactive intestinal peptide (VIP). Binding sites for PACAP in membranes from postmortem human brain tissue were studied using [ 125 I]PACAP27 as the radioligand. High specific binding sites (amount of specific binding measured at 0.25 nM [ 125 I]PACAP27 in femtomoles per mg protein +/- SEM; n = 4) were present in hypothalamus (344.5 +/- 13.0), brain stem (343.0 +/- 29.3), cerebellum (292.0 +/- 21.1), cortex (259.6 +/- 19.8), and basal ganglia (259.2 +/- 50.3). Specific binding sites in pituitary, although present, were less abundant (35.0 +/- 8.9). Binding of [ 125 I]PACAP27 was reversible and time, pH, and temperature dependent. Despite the homology with VIP, VIP was a poor inhibitor of [ 125 I]PACAP27 binding (IC50, greater than 1 microM) compared with PACAP27 (IC50, 0.5-1.3 nM) and PACAP38 (IC50, 0.2-1.3 nM). Scatchard plots of [ 125 I]PACAP27 binding showed the presence of both high and lower affinity sites. Chemical cross-linking of PACAP-binding sites revealed that [ 125 I]PACAP27 was bound to polypeptide chains of 67,000 and 48,000 mol wt. Thus, we have demonstrated the presence of PACAP-specific receptors in human brain which are not VIP receptors. This opens the possibility of PACAP functioning as a novel neurotransmitter/neuromodulator in human brain

  4. Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus.

    Science.gov (United States)

    Mahoney, Megan M; Padmanabhan, Vasantha

    2010-09-01

    Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC, or BPA (5mg/kg/day) from day 30 to 90 of gestation (term 147d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F(2alpha), just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female. 2010 Elsevier Inc. All rights reserved.

  5. Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis

    Science.gov (United States)

    Takamura, Takeyuki; Harama, Daisuke; Fukumoto, Suguru; Nakamura, Yuki; Shimokawa, Naomi; Ishimaru, Kayoko; Ikegami, Shuji; Makino, Seiya; Kitamura, Masanori; Nakao, Atsuhito

    2011-01-01

    Increasing evidence suggests that the aryl hydrocarbon receptor (AhR) pathway has an important role in the regulation of inflammatory responses. Most recently, we have shown that the activation of the AhR pathway by a potent AhR agonist inhibits the development of dextran sodium sulfate (DSS)-induced colitis, a model of human ulcerative colitis, by the induction of prostaglandin E2 (PGE2) in the large intestine. Because several strains of probiotic lactic acid bacteria have been reported to inhibit DSS-induced colitis by unidentified mechanisms, we hypothesized that particular strains of lactic acid bacterium might have the potential to activate the AhR pathway, thereby inhibiting DSS-induced colitis. This study investigated whether there are specific lactic acid bacterial strains that can activate the AhR pathway, and if so, whether this AhR-activating potential is associated with suppression of DSS-induced colitis. By using AhR signaling reporter cells, we found that Lactobacillus bulgaricus OLL1181 had the potential to activate the AhR pathway. OLL1181 also induced the mRNA expression of cytochrome P450 family 1A1 (CYP1A1), a target gene of the AhR pathway, in human colon cells, which was inhibited by the addition of an AhR antagonist, α-naphthoflavon (αNF). In addition, mice treated orally with OLL1181 showed an increase in CYP1A1 mRNA expression in the large intestine and amelioration of DSS-induced colitis. Thus, OLL1181 can induce activation of the intestinal AhR pathway and inhibit DSS-induced colitis in mice. This strain of lactic acid bacterium has therefore the potential to activate the AhR pathway, which may be able to suppress colitis. PMID:21321579

  6. TCDD and a putative endogenous AhR ligand, ITE, elicit the same immediate changes in gene expression in mouse lung fibroblasts.

    Science.gov (United States)

    Henry, Ellen C; Welle, Stephen L; Gasiewicz, Thomas A

    2010-03-01

    The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, mediates toxicity of several classes of xenobiotics and also has important physiological roles in differentiation, reproduction, and immunity, although the endogenous ligand(s) mediating these functions is/are as yet unidentified. One candidate endogenous ligand, 2-(1'H-indolo-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), is a potent AhR agonist in vitro, activates the murine AhR in vivo, but does not induce toxicity. We hypothesized that ITE and the toxic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may modify transcription of different sets of genes to account for their different toxicity. To test this hypothesis, primary mouse lung fibroblasts were exposed to 0.5muM ITE, 0.2nM TCDD, or vehicle for 4 h, and total gene expression was evaluated using microarrays. After this short-term and low-dose treatment, several hundred genes were changed significantly, and the response to ITE and TCDD was remarkably similar, both qualitatively and quantitatively. Induced gene sets included the expected battery of AhR-dependent xenobiotic-metabolizing enzymes, as well as several sets that reflect the inflammatory role of lung fibroblasts. Real time quantitative RT-qPCR assay of several selected genes confirmed these microarray data and further suggested that there may be kinetic differences in expression between ligands. These data suggest that ITE and TCDD elicit an analogous change in AhR conformation such that the initial transcription response is the same. Furthermore, if the difference in toxicity between TCDD and ITE is mediated by differences in gene expression, then it is likely that secondary changes enabled by the persistent TCDD, but not by the shorter lived ITE, are responsible.

  7. iNR-PhysChem: a sequence-based predictor for identifying nuclear receptors and their subfamilies via physical-chemical property matrix.

    Directory of Open Access Journals (Sweden)

    Xuan Xiao

    Full Text Available Nuclear receptors (NRs form a family of ligand-activated transcription factors that regulate a wide variety of biological processes, such as homeostasis, reproduction, development, and metabolism. Human genome contains 48 genes encoding NRs. These receptors have become one of the most important targets for therapeutic drug development. According to their different action mechanisms or functions, NRs have been classified into seven subfamilies. With the avalanche of protein sequences generated in the postgenomic age, we are facing the following challenging problems. Given an uncharacterized protein sequence, how can we identify whether it is a nuclear receptor? If it is, what subfamily it belongs to? To address these problems, we developed a predictor called iNR-PhysChem in which the protein samples were expressed by a novel mode of pseudo amino acid composition (PseAAC whose components were derived from a physical-chemical matrix via a series of auto-covariance and cross-covariance transformations. It was observed that the overall success rate achieved by iNR-PhysChem was over 98% in identifying NRs or non-NRs, and over 92% in identifying NRs among the following seven subfamilies: NR1--thyroid hormone like, NR2--HNF4-like, NR3--estrogen like, NR4--nerve growth factor IB-like, NR5--fushi tarazu-F1 like, NR6--germ cell nuclear factor like, and NR0--knirps like. These rates were derived by the jackknife tests on a stringent benchmark dataset in which none of protein sequences included has ≥60% pairwise sequence identity to any other in a same subset. As a user-friendly web-server, iNR-PhysChem is freely accessible to the public at either http://www.jci-bioinfo.cn/iNR-PhysChem or http://icpr.jci.edu.cn/bioinfo/iNR-PhysChem. Also a step-by-step guide is provided on how to use the web-server to get the desired results without the need to follow the complicated mathematics involved in developing the predictor. It is anticipated that iNR-PhysChem may

  8. Aeroelastic characteristics of the AH-64 bearingless tail rotor

    Science.gov (United States)

    Banerjee, D.

    1988-01-01

    The results of a wind tunnel test program to determine the performance loads and dynamic characteristics of the Composite Flexbeam Tail Rotor (CFTR) for the AH-64 Advanced Attack Helicopter are reported. The CFTR uses an elastomeric shear attachment of the flexbeam to the hub to provide soft-inplane S-mode and stiff-inplane C-mode configuration. The properties of the elastomer were selected for proper frequency placement and scale damping of the inplane S-mode. Kinematic pitch-lag coupling was introduced to provide the first cyclic inplane C-mode damping at high collective pitch. The CFTR was tested in a wind tunnel over the full slideslip envelop of the AH-64. It is found that the rotor was aeroelastically stable throughout the complete collective pitch range and up to rotor speeds of 1403 rpm. The dynamic characteristics of the rotor were found to be satisfactory at all pitch angles and rotor speeds of the tunnel tests. The design characteristics of the rotor which permit the high performance characteristics are discussed. Several schematic drawings and photographs of the rotor are provided.

  9. Productive infection of human skeletal muscle cells by pandemic and seasonal influenza A(H1N1 viruses.

    Directory of Open Access Journals (Sweden)

    Marion Desdouits

    Full Text Available Besides the classical respiratory and systemic symptoms, unusual complications of influenza A infection in humans involve the skeletal muscles. Numerous cases of acute myopathy and/or rhabdomyolysis have been reported, particularly following the outbreak of pandemic influenza A(H1N1 in 2009. The pathogenesis of these influenza-associated myopathies (IAM remains unkown, although the direct infection of muscle cells is suspected. Here, we studied the susceptibility of cultured human primary muscle cells to a 2009 pandemic and a 2008 seasonal influenza A(H1N1 isolate. Using cells from different donors, we found that differentiated muscle cells (i. e. myotubes were highly susceptible to infection by both influenza A(H1N1 isolates, whereas undifferentiated cells (i. e. myoblasts were partially resistant. The receptors for influenza viruses, α2-6 and α2-3 linked sialic acids, were detected on the surface of myotubes and myoblasts. Time line of viral nucleoprotein (NP expression and nuclear export showed that the first steps of the viral replication cycle could take place in muscle cells. Infected myotubes and myoblasts exhibited budding virions and nuclear inclusions as observed by transmission electron microscopy and correlative light and electron microscopy. Myotubes, but not myoblasts, yielded infectious virus progeny that could further infect naive muscle cells after proteolytic treatment. Infection led to a cytopathic effect with the lysis of muscle cells, as characterized by the release of lactate dehydrogenase. The secretion of proinflammatory cytokines by muscle cells was not affected following infection. Our results are compatible with the hypothesis of a direct muscle infection causing rhabdomyolysis in IAM patients.

  10. Relation among cytochrome P450, AH-active PCB congeners and dioxin equivalents in pipping black-crowned night-heron embryos

    Science.gov (United States)

    Rattner, B.A.; Hatfield, J.S.; Melancon, M.J.; Custer, T.W.; Tillitt, D.E.

    1994-01-01

    Pipping black-crowned night-heron (Nycticorax nycticorax) embryos were collected from a relatively uncontaminated site (next to Chincoteague National Wildlife Refuge, VA) and three polluted sites (Cat Island, Green Bay, Lake Michigan, WI; Bair Island, San Francisco Bay, CA; West Marin Island, San Francisco Bay, CA). Hepatic cytochrome P-450-associated monooxygenases and cytochrome P-450 proteins, induced up to 85-fold relative to the reference site, were associated with concentrations of total polychlorinated biphenyls (PCBs) and 11 PCB congeners that are presumed to express toxicity through the arylhydrocarbon (Ah) receptor. Multiple regression revealed that up to 86% of the variation of cytochrome P450 measurements was accounted for by variation in the concentration of these PCB congeners. Toxic equivalents (TEQs) of sample extracts, predicted mathematically (summed product of PCB congener concentrations and toxic equivalency factors), and dioxin equivalents (TCDD-EQs), derived by bioassay (ethoxyresorufin-O-dealkylase activity of treated H4IIE rat hepatoma cells), were greatest in Cat Island samples. Cytochrome P450-associated monooxygenases and cytochrome P450 proteins were related to TEQs and TCDD-EQs; adjusted r-2 often exceeded 0.5 for the relation among mathematically predicted TEQs and cytochrome P450 measurements. These data extend previous observations in heron embryos of an association between P450 and total PCB burdens to include Ah-active PCB congeners, and presumably other compounds, which interact similarly with the Ah receptor. Benzyloxyresorufin O-dealkylase, ethoxyresorufin O-dealkylase, and cytochrome P450 1A appear to be the most reliable measures of exposure to Ah-active PCB congeners in black-crowned night-heron embryos. These findings provide further evidence that cytochrome P450-associated parameters have considerable value as a biomarker for assessing environmental contamination of wetlands.

  11. Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Aneta Novotna

    Full Text Available Azole antifungal ketoconazole (KET was demonstrated to activate aryl hydrocarbon receptor (AhR. Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S-(+-KET and (2S,4R-(--KET, we examined the effects of KET enantiomers on AhR signaling pathway. (+-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR, and displayed 5-20× higher agonist activity (efficacy, as compared to (--KET; both enantiomers were AhR antagonists with equal potency (IC50. Consistently, (+-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells, while (--KET exerted less than 10% of (+-KET activity. In primary human hepatocytes, both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein, and the potency of (+-KET was slightly higher as compared to (--KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+-KET and (--KET are weak ligands of AhR that displaced [3H]-TCDD with comparable potency. Similarly, both enantiomers weakly transformed AhR to DNA-binding form with similar potency, as showed by EMSA, in guinea pig liver cytosolic extracts and nuclear extracts from mouse Hepa-1 cells. We also examined effects of KET on glucocorticoid receptor (GR, a regulator of AhR activity. Both KET enantiomers antagonized GR with similar potency, as revealed by gene reporter assay in AZ-GR cell line and down-regulation of tyrosine aminotransferase mRNA in human hepatocytes. Finally, we demonstrate enantiospecific antifungal activities of KET enantiomers in six Candida spp. strains. In conclusion, the significance of current study is providing the first evidence of enatiospecific effects of cis-enantiomers of ketoconazole on AhR-CYP1A pathway.

  12. Lower concentrations of receptor for advanced glycation end products and epiregulin in amniotic fluid correlate to chemically induced cleft palate in mice.

    Science.gov (United States)

    Wang, Xinhuan; Zhu, Jingjing; Fang, Yanjun; Bian, Zhuan; Meng, Liuyan

    2017-04-01

    This study investigated the correlation between differentially expressed proteins in amniotic fluid (AF) and cleft palate induced by all-trans retinoic acid (atRA), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Seven proteins were differentially expressed at embryonic day (E) 16.5 in atRA and control groups as revealed by label-based mouse antibody array. Enzyme-linked immunosorbent assay was further used to detect the expression levels of these proteins in AF from E13.5 to E16.5 in atRA, TCDD, and control groups. The cleft palate groups showed lower concentrations of receptor for advanced glycation end products (RAGE) and epiregulin at E16.5. RAGE immunostaining obviously decreased in palatal tissue sections obtained from E14.5 to E16.5 in the cleft palate groups as revealed by immunohistochemistry. These findings indicate that reduced levels of RAGE and epiregulin in AF are correlated to chemically induced cleft palate in mice. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Increased aryl hydrocarbon receptor expression in patients with allergic rhinitis.

    Science.gov (United States)

    Wei, P; Hu, G-H; Kang, H-Y; Yao, H-B; Kou, W; Liu, H; Hong, S-L

    2014-02-01

    A predominant Th17 population is a marker of allergic rhinitis (AR). As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) plays a vital role in promoting or inhibiting the development of specific Th cells. However, its role in AR remains undefined. To analyze the potential role of AhR in the pathogenesis of AR. In total, 30 AR patients and 13 healthy controls were recruited for this study and AR patients had clinical features, as demonstrated by rhinoconjunctivitis quality of life questionnaires, total symptom scores and visual analog scale scores. The expression of AhR, IL-17 and IL-22 and the presence of Th17 cells in peripheral blood mononuclear cells were measured before and after treatment with the nontoxic AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Pretreatment ITE studies revealed that all AR patients had a significant increase in AhR expression compared with controls and AhR expression positively correlated with clinical parameters. After ITE intervention, a severe reduction in the differentiation of Th17 cells and the production of IL-17 and IL-22 was noted in both AR patients and normal subjects. Simultaneously, a dramatic enhancement of AhR expression was also observed in all healthy controls, but not in AR patients. The results suggested that the AhR may be one of the mechanisms underlying the Th17 response during the pathogenesis of AR and AhR levels were closely related to clinical severity in all AR patients. Additionally, ITE may represent a new drug candidate in the treatment of AR.

  14. An endogenous aryl hydrocarbon receptor ligand inhibits proliferation and migration of human ovarian cancer cells.

    Science.gov (United States)

    Wang, Kai; Li, Yan; Jiang, Yi-Zhou; Dai, Cai-Feng; Patankar, Manish S; Song, Jia-Sheng; Zheng, Jing

    2013-10-28

    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor mediates many biological processes. Herein, we investigated if 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, an endogenous AhR ligand) regulated proliferation and migration of human ovarian cancer cells via AhR. We found that AhR was widely present in many histotypes of ovarian cancer tissues. ITE suppressed OVCAR-3 cell proliferation and SKOV-3 cell migration in vitro, which were blocked by AhR knockdown. ITE also suppressed OVCAR-3 cell growth in mice. These data suggest that the ITE might potentially be used for therapeutic intervention for at least a subset of human ovarian cancer. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. New genetic variants of influenza A(H1N1)pdm09 detected in Cuba during 2011-2013.

    Science.gov (United States)

    Arencibia, Amely; Acosta, Belsy; Muné, Mayra; Valdés, Odalys; Fernandez, Leandro; Medina, Isel; Savón, Clara; Oropesa, Suset; Gonzalez, Grehete; Roque, Rosmery; Gonzalez, Guelsys; Hernández, Bárbara; Goyenechea, Angel; Piñón, Alexander

    2015-06-01

    Influenza A(H1N1)pdm09 virus has evolved continually since its emergence in 2009. For influenza virus strains, genetic changes occurring in HA1 domain of the hemagglutinin cause the emergence of new variants. The aim of our study is to establish genetic associations between 35 A(H1N1)pdm09 viruses circulating in Cuba in 2011-2012 and 2012-2013 seasons, and A/California/07/2009 strain recommended by WHO as the H1N1 component of the influenza vaccine. The phylogenetic analysis revealed the circulation of clades 3, 6A, 6B, 6C and 7. Mutations were detected in the antigenic site or in the receptor-binding domains of HA1 segment, including S174P, S179N, K180Q, S202T, S220T and R222K. Substitutions S174P, S179N, K180Q and R222K were detected in Cuban strains for the first time. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. The morphological and chemical characteristics of striatal neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the rat.

    Science.gov (United States)

    Waldvogel, H J; Kubota, Y; Trevallyan, S C; Kawaguchi, Y; Fritschy, J M; Mohler, H; Faull, R L

    1997-10-01

    The distribution, morphology and chemical characteristics of neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the striatum of the basal ganglia in the rat brain were investigated at the light, confocal and electron microscope levels using single, double and triple immunohistochemical labelling techniques. The results showed that alpha1-subunit immunoreactive neurons were sparsely distributed throughout the rat striatum. Double and triple labelling results showed that all the alpha1-subunit-immunoreactive neurons were positive for glutamate decarboxylase and immunoreactive for the beta2,3 and gamma2 subunits of the GABA(A) receptor. Three types of alpha1-subunit-immunoreactive neurons were identified in the striatum on the basis of cellular morphology and chemical characteristics. The most numerous alpha1-subunit-immunoreactive neurons were medium-sized, aspiny neurons with a widely branching dendritic tree. They were parvalbumin-negative and were located mainly in the dorsolateral regions of the striatum. Electron microscopy showed that these neurons had an indented nuclear membrane, typical of striatal interneurons, and were surrounded by small numbers of axon terminals which established alpha1-subunit-immunoreactive synaptic contacts with the soma and dendrites. These cells were classified as type 1 alpha1-subunit-immunoreactive neurons and comprised 75% of the total population of alpha1-subunit-immunoreactive neurons in the striatum. The remaining alpha1-subunit-immunoreactive neurons comprised of a heterogeneous population of large-sized neurons localized in the ventral and medial regions of the striatum. The most numerous large-sized cells were parvalbumin-negative, had two to three relatively short branching dendrites and were designated type 2 alpha1-subunit-immunoreactive neurons. Electron microscopy showed that the type 2 neurons were characterized by a highly convoluted nuclear membrane and were sparsely covered with small axon

  17. An Exploratory Study of the Rhetoric in CSR Reports: A Comparison of Shari’ah Compliant Company and Non –Shari’ah Compliant Company in Malaysia

    OpenAIRE

    Abdul Razak Rafizan

    2017-01-01

    This paper advances previous research in corporate social reporting (CSR) by using a taxonomy of five distinct rhetorical strategies to examine any differences in term of type of ethical categories and to identify moral attitudes towards different societal activities between Shari’ah compliant company Bank Islam Malaysia Berhad (BIMB) and Non-Shari’ah compliant company Malayan Banking Berhad (Maybank). The data is analyzed using content analysis. The findings revealed that there are different...

  18. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    International Nuclear Information System (INIS)

    Zgoda-Pols, Joanna R.; Chowdhury, Swapan; Wirth, Mark; Milburn, Michael V.; Alexander, Danny C.; Alton, Kevin B.

    2011-01-01

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research highlights: → Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. → MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. → 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than

  19. Subclinical avian influenza A(H5N1) virus infection in human, Vietnam

    NARCIS (Netherlands)

    Le, Mai Quynh; Horby, Peter; Fox, Annette; Nguyen, Hien Tran; Le Nguyen, Hang Khanh; Hoang, Phuong Mai Vu; Nguyen, Khanh Cong; de Jong, Menno D.; Jeeninga, Rienk E.; Rogier van Doorn, H.; Farrar, Jeremy; Wertheim, Heiman F. L.

    2013-01-01

    Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern

  20. Towards locating the Nigerian Shari'ah Penal Codes' provisions for ...

    African Journals Online (AJOL)

    However, relatives of the murdered are at liberty to waive this and accept compensation money (diyah) or pardon the culprit absolutely. These provisions of the Sharī'ah were not in force in Nigeria until1999 when Zamfara State adopted Sharī'ah as its legal system and eleven other states later followed suit. With the creation ...

  1. Effects of currently used pesticides in the AhR-CALUX assay

    DEFF Research Database (Denmark)

    Long, Manhai; Laier, Peter; Vinggaard, Anne Marie

    2003-01-01

    101L hepatoma cell lines. In comparison the results indicated that the rat H4IIE cell line is more sensitive than the human TV101L for detection of TCDD inducing AhR-CALUX activity. The pesticides iprodione, chlorpyrifos and prochloraz showed dose-dependent AhR agonistic effects in both cell lines...

  2. 75 Ah and 10 boilerplate nickel-hydrogen battery designs and test results

    Science.gov (United States)

    Daman, M. E.; Manzo, Michelle A.; Chang, R.; Cruz, E.

    1992-01-01

    The results of initial characterization testing of 75 Ah actively cooled bipolar battery designs and 10 boilerplate nickel-hydrogen battery designs are presented. The results demonstrate the extended cycle life capability of the Ah batteries and the high capacity utilizations at various discharge rates of the nickel-hydrogen batteries.

  3. A historical perspective of influenza A(H1N2) virus.

    Science.gov (United States)

    Komadina, Naomi; McVernon, Jodie; Hall, Robert; Leder, Karin

    2014-01-01

    The emergence and transition to pandemic status of the influenza A(H1N1)A(H1N1)pdm09) virus in 2009 illustrated the potential for previously circulating human viruses to re-emerge in humans and cause a pandemic after decades of circulating among animals. Within a short time of the initial emergence of A(H1N1)pdm09 virus, novel reassortants were isolated from swine. In late 2011, a variant (v) H3N2 subtype was isolated from humans, and by 2012, the number of persons infected began to increase with limited person-to-person transmission. During 2012 in the United States, an A(H1N2)v virus was transmitted to humans from swine. During the same year, Australia recorded its first H1N2 subtype infection among swine. The A(H3N2)v and A(H1N2)v viruses contained the matrix protein from the A(H1N1)pdm09 virus, raising the possibility of increased transmissibility among humans and underscoring the potential for influenza pandemics of novel swine-origin viruses. We report on the differing histories of A(H1N2) viruses among humans and animals.

  4. Discharge of 1400 AH lithium thionyl chloride cells into voltage reversal

    Science.gov (United States)

    Zolla, A. E.

    1982-03-01

    The development of a high energy density battery is discussed. Tests were conducted on a 1400 AH cell and they include: drop tests, crush tests, vibration and shock tests, hydrostatic pressure effects, charge current tests, and discharge tests. None of these tests led to a venting or explosion of the cell. Criteria are presented for extending RV safety of a 1400 AH cell.

  5. Human Infection with Avian Influenza A(H7N9) Virus - China

    Science.gov (United States)

    ... response operations Diseases Biorisk reduction Disease outbreak news Human infection with avian influenza A(H7N9) virus – China ... Region (SAR) notified WHO of a laboratory-confirmed human infection with avian influenza A(H7N9) virus and ...

  6. Spinal Pain and Occupational Disability: A Cohort Study of British Apache AH Mk1 Pilots

    Science.gov (United States)

    2013-09-01

    British RW community. 33 References Apache AH Mk1. 2012. Agusta Westland. http://www.agustawestland.com/ product /apache-ah- mk1-0. Ang, B., and...muscles Physical ex and stretching Continued pt and stretching exercises Use pt session included pumpkin bobs to stretch the neck. No effects noticed

  7. Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital.

    Science.gov (United States)

    Schraplau, Anne; Schewe, Bettina; Neuschäfer-Rube, Frank; Ringel, Sebastian; Neuber, Corinna; Kleuser, Burkhard; Püschel, Gerhard P

    2015-02-03

    Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. Copyright © 2014. Published by Elsevier Ireland Ltd.

  8. Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital

    International Nuclear Information System (INIS)

    Schraplau, Anne; Schewe, Bettina; Neuschäfer-Rube, Frank; Ringel, Sebastian; Neuber, Corinna; Kleuser, Burkhard; Püschel, Gerhard P.

    2015-01-01

    Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR

  9. Aryl hydrocarbon receptor-dependent regulation of miR-196a expression controls lung fibroblast apoptosis but not proliferation

    International Nuclear Information System (INIS)

    Hecht, Emelia; Zago, Michela; Sarill, Miles; Rico de Souza, Angela; Gomez, Alvin; Matthews, Jason; Hamid, Qutayba; Eidelman, David H.; Baglole, Carolyn J.

    2014-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor implicated in the regulation of apoptosis and proliferation. Although activation of the AhR by xenobiotics such as dioxin inhibits the cell cycle and control apoptosis, paradoxically, AhR expression also promotes cell proliferation and survival independent of exogenous ligands. The microRNA (miRNA) miR-196a has also emerged as a regulator of proliferation and apoptosis but a relationship between the AhR and miR-196a is not known. Therefore, we hypothesized that AhR-dependent regulation of endogenous miR-196a expression would promote cell survival and proliferation. Utilizing lung fibroblasts from AhR deficient (AhR −/− ) and wild-type (AhR +/+ ) mice, we show that there is ligand-independent regulation of miRNA, including low miR-196a in AhR −/− cells. Validation by qRT-PCR revealed a significant decrease in basal expression of miR-196a in AhR −/− compared to AhR +/+ cells. Exposure to AhR agonists benzo[a]pyrene (B[a]P) and FICZ as well as AhR antagonist CH-223191 decreased miR-196a expression in AhR +/+ fibroblasts concomitant with decreased AhR protein levels. There was increased proliferation only in AhR +/+ lung fibroblasts in response to serum, corresponding to a decrease in p27 KIP1 protein, a cyclin-dependent kinase inhibitor. Increasing the cellular levels of miR-196a had no effect on proliferation or expression of p27 KIP1 in AhR −/− fibroblasts but attenuated cigarette smoke-induced apoptosis. This study provides the first evidence that AhR expression is essential for the physiological regulation of cellular miRNA levels- including miR-196a. Future experiments designed to elucidate the functional relationship between the AhR and miR-196a may delineate additional novel ligand-independent roles for the AhR. - Highlights: • The AhR controls proliferation and apoptosis in lung cells. • The AhR regulates the expression of the microRNA miR-196a independent of

  10. Aryl hydrocarbon receptor-dependent regulation of miR-196a expression controls lung fibroblast apoptosis but not proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Hecht, Emelia [Department of Medicine, McGill University, Montreal, Quebec (Canada); Zago, Michela [Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Sarill, Miles [Department of Medicine, McGill University, Montreal, Quebec (Canada); Rico de Souza, Angela [Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Gomez, Alvin; Matthews, Jason [Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON (Canada); Hamid, Qutayba; Eidelman, David H. [Department of Medicine, McGill University, Montreal, Quebec (Canada); Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Baglole, Carolyn J., E-mail: Carolyn.baglole@McGill.ca [Department of Medicine, McGill University, Montreal, Quebec (Canada); Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada)

    2014-11-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor implicated in the regulation of apoptosis and proliferation. Although activation of the AhR by xenobiotics such as dioxin inhibits the cell cycle and control apoptosis, paradoxically, AhR expression also promotes cell proliferation and survival independent of exogenous ligands. The microRNA (miRNA) miR-196a has also emerged as a regulator of proliferation and apoptosis but a relationship between the AhR and miR-196a is not known. Therefore, we hypothesized that AhR-dependent regulation of endogenous miR-196a expression would promote cell survival and proliferation. Utilizing lung fibroblasts from AhR deficient (AhR{sup −/−}) and wild-type (AhR{sup +/+}) mice, we show that there is ligand-independent regulation of miRNA, including low miR-196a in AhR{sup −/−} cells. Validation by qRT-PCR revealed a significant decrease in basal expression of miR-196a in AhR{sup −/−} compared to AhR{sup +/+} cells. Exposure to AhR agonists benzo[a]pyrene (B[a]P) and FICZ as well as AhR antagonist CH-223191 decreased miR-196a expression in AhR{sup +/+} fibroblasts concomitant with decreased AhR protein levels. There was increased proliferation only in AhR{sup +/+} lung fibroblasts in response to serum, corresponding to a decrease in p27{sup KIP1} protein, a cyclin-dependent kinase inhibitor. Increasing the cellular levels of miR-196a had no effect on proliferation or expression of p27{sup KIP1} in AhR{sup −/−} fibroblasts but attenuated cigarette smoke-induced apoptosis. This study provides the first evidence that AhR expression is essential for the physiological regulation of cellular miRNA levels- including miR-196a. Future experiments designed to elucidate the functional relationship between the AhR and miR-196a may delineate additional novel ligand-independent roles for the AhR. - Highlights: • The AhR controls proliferation and apoptosis in lung cells. • The AhR regulates the

  11. Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells

    International Nuclear Information System (INIS)

    Brinkman, Ashley M; Wu, Jiacai; Ersland, Karen; Xu, Wei

    2014-01-01

    Numerous studies have implicated the aryl hydrocarbon receptor (AhR) as a potential therapeutic target for several human diseases, including estrogen receptor alpha (ERα) positive breast cancer. Aminoflavone (AF), an activator of AhR signaling, is currently undergoing clinical evaluation for the treatment of solid tumors. Of particular interest is the potential treatment of triple negative breast cancers (TNBC), which are typically more aggressive and characterized by poorer outcomes. Here, we examined AF’s effects on two TNBC cell lines and the role of AhR signaling in AF sensitivity in these model cell lines. AF sensitivity in MDA-MB-468 and Cal51 was examined using cell counting assays to determine growth inhibition (GI 50 ) values. Luciferase assays and qPCR of AhR target genes cytochrome P450 (CYP) 1A1 and 1B1 were used to confirm AF-mediated AhR signaling. The requirement of endogenous levels of AhR and AhR signaling for AF sensitivity was examined in MDA-MB-468 and Cal51 cells stably harboring inducible shRNA for AhR. The mechanism of AF-mediated growth inhibition was explored using flow cytometry for markers of DNA damage and apoptosis, cell cycle analysis, and β-galactosidase staining for senescence. Luciferase data was analyzed using Student’s T test. Three-parameter nonlinear regression was performed for cell counting assays. Here, we report that ERα-negative TNBC cell lines MDA-MB-468 and Cal51 are sensitive to AF. Further, we presented evidence suggesting that neither endogenous AhR expression levels nor downstream induction of AhR target genes CYP1A1 and CYP1B1 is required for AF-mediated growth inhibition in these cells. Between these two ERα negative cell lines, we showed that the mechanism of AF action differs slightly. Low dose AF mediated DNA damage, S-phase arrest and apoptosis in MDA-MB-468 cells, while it resulted in DNA damage, S-phase arrest and cellular senescence in Cal51 cells. Overall, this work provides evidence against the

  12. Inhibition of the MEK-1/p42 MAP kinase reduces aryl hydrocarbon receptor-DNA interactions

    International Nuclear Information System (INIS)

    Yim, Sujin; Oh, Myoungsuk; Choi, Su Mi; Park, Hyunsung

    2004-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces expression of the cytochrome P450 1A1 gene, cyp1a1, by binding to its receptor, aryl hydrocarbon receptor (AhR). TCDD-bound AhR translocates to the nucleus and forms a heterodimer with its partner protein, AhR nuclear translocator (Arnt). The AhR/Arnt heterodimer then binds to the dioxin-response elements (DREs) in the cyp1a1 enhancer and stimulates transcription of cyp1a1. We tested whether kinase pathways are involved in this process by treating Hepa1c1c7 cells with kinase inhibitors. The MEK-1 inhibitor PD98059 reduced TCDD-induced transcription of cyp1a1. TCDD treatment results in phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK), a substrate of MEK-1. Overexpression of dominant negative form of p42 MAPK suppressed TCDD-dependent transcription of a reporter gene controlled by dioxin-response elements (DREs), and pretreatment with PD98059 also blocked this transcription. PD98059 pretreatment also inhibited TCDD-induced DRE binding of the AhR/Arnt heterodimer. Together these results indicate that TCDD activates the MEK-1/p44/p42 MAPK pathway, which in turn activates AhR and so facilitates binding of AhR to the cyp1a1 DRE

  13. DESAKAN SOSIOPOLITIK MUNCULNYA GAGASAN EVOLUSI SYARÎ'AH OLEH AN-NA’IM

    Directory of Open Access Journals (Sweden)

    Mohammad Hefni

    2014-10-01

    Full Text Available Semenjak abad ke-19 M, telah tumbuh perjumpaan intensifantara dunia Muslim dengan peradaban Barat, yangmelahirkan implikasi yang cukup mencengangkan bagiperubahan struktur sosial dunia Muslim. Ketika dunia Muslimmeraih kembali independensinya secara politik daricengkeraman imperialisme dan hegemoni Barat pada abad ke-20 M, salah satu persoalan yang muncul kemudian adalahbagaimana memosisikan syarî'ah dan menjabarkannya kedalam sebuah formulasi yang ideal dan aktual agar mampumengakomodasikan seluruh warga negara dengan latarbelakang suku dan agama yang heterogen. Karenanya, iamenawarkan gagasan evolusi syarî'ah yang meniscayakansyarî'ah dapat menyahuti isu-isu penting bagi masa depankemanusiaan. Dalam membangun gagasannya tentang evolusisyarî’ah, An-Na’im menggunakan teori naskh. Naskh, menurutAn-Na’im, adalah menghapus ayat-ayat Madâniyah denganayat-ayat Makkiyah. Gagasan evolusi syarî’ah dilatarbelakangioleh setting sosiopolitik Sudan sebelum pecah menjadi SudanUtara dan Sudan Selatan.

  14. Structure and receptor binding preferences of recombinant hemagglutinins from avian and human H6 and H10 influenza A virus subtypes.

    Science.gov (United States)

    Yang, Hua; Carney, Paul J; Chang, Jessie C; Villanueva, Julie M; Stevens, James

    2015-04-01

    During 2013, three new avian influenza A virus subtypes, A(H7N9), A(H6N1), and A(H10N8), resulted in human infections. While the A(H7N9) virus resulted in a significant epidemic in China across 19 provinces and municipalities, both A(H6N1) and A(H10N8) viruses resulted in only a few human infections. This study focuses on the major surface glycoprotein hemagglutinins from both of these novel human viruses. The detailed structural and glycan microarray analyses presented here highlight the idea that both A(H6N1) and A(H10N8) virus hemagglutinins retain a strong avian receptor binding preference and thus currently pose a low risk for sustained human infections. Human infections with zoonotic influenza virus subtypes continue to be a great public health concern. We report detailed structural analysis and glycan microarray data for recombinant hemagglutinins from A(H6N1) and A(H10N8) viruses, isolated from human infections in 2013, and compare them with hemagglutinins of avian origin. This is the first structural report of an H6 hemagglutinin, and our results should further the understanding of these viruses and provide useful information to aid in the continuous surveillance of these zoonotic influenza viruses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ya-Hsin [Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China); Huang, Su-Chin; Lin, Chun-Ju; Cheng, Li-Chuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China); Li, Lih-Ann, E-mail: lihann@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China)

    2012-03-15

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

  17. AhR- and ER-mediated activities in human blood samples collected from PCB-contaminated and background region in Slovakia

    Energy Technology Data Exchange (ETDEWEB)

    Pliskova, M. [Veterinary Researcch Institute, Brno (Czech Republic); Canton, R.F.; Duursen, M.B.M. van [Utrecht Univ. (NL). Institute for Risk Assessment Sciences (IRAS)] (and others)

    2004-09-15

    Endocrine disruption mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) by polychlorinated biphenyls (PCBs) and other persistent organic pollutants (POPs) has been studied extensively both in vivo and in vitro. Non-ortho- and mono-ortho-substituted polychlorinated biphenyls (PCBs) are potent AhR agonists therefore, increased dioxin-like activity of complex blood samples might reflect an increased exposure to PCBs. The induction of expression of CYP1A1 and CYP1B1 in different tissues, including lymphocytes, also depends on activation of AhR and it could be useful as a potential biomarker of exposure to dioxin-like compounds. Using various in vivo and in vitro models, the exposure to PCBs or hydroxy-PCBs has been reported to lead to either induction of ER-mediated activity or to an antiestrogenic effect associated with a suppression of estradiol-induced ER-dependent gene expression. Nevertheless, relative (anti)estrogenic potencies of a large set of prevalent environmental PCBs have not been yet compared in a single bioassay. A cross-talk between AhR and ER has been suggested to lead to a suppression of ER-mediated gene expression. Therefore, presence of dioxin-like compounds in blood could potentially suppress the ER-mediated activity. Additionally, AhR-dependent induction of CYP1A1 and especially CYP1B1, two enzymes involved in oxidative metabolism of estradiol and other estrogens, might enhance the metabolism of estradiol and it has been suggested to cause a potential depression of estrogen levels in the body. The aim of the present study was to determine dioxin-like, estrogenic and antiestrogenic activities in human blood samples collected in two Eastern Slovakia regions differently polluted with PCBs using established in vitro bioassays. We also studied mRNA expression of CYP1A1 and 1B1 in lymphocytes and the genotypes of CYP1B1 as possible biomarkers of exposure for PCBs and related compounds. The biological data obtained

  18. Airborne urban particles (Milan winter-PM2.5) cause mitotic arrest and cell death: Effects on DNA, mitochondria, AhR binding and spindle organization

    Energy Technology Data Exchange (ETDEWEB)

    Gualtieri, Maurizio [Applied Cell Biology and Particles Effects, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Ovrevik, Johan [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Mollerup, Steen [Section for Toxicology, National Institute of Occupational Health, N-0033 Oslo (Norway); Asare, Nana [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Longhin, Eleonora [Applied Cell Biology and Particles Effects, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Dahlman, Hans-Jorgen [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Camatini, Marina [Applied Cell Biology and Particles Effects, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Centre Research POLARIS, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Holme, Jorn A., E-mail: jorn.holme@fhi.no [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway)

    2011-08-01

    Highlights: {yields} PM2.5 induces mitotic arrest in BEAS-2B cells. {yields} PM2.5 induces DNA damage and activates DNA damage response. {yields} AhR regulated genes (Cyp1A1, Cyp1B1 and AhRR) are upregulated after PM exposure. {yields} Mitotic spindle assembly is perturbed in PM exposed cells. - Abstract: Airborne particulate matter (PM) is considered to be an important contributor to lung diseases. In the present study we report that Milan winter-PM2.5 inhibited proliferation in human bronchial epithelial cells (BEAS-2B) by inducing mitotic arrest. The cell cycle arrest was followed by an increase in mitotic-apoptotic cells, mitotic slippage and finally an increase in 'classical' apoptotic cells. Exposure to winter-PM10 induced only a slight effect which may be due to the presence of PM2.5 in this fraction while pure combustion particles failed to disturb mitosis. Fewer cells expressing the mitosis marker phospho-histone H3 compared to cells with condensed chromosomes, suggest that PM2.5 induced premature mitosis. PM2.5 was internalized into the cells and often localized in laminar organelles, although particles without apparent plasma membrane covering were also seen. In PM-containing cells mitochondria and lysosomes were often damaged, and in mitotic cells fragmented chromosomes often appeared. PM2.5 induced DNA strands breaks and triggered a DNA-damage response characterized by increased phosphorylation of ATM, Chk2 and H2AX; as well as induced a marked increase in expression of the aryl hydrocarbon receptor (AhR)-regulated genes, CYP1A1, CYP1B1 and AhRR. Furthermore, some disturbance of the organization of microtubules was indicated. It is hypothesized that the induced mitotic arrest and following cell death was due to a premature chromosome condensation caused by a combination of DNA, mitochondrial and spindle damage.

  19. Aryl hydrocarbon receptor-dependent retention of nuclear HuR suppresses cigarette smoke-induced cyclooxygenase-2 expression independent of DNA-binding.

    Science.gov (United States)

    Zago, Michela; Sheridan, Jared A; Nair, Parameswaran; Rico de Souza, Angela; Gallouzi, Imed-Eddine; Rousseau, Simon; Di Marco, Sergio; Hamid, Qutayba; Eidelman, David H; Baglole, Carolyn J

    2013-01-01

    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to man-made environmental toxicants, has emerged as an endogenous regulator of cyclooxygenase-2 (Cox-2) by a mechanism that is poorly understood. In this study, we first used AhR-deficient (AhR(-/-) ) primary pulmonary cells, together with pharmacological tools to inhibit new RNA synthesis, to show that the AhR is a prominent factor in the destabilization of Cox-2 mRNA. The destabilization of Cox-2 mRNA and subsequent suppression of cigarette smoke-induced COX-2 protein expression by the AhR was independent of its ability to bind the dioxin response element (DRE), thereby differentiating the DRE-driven toxicological AhR pathway from its anti-inflammatory abilities. We further describe that the AhR destabilizes Cox-2 mRNA by sequestering HuR within the nucleus. The role of HuR in AhR stabilization of Cox-2 mRNA was confirmed by knockdown of HuR, which resulted in rapid Cox-2 mRNA degradation. Finally, in the lungs of AhR(-/-) mice exposed to cigarette smoke, there was little Cox-2 mRNA despite robust COX-2 protein expression, a finding that correlates with almost exclusive cytoplasmic HuR within the lungs of AhR(-/-) mice. Therefore, we propose that the AhR plays an important role in suppressing the expression of inflammatory proteins, a function that extends beyond the ability of the AhR to respond to man-made toxicants. These findings open the possibility that a DRE-independent AhR pathway may be exploited therapeutically as an anti-inflammatory target.

  20. PENILAIAN KINERJA FISIK (MATERI KOPERASI SYARI’AH MENURUT PERSPEKTIF SHARI’ATE ENTERPRISE THEORY DENGAN NILAI TAMBAH SYARI’AH DAN ZAKAT SEBAGAI INDIKATOR

    Directory of Open Access Journals (Sweden)

    Elvyra Handayani Soedarso

    2013-12-01

    Full Text Available The results of the assessment on the performance of sharia cooperatives are strongly influenced by the analytical tools used. Analyzes that have been there only focused on a mere financial perspective with the meaning of finances limited to property or material. Whereas should the assessment of Sharia cooperative performance should be more comprehensive and comprehensive considering the role and function of Shari'ah cooperative which is not only limited to profit oriented but also non profit oriented. Assessment of Shari'ah cooperative performance according to shari'ate enterprise theory perspective assesses the performance of three forms of reality: physical reality, psychic reality and spiritual reality. Performance appraisal of physical reality is viewed from the perspective of financial piety, mental and social reality seen from the perspective of mental and social piety and spiritual reality seen from the perspective of spiritual piety. In this study, the discussion is limited only to the assessment of the physical performance of Shari'ah cooperatives by using the added value of Shariah and Zakat as an indicator of its assessment. The results showed that Sharia Added Value as the first indicator used to assess the physical performance of Shari'ah cooperatives assessed performance based on economic added value, mental added value and spiritual added value. While zakat as the second indicator of physical performance of Shari'ah cooperative is the transformation from the achievement of net profit to the achievement of zalcat, by using the object of zakat appraisal that is optimum.

  1. Kontroversi Produk Bank Sharî‘ah

    Directory of Open Access Journals (Sweden)

    Abdul Rokhim

    2014-01-01

    Full Text Available This paper discusses the views of Muslims on the nature and legitimacy of bank interest as far as Syari’ah law is concerned. Three views are presented here. First is the view of the neo-revivalists who argue that bank interest is legally illegitimate and that it is a form of riba. Second is the view of—among others—Fazlur Rahman who believes that bank interest is not riba. And third is the view that bank interest is in the state of legal doubtfulness (shubhat. We do not support particular view in this paper. But in principle it seems particularly legitimate to argue that Islam is a religion of social wellbeing in which any transaction should be free from such illegitimate practices as riba, gharar (cheating, and financial speculation. However, we also argue that bank interest is too complicated to be equated with riba. There are no accepted standards and qualifications by which the two can be said as the same. To this complex issue we dedicate our paper as a contribution to the issue at hand.

  2. PENGEMBANGAN BAHAN AJAR (BMK DENGAN MODEL METODE QIRO’AH

    Directory of Open Access Journals (Sweden)

    Abdul Muis

    2016-10-01

    Full Text Available Islamic education learning is a learning that has many a role in knowledge. It caused religion is becoming guide for all of human being Islamic in the world. Besides, Islamic religion is able to guarantee a requirement life all mankind either in the world or the hereafter. Therefore, presumably in teaching and learning Islamic religion education, a teacher should have many a matter learning that variously and be able to implement it. One of it is the development of material with Qiro’ati model which is teacher guidance student as well. The material before need to be renovating in order that the material can be running well and appropriate with next era it will be felt by student. The alteration cannot be avoided again, in order that it become requirement human being Islam, but the alteration who doesn’t come out from regulation Islamic precept who has been teaching it. So that, the material lesson is possible give opportunity to the teacher Islamic religion education always actively do learning process that agree with institution of Islamic education requirement. The focus this research is how the effectively of material Islamic religion education with Qiro’ah model?

  3. BATAS USIA NAFKAH ANAK BERDASARKAN MAQASID AL-SYARI‘AH

    Directory of Open Access Journals (Sweden)

    Marwan Marwan

    2014-02-01

    Full Text Available The stipulation of the age limit of child’s livelihood based on to the number of year is important to do, because standard of age maturity (not child authonomy that has been used can lead to the harm to the child who has been in age maturity but she or he is not authonomous yet. On the other hand, the lack of independent age limit can be burden to the parents, because granting a living become limitless. The age limit is not available through the texts of the Shari‘a, therefore, it should be studied by using uṣūl al-fiqh approach (maqāṣid al-syarī‘ah. This study use mixed method; deductive and inductive. The findings were analyzed by using istiṣlāḥiyyah reasoning patterns. Based on this study, it was concluded that the limit of liability of parents for their children is until the child reaches the age of 23 years. Because at the age of 22 years, children in Indonesia generally have completed undergraduate. So at least it takes a year to prepare for finding a job to pay for his life before actually independent living. In addition, there are companies in Indonesia generally limits the prospective new employee at the age of 25 years.

  4. Novel Chemical Strategies for Labeling Small Molecule Ligands for Androgen, Progestin, and Peroxisome Proliferator-Activated Receptors for Imaging Prostate and Breast Cancer and the Heart

    International Nuclear Information System (INIS)

    Katzenellenbogen, John A.

    2007-01-01

    Summary of Progress The specific aims of this project can be summarized as follows: Aim 1: Prepare and evaluate radiolabeled ligands for the peroxisome proliferator-activated receptor γ (PPARγ), a new nuclear hormone receptor target for tumor imaging and hormone therapy. Aim 2: Prepare steroids labeled with a cyclopentadienyl tricarbonyl technetium or rhenium unit. Aim 3: Prepare and evaluate other organometallic systems of novel design as ligand mimics and halogenated ligands for nuclear hormone receptor-based tumor imaging. As is described in detail in the report, we made excellent progress on all three of these aims; the highlights of our progress are the following: (1) we have prepared the first fluorine-18 labeled analogs of ligands for the PPARγ receptor and used these in tissue distribution studies in rats; (2) we have developed three new methods for the synthesis of cyclopentadienyltricarbonyl rhenium and technetium (CpRe(CO)3 and CpTc(CO)3) systems and we have adapted these to the synthesis of steroids labeled with these metals, as well as ligands for other receptor systems; (3) we have prepared a number of fluorine-18 labeled steroidal and non-steroidal androgens and measured their tissue distribution in rats; (4) we have prepared iodine and bromine-labeled progestins with high progesterone receptor binding affinity; and (5) we have prepared inorganic metal tricarbonyl complexes and steroid receptor ligands in which the metal tricarbonyl unit is an integral part off the ligand core

  5. A Historical Perspective of Influenza A(H1N2) Virus

    OpenAIRE

    Komadina, Naomi; McVernon, Jodie; Hall, Robert; Leder, Karin

    2014-01-01

    The emergence and transition to pandemic status of the influenza A(H1N1)A(H1N1)pdm09) virus in 2009 illustrated the potential for previously circulating human viruses to re-emerge in humans and cause a pandemic after decades of circulating among animals. Within a short time of the initial emergence of A(H1N1)pdm09 virus, novel reassortants were isolated from swine. In late 2011, a variant (v) H3N2 subtype was isolated from humans, and by 2012, the number of persons infected began to increase ...

  6. A comparison of 802.11ah and 802.15.4 for IoT

    Directory of Open Access Journals (Sweden)

    N. Ahmed

    2016-09-01

    Full Text Available The emerging IEEE 802.11ah is a promising communication standard that supports a massive number of heterogeneous devices in the Internet of Things (IoT. It provides attractive features like improved scalability, low energy consumption, and coverage of large area. In this paper, we analyze the performance of IEEE 802.11ah, and compare it with a prominent alternative, the IEEE 802.15.4. The simulation results show that the new 802.11ah standard performs better than the 802.15.4 in terms of association time, throughput, delay, and coverage range.

  7. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  8. Technical structure of Complaint Poetry Until 3 A.H

    Directory of Open Access Journals (Sweden)

    2010-12-01

    Full Text Available Technical structure of Complaint Poetry Until 3 A.H       * Gholam Abbas Rezai   * * Sherafat Karimi     Abstract   Complaint refers to the poetic works in which the poet talks about the Vehemence of his/her painful feeling. It is the description of pains, personal and social problems and in a way is confiding whatever has annoyed his/her soul and body. Complaint can be categorized into social and personal ones. The personal complaints composed at the time of Islam were generally complaining about the Time, death, aging and separation from the beloved. This was due to the poets' shallow viewpoint on life and their nihilistic inclinations. These subjects were still present in first three centuries and were added by new subjects such as complaining about sensual desires.   The general characteristic, style, structure and elements of meaning were simplicity in word and meaning , sincere and ample feeling, using many words with denotative meanings, utilizing maxims, proverbs and wise sayings, rhetorical statements, rich cadence (musical tones, as well as uniformity and simple imagination. Complaint is an independent poetic technique which as a result of the close relation to other sorts of poetic subjects is threaded through various sorts of elegy and sometimes is composed as an independent elegy.     Key words : Complaint Poetry Structure Style Poetic Subject       * Associate Professor, Department of Arabic Language and Literature, university of Tehran . E-mail: GHREZAEE@UT.AC.IR .   ** PhD .candidate university of Tehran .E-mail: KARIMI.SHARAFAT@yahoo.com

  9. Imaging of sigma receptors in tumors by PET with [C-11]SA4503

    International Nuclear Information System (INIS)

    Kawamura, K.; Kobayashi, T.; Oda, K.; Ishiwata, K.; Kubota, K.

    2002-01-01

    Aim: Sigma receptors are implicated in some diseases in the central nervous system (CNS), such as schizophrenia, depression, dementia and ischemia, and are also expressed in a variety of human tumors, such as melanoma, carcinoma of the breast, lung and prostate, and the brain tumor. Therefore, several radioligands have been proposed for imaging of sigma receptors by positron emission tomography (PET) and by single photon emission computed tomography. Recently, we have applied [C-11]labeled 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([C-11]SA4503) to mapping sigma1 receptors in the brain of monkeys and human. In the present study, we evaluated the potential of the [C-11]SA4503 PET for imaging of sigma receptors using the AH109A bearing rats, and the VX-2 carcinoma bearing rabbits. Materials and Methods: [C-11]SA4503 was injected i.v. into AH109A bearing rats, and the tissue distribution was measured by tissue dissection. To determine the receptor-specific uptake, cold SA4503 or haloperidol was co-injected into the other group of rats. The PET scanning were performed in the rats in the baseline condition and after pretreatment with haloperidol. In the VX-2 carcinoma bearing rabbits, PET scanning was also performed in the baseline and blockade conditions. The sigma receptors in the AH109A and VX-2 were measured in vitro by the standard membrane binding assays. Results: The sigma receptors were found in AH109A and VX-2. The density was much higher in VX-2 than in AH109A. In the tissue dissection study, the AH109A uptake of [C-11]SA4503 increased for 60 min after injection. By the co-injection of SA4503 or haloperidol, the AH109A uptake was enhanced. The PET study also confirmed that the radioactivity level in the AH109A was enhanced by the pretreatment with haloperidol. On the other hand, In the VX-2 carcinoma bearing rabbits, the radioactivity level of in VX-2 remained constant after initial uptake in the baseline PET measurement, but the VX-2 uptake was

  10. Influence of Shari'ah on Socio-Cultural and Economic Development ...

    African Journals Online (AJOL)

    This study investigated the socio-economic influence of Shari'ah marketing practices in Northwestern ... production, societal marketing, marketing orientation and selling practices were correlated with ... EMAIL FULL TEXT EMAIL FULL TEXT

  11. Comparative Resistance of AH26 and a New Sealer Prototype to a Bacterial Challenge

    Directory of Open Access Journals (Sweden)

    Derek Duggan

    2012-01-01

    Full Text Available Objective. This study compared the leakage resistance of a New Sealer Prototype (NSP with a traditional sealer (AH 26 in Resilon-filled roots subjected to a bacterial challenge. Study Design. 41 roots were instrumented to ISO size 50 apically. Group 1 (=20 contained Resilon and AH 26 sealer and roots in group 2 (=21 contained Resilon and NSP. Roots were embedded in a dual-chamber model with the upper chamber containing Streptococcus mutans inoculum. Evidence of bacterial penetration was observed for 1 month. Fisher's Test was used to analyze the data. Results. 8 of 20 roots (40% in the AH 26 group demonstrated leakage whereas 3 of 21 roots (14% in the NSP group leaked. The difference in leakage rates was not statistically significant (=0.053. Conclusion. The traditional sealer (AH 26 demonstrated increased leakage rates compared to the New Sealer Prototype (NSP, but the difference did not reach statistical significance in this study.

  12. A Comparison of AH-64 Pilot Attitudes Toward Traditional and Glass Cockpit Crewstation Designs

    National Research Council Canada - National Science Library

    Francis, Gregory

    2002-01-01

    .... This finding suggested that the differences of crewstation design needed to be examined. To identify significant differences, this study assessed pilots' attitudes toward traditional and glass cockpit designs in the AH-64 Apache helicopter...

  13. Comparison of Portfolio Selection and Performance: Shari’ah-Compliant and Socially Responsible Investment Portfolios

    Directory of Open Access Journals (Sweden)

    Mehmet Asutay

    2015-04-01

    Full Text Available This study examines the effect of Islamic screening criteria on Shari’ah-compliant portfolio selection and performance compared to Socially Responsible Investment (SRI portfolio. Each portfolio constructed from 15 stocks based on FTSE 100 using data from year 1997. Mean-variance portfolio optimization is employed with some financial ratios added as constraints for the Shari’ah portfolio. Annual expected return of each portfolio from 2008 to 2013 is used to calculate Sharpe’s ratio, Treynor ratio and Jensen’s alpha as the performance measurement tools. Macroeconomic variables are assessed using ordinary least square to examine whether they influence the portfolios’ expected returns or not. The result finds that Shari’ah portfolio has a better performance than SRI from year 2008 to 2010 shown by higher value of the measurement tools. However, from 2011 to 2013, SRI portfolio has better performance than Shari’ah portfolio. 

  14. Tissue-specific expression of aryl hydrocarbon receptor and putative developmental regulatory modules in Baltic salmon yolk-sac fry

    Energy Technology Data Exchange (ETDEWEB)

    Vuori, Kristiina A. [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland)], E-mail: kristiina.vuori@utu.fi; Nordlund, Eija [Department of Information Technology, University of Turku, and Turku Centre for Computer Science (TUCS), FI-20014 Turku (Finland); Kallio, Jenny [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland); Salakoski, Tapio [Department of Information Technology, University of Turku, and Turku Centre for Computer Science (TUCS), FI-20014 Turku (Finland); Nikinmaa, Mikko [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland)

    2008-04-08

    The aryl hydrocarbon receptor (AhR) is an ancient protein that is conserved in vertebrates and invertebrates, indicating its important function throughout evolution. AhR has been studied largely because of its role in toxicology-gene expression via AhR is induced by many aromatic hydrocarbons in mammals. Recently, however, it has become clear that AhR is involved in various aspects of development such as cell proliferation and differentiation, and cell motility and migration. The mechanisms by which AhR regulates these various functions remain poorly understood. Across-species comparative studies of AhR in invertebrates, non-mammalian vertebrates and mammals may help to reveal the multiple functions of AhR. Here, we have studied AhR during larval development of Baltic salmon (Salmon salar). Our results indicate that AhR protein is expressed in nervous system, liver and muscle tissues. We also present putative regulatory modules and module-matching genes, produced by chromatin immunoprecipitation (ChIP) cloning and in silico analysis, which may be associated with evolutionarily conserved functions of AhR during development. For example, the module NFKB-AHRR-CREB found from salmon ChIP sequences is present in human ULK3 (regulating formation of granule cell axons in mouse and axon outgrowth in Caernohabditis elegans) and SRGAP1 (GTPase-activating protein involved in the Slit/Robo pathway) promoters. We suggest that AhR may have an evolutionarily conserved role in neuronal development and nerve cell targeting, and in Wnt signaling pathway.

  15. Tissue-specific expression of aryl hydrocarbon receptor and putative developmental regulatory modules in Baltic salmon yolk-sac fry

    International Nuclear Information System (INIS)

    Vuori, Kristiina A.; Nordlund, Eija; Kallio, Jenny; Salakoski, Tapio; Nikinmaa, Mikko

    2008-01-01

    The aryl hydrocarbon receptor (AhR) is an ancient protein that is conserved in vertebrates and invertebrates, indicating its important function throughout evolution. AhR has been studied largely because of its role in toxicology-gene expression via AhR is induced by many aromatic hydrocarbons in mammals. Recently, however, it has become clear that AhR is involved in various aspects of development such as cell proliferation and differentiation, and cell motility and migration. The mechanisms by which AhR regulates these various functions remain poorly understood. Across-species comparative studies of AhR in invertebrates, non-mammalian vertebrates and mammals may help to reveal the multiple functions of AhR. Here, we have studied AhR during larval development of Baltic salmon (Salmon salar). Our results indicate that AhR protein is expressed in nervous system, liver and muscle tissues. We also present putative regulatory modules and module-matching genes, produced by chromatin immunoprecipitation (ChIP) cloning and in silico analysis, which may be associated with evolutionarily conserved functions of AhR during development. For example, the module NFKB-AHRR-CREB found from salmon ChIP sequences is present in human ULK3 (regulating formation of granule cell axons in mouse and axon outgrowth in Caernohabditis elegans) and SRGAP1 (GTPase-activating protein involved in the Slit/Robo pathway) promoters. We suggest that AhR may have an evolutionarily conserved role in neuronal development and nerve cell targeting, and in Wnt signaling pathway

  16. Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells

    Energy Technology Data Exchange (ETDEWEB)

    Kovalova, Natalia, E-mail: kovalova@msu.edu [Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI 48824 (United States); Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Nault, Rance, E-mail: naultran@msu.edu [Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824 (United States); Crawford, Robert, E-mail: crawfo28@msu.edu [Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Zacharewski, Timothy R., E-mail: tzachare@msu.edu [Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824 (United States); Kaminski, Norbert E., E-mail: kamins11@msu.edu [Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI 48824 (United States); Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States)

    2017-02-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12 h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized that TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes. - Highlights: • Kovalova TAAP Highlights Nov. 2016 • RNA-Seq identified TCDD-induced gene expression in PWM-activated primary B cells. • TCDD elicited differential expression of 515 human, 2371 mouse and 712

  17. Evolution and adaptation of the pandemic A/H1N1 2009 influenza virus

    Directory of Open Access Journals (Sweden)

    Ducatez MF

    2011-07-01

    Full Text Available Mariette F Ducatez, Thomas P Fabrizio, Richard J WebbyDepartment of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USAAbstract: The emergence of the 2009 H1N1 pandemic influenza virus [A(H1N1pdm09] has provided the public health community with many challenges, but also the scientific community with an opportunity to monitor closely its evolution through the processes of drift and shift. To date, and despite having circulated in humans for nearly two years, little antigenic variation has been observed in the A(H1N1pdm09 viruses. However, as the A(H1N1pdm09 virus continues to circulate and the immunologic pressure within the human population increases, future antigenic change is almost a certainty. Several coinfections of A(H1N1pdm09 and seasonal A(H1N1 or A(H3N2 viruses have been observed, but no reassortant viruses have been described in humans, suggesting a lack of fitness of reassortant viruses or a lack of opportunities for interaction of different viral lineages. In contrast, multiple reassortment events have been detected in swine populations between A(H1N1 pdm09 and other endemic swine viruses. Somewhat surprisingly, many of the well characterized influenza virus virulence markers appear to have limited impact on the phenotype of the A(H1N1pdm09 viruses when they have been introduced into mutant viruses in laboratory settings. As such, it is unclear what the evolutionary path of the pandemic virus will be, but the monitoring of any changes in the circulating viruses will remain a global public and animal health priority.Keywords: influenza, pandemic, evolution, adaptation

  18. Gene expression profiling of the Notch-AhR-IL22 axis at homeostasis and in response to tissue injury.

    Science.gov (United States)

    Weidenbusch, Marc; Rodler, Severin; Song, Shangqing; Romoli, Simone; Marschner, Julian A; Kraft, Franziska; Holderied, Alexander; Kumar, Santosh; Mulay, Shrikant R; Honarpisheh, Mohsen; Kumar Devarapu, Satish; Lech, Maciej; Anders, Hans-Joachim

    2017-12-22

    Notch and interleukin-22 (IL-22) signaling are known to regulate tissue homeostasis and respond to injury in humans and mice, and the induction of endogenous aryl hydrocarbon receptor (Ahr) ligands through Notch links the two pathways in a hierarchical fashion. However in adults, the species-, organ- and injury-specific gene expression of the Notch-AhR-IL22 axis components is unknown. We therefore performed gene expression profiling of DLL1, DLL3, DLL4, DLK1, DLK2, JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, ADAM17/TNF-α ADAM metalloprotease converting enzyme (TACE), PSEN1, basigin (BSG)/CD147, RBP-J, HES1, HES5, HEY1, HEYL, AHR, ARNT, ARNT2, CYP1A1, CYP24A1, IL-22, IL22RA1, IL22RA2, IL10RB, and STAT3 under homeostatic conditions in ten mature murine and human organs. Additionally, the expression of these genes was assessed in murine models of acute sterile inflammation and progressive fibrosis. We show that there are organ-specific gene expression profiles of the Notch-AhR-IL22 axis in humans and mice. Although there is an overall interspecies congruency, specific differences between human and murine expression signatures do exist. In murine tissues with AHR/ARNT expression CYP1A1 and IL-22 were correlated with HES5 and HEYL expression, while in human tissues no such correlation was found. Notch and AhR signaling are involved in renal inflammation and fibrosis with specific gene expression changes in each model. Despite the presence of all Notch pathway molecules in the kidney and a model-specific induction of Notch ligands, IL-22 was only up-regulated in acute inflammation, but rapidly down-regulated during regeneration. This implies that for targeting injury responses, e.g. via IL-22, species-specific differences, injury type and time points have to be considered. © 2017 The Author(s).

  19. RELEVANSI KAFĀ’AH TERHADAP KEHARMONISAN RUMAH TANGGA PERSPEKTIF NORMATIF DAN YURIDIS

    Directory of Open Access Journals (Sweden)

    Asrizal Saiin

    2015-06-01

    Full Text Available Kafā’ah is a concept of equivalence between the couples who want to get married to create family which is sakinah, mawaddah and rahmah. Religious elements is the main and most important in equality while the others just as a supporting factor, such as: education, offspring, position and economic degree. In determining the partner, every one should understand the kafa’ah concepts and criteria in integrated, inductive and comprehensive, what intended to avoid mistakes in choosing a good couple. This article examine the equality relevance on household harmony in terms of normative and juridical value. [Kafā’ah merupakan suatu konsep kesepadanan antara calon suami dan isteri yang ingin menikah untuk membentuk keluarga sakinah, mawaddah dan rahmah. Unsur agama merupakan unsur utama dan terpenting dalam kafā’ah sedangkan unsur yang lain hanya sebagai pendukung, seperti pendidikan, keturunan, kedudukan dan ekonomi. Dalam menentukan pasangan hidup, perlu dipahami konsep kafā’ah dan kriteria-kriteria yang ada di dalamnya secara integratif, induktif dan konprehensif, yang ditujukan agar tidak terjadi kesalahan dalam memilih jodoh yang baik. Artikel ini mencoba mengkaji relevansi kafā’ah terhadap keharmonisan rumah tangga ditinjau dari nilai normatif dan yuridis.

  20. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    DEFF Research Database (Denmark)

    Billestrup, N; Møldrup, A; Serup, P

    1990-01-01

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, we have transfected ...

  1. Decreased Expression of the Aryl Hydrocarbon Receptor in Ocular Behcet’s Disease

    Directory of Open Access Journals (Sweden)

    Chaokui Wang

    2014-01-01

    Full Text Available Recent studies show that the aryl hydrocarbon receptor (AhR is involved in immune responses. AhR is activated following interaction with its ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ and 2-(1′H-indole-3′-carbonyl-thiazole-4-carboxylic acid methyl ester (ITE. In this study, we investigated the role of AhR activation by its endogenous ligands in the pathogenesis of ocular Behcet’s disease (BD. The expression of AhR was significantly decreased in active BD patients as compared to inactive BD patients and normal controls. Both FICZ and ITE inhibited Th1 and Th17 polarization and induced the expression of IL-22 by PBMCs and by CD4+T cells in active BD patients and normal controls. Stimulation of purified CD4+T cells with FICZ or ITE caused a decreased expression of RORC, IL-17, IL-23R, and CCR6 and an increased phosphorylation of STAT3 and STAT5. The present study suggests that a decreased AhR expression is associated with disease activity in BD patients. The activation of AhR by either FICZ or ITE was able to inhibit Th1 and Th17 cell polarization. Further studies are needed to investigate whether modulation of AhR might be used in the treatment of BD.

  2. Polymorphism of the aryl-hydrocarbon receptor gene in intron 10 of human cancers

    Directory of Open Access Journals (Sweden)

    M. Rocas

    2011-11-01

    Full Text Available Polychlorinated dibenzo-p-dioxins (PCDDs and related halogenated aromatic hydrocarbons (e.g., PCDFs, often called "dioxins", are ubiquitously present environmental contaminants. Some of them, notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, are among the most toxic synthetic compounds known. The biological effects of dioxins are mediated via the aryl hydrocarbon receptor (AhR. Mutations in the AhR transactivation domain are linked to sensitivity to the acute lethality of TCDD. We present here a study of AhR gene polymorphism in normal and cancer human tissues affecting pre-mRNA splicing in the AhR gene-coding transactivation domain region (exon 10, intron 10, exon 11 region, previously shown to be associated with AhR dysfunction. We tested 126 pairs of normal and cancer tissue samples from liver, lung, stomach, kidney, mucous, breast, and pancreas of 49 males and 77 females (45-70 years of age. We used in vitro splicing assay, RT-PCR and sequencing methods. Our results showed that in an in vitro system it is possible to reconstitute cellular pre-mRNA splicing events. Tested cancer tissues did not contain mutations in the AhR transactivation domain region when the DNA sequences were compared with those from normal tissues. There were also no differences in AhR mRNA splice variants between normal and malignant breast tissues and no polymorphisms in the studied regions or cDNA.

  3. Decreased expression of the aryl hydrocarbon receptor in ocular Behcet's disease.

    Science.gov (United States)

    Wang, Chaokui; Ye, Zi; Kijlstra, Aize; Zhou, Yan; Yang, Peizeng

    2014-01-01

    Recent studies show that the aryl hydrocarbon receptor (AhR) is involved in immune responses. AhR is activated following interaction with its ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). In this study, we investigated the role of AhR activation by its endogenous ligands in the pathogenesis of ocular Behcet's disease (BD). The expression of AhR was significantly decreased in active BD patients as compared to inactive BD patients and normal controls. Both FICZ and ITE inhibited Th1 and Th17 polarization and induced the expression of IL-22 by PBMCs and by CD4(+)T cells in active BD patients and normal controls. Stimulation of purified CD4(+)T cells with FICZ or ITE caused a decreased expression of RORC, IL-17, IL-23R, and CCR6 and an increased phosphorylation of STAT3 and STAT5. The present study suggests that a decreased AhR expression is associated with disease activity in BD patients. The activation of AhR by either FICZ or ITE was able to inhibit Th1 and Th17 cell polarization. Further studies are needed to investigate whether modulation of AhR might be used in the treatment of BD.

  4. AhR-dependent secretion of PDGF-BB by human classically activated macrophages exposed to DEP extracts stimulates lung fibroblast proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Jaguin, Marie [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex (France); Fardel, Olivier [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex (France); Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes Cedex (France); Lecureur, Valérie, E-mail: valerie.lecureur@univ-rennes1.fr [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex (France)

    2015-06-15

    Lung diseases are aggravated by exposure to diesel exhaust particles (DEPs) found in air pollution. Macrophages are thought to play a crucial role in lung immune response to these pollutants, even if the mechanisms involved remain incompletely characterized. In the present study, we demonstrated that classically and alternative human macrophages (MΦ) exhibited increased secretion of PDGF-B in response to DEP extract (DEPe). This occurred via aryl hydrocarbon receptor (AhR)-activation because DEPe-induced PDGF-B overexpression was abrogated after AhR expression knock-down by RNA interference, in both M1 and M2 polarizing MΦ. In addition, TCDD and benzo(a)pyrene, two potent AhR ligands, also significantly increased mRNA expression of PDGF-B in M1 MΦ, whereas some weak ligands of AhR did not. We next evaluated the impact of conditioned media (CM) from MΦ culture exposed to DEPe or of recombinant PDGF-B onto lung fibroblast proliferation. The tyrosine kinase inhibitor, AG-1295, prevents phosphorylations of PDGF-Rβ, AKT and ERK1/2 and the proliferation of MRC-5 fibroblasts induced by recombinant PDGF-B and by CM from M1 polarizing MΦ, strongly suggesting that the PDGF-BB secreted by DEPe-exposed MΦ is sufficient to activate the PDGF-Rβ pathway of human lung fibroblasts. In conclusion, we demonstrated that human MΦ, whatever their polarization status, secrete PDGF-B in response to DEPe and that PDGF-B is a target gene of AhR. Therefore, induction of PDGF-B by DEP may participate in the deleterious effects towards human health triggered by such environmental urban contaminants. - Highlights: • PDGF-B expression and secretion are increased by DEPe exposure in human M1 and M2 MΦ. • DEPe-induced PDGF-B expression is aryl-hydrocarbon-dependent. • DEPe-exposed M1 MΦ secrete sufficient PDGF-B to increase lung fibroblast proliferation.

  5. Comparative liver accumulation of dioxin-like compounds in sheep and cattle: Possible role of AhR-mediated xenobiotic metabolizing enzymes.

    Science.gov (United States)

    Girolami, F; Spalenza, V; Benedetto, A; Manzini, L; Badino, P; Abete, M C; Nebbia, C

    2016-11-15

    PCDDs, PCDFs, and PCBs are persistent organic pollutants (POPs) that accumulate in animal products and may pose serious health problems. Those able to bind the aryl hydrocarbon receptor (AhR), eliciting a plethora of toxic responses, are defined dioxin-like (DL) compounds, while the remainders are called non-DL (NDL). An EFSA opinion has highlighted the tendency of ovine liver to specifically accumulate DL-compounds to a greater extent than any other farmed ruminant species. To examine the possible role in such an accumulation of xenobiotic metabolizing enzymes (XME) involved in DL-compound biotransformation, liver samples were collected from ewes and cows reared in an area known for low dioxin contamination. A related paper reported that sheep livers had about 5-fold higher DL-compound concentrations than cattle livers, while the content of the six marker NDL-PCBs did not differ between species. Specimens from the same animals were subjected to gene expression analysis for AhR, AhR nuclear translocator (ARNT) and AhR-dependent oxidative and conjugative pathways; XME protein expression and activities were also investigated. Both AhR and ARNT mRNA levels were about 2-fold lower in ovine samples and the same occurred for CYP1A1 and CYP1A2, being approximately 3- and 9-fold less expressed in sheep compared to cattle, while CYP1B1 could be detectable in cattle only. The results of the immunoblotting and catalytic activity (most notably EROD) measurements of the CYP1A family enzymes were in line with the gene expression data. By contrast, phase II enzyme expression and activities in sheep were higher (UGT1A) or similar (GSTA1, NQO1) to those recorded in cattle. The overall low expression of CYP1 family enzymes in the sheep is in line with the observed liver accumulation of DL-compounds and is expected to affect the kinetics and the dynamics of other POPs such as many polycyclic aromatic hydrocarbons, as well as of toxins (e.g. aflatoxins) or drugs (e.g. benzimidazole

  6. Blocking oxytocin receptors inhibits vaginal marking to male odors in female Syrian hamsters.

    Science.gov (United States)

    Martinez, Luis A; Albers, H Elliott; Petrulis, Aras

    2010-12-02

    In Syrian hamsters (Mesocricetus auratus), precopulatory behaviors such as vaginal scent marking are essential for attracting a suitable mate. Vaginal marking is dependent on forebrain areas implicated in the neural regulation of reproductive behaviors in rodents, including the medial preoptic/anterior hypothalamus (MPOA-AH). Within MPOA-AH, the neuropeptide oxytocin (OT) acts to facilitate copulation (lordosis), as well as ultrasonic vocalizations towards males. It is not known, however, if OT in this area also facilitates vaginal marking. In the present study, a specific oxytocin receptor antagonist (OTA) was injected into MPOA-AH of intact female Syrian hamsters to determine if oxytocin receptor-dependent signaling is critical for the normal expression of vaginal marking elicited by male, female, and clean odors. OTA injections significantly inhibited vaginal marking in response to male odors compared with vehicle injections. There was no effect of OTA on marking in response to either female or clean odors. When injected into the bed nucleus of the stria terminalis (BNST), a nearby region to MPOA-AH, OTA was equally effective in decreasing marking. Finally, the effects of OTA appear to be specific to vaginal marking, as OTA injections in MPOA-AH or BNST did not alter general locomotor activity, flank marking, or social odor investigation. Considered together, these results suggest that OT in MPOA-AH and/or BNST normally facilitates male odor-induced vaginal marking, providing further evidence that OT generally supports prosocial interactions among conspecifics. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. Dual Infection of Novel Influenza Viruses A/H1N1 and A/H3N2 in a Cluster of Cambodian Patients

    Science.gov (United States)

    2011-01-01

    influenza viruses as well as the avian influenza virus A/H5N1...on full genome sequencing. This incident confirms dual influenza virus infections and highlights the risk of zoonotic and seasonal influenza viruses ...North American swine influenza viruses , North American avian influenza viruses , human influenza viruses , and a Eurasian swine influenza virus . 18

  8. Regulation of mouse small heat shock protein αb-crystallin gene by aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Shuang Liu

    2011-04-01

    Full Text Available The stress-inducible small heat shock protein (shsp/αB-crystallin gene is expressed highly in the lens and moderately in other tissues. Here we provide evidence that it is a target gene of the aryl hydrocarbon receptor (AhR transcription factor. A sequence (-329/-323, CATGCGA similar to the consensus xenobiotic responsive element (XRE, called here XRE-like, is present in the αBE2 region of αB-crystallin enhancer and can bind AhR in vitro and in vivo. αB-crystallin protein levels were reduced in retina, lens, cornea, heart, skeletal muscle and cultured muscle fibroblasts of AhR(-/- mice; αB-crystallin mRNA levels were reduced in the eye, heart and skeletal muscle of AhR(-/- mice. Increased AhR stimulated αB-crystallin expression in transfection experiments conducted in conjunction with the aryl hydrocarbon receptor nuclear translocator (ARNT and decreased AhR reduced αB-crystallin expression. AhR effect on aB-crystallin promoter activity was cell-dependent in transfection experiments. AhR up-regulated αB-crystallin promoter activity in transfected HeLa, NIH3T3 and COS-7 cells in the absence of exogenously added ligand (TCDD, but had no effect on the αB-crystallin promoter in C(2C(12, CV-1 or Hepa-1 cells with or without TCDD. TCDD enhanced AhR-stimulated αB-crystallin promoter activity in transfected αTN4 cells. AhR could bind to an XRE-like site in the αB-crystallin enhancer in vitro and in vivo. Finally, site-specific mutagenesis experiments showed that the XRE-like motif was necessary for both basal and maximal AhR-induction of αB-crystallin promoter activity. Our data strongly suggest that AhR is a regulator of αB-crystallin gene expression and provide new avenues of research for the mechanism of tissue-specific αB-crystallin gene regulation under normal and physiologically stressed conditions.

  9. Biological role of Trichoderma harzianum-derived platelet-activating factor acetylhydrolase (PAF-AH) on stress response and antagonism.

    Science.gov (United States)

    Yu, Chuanjin; Fan, Lili; Wu, Qiong; Fu, Kehe; Gao, Shigang; Wang, Meng; Gao, Jinxin; Li, Yaqian; Chen, Jie

    2014-01-01

    We investigated the properties of platelet-activating factor acetylhydrolase (PAF-AH) derived from Trichoderma harzianum. The enzyme, comprised of 572 amino acids, shares high homology with PAF-AH proteins from T. koningii and other microbial species. The optimum enzymatic activity of PAF-AH occurred at pH 6 in the absence of Ca2+ and it localized in the cytoplasm, and we observed the upregulation of PAF-AH expression in response to carbon starvation and strong heat shock. Furthermore, PAF-AH knockout transformant growth occurred more slowly than wild type cells and over-expression strains grown in SM medium at 37°C and 42°C. In addition, PAF-AH expression significantly increased under a series of maize root induction assay. Eicosanoic acid and ergosterol levels decreased in the PAF-AH knockouts compared to wild type cells, as revealed by GC/MS analysis. We also determined stress responses mediated by PAF-AH were related to proteins HEX1, Cu/Zn superoxide dismutase, and cytochrome c. Finally, PAF-AH exhibited antagonistic activity against Rhizoctonia solani in plate confrontation assays. Our results indicate PAF-AH may play an important role in T. harzianum stress response and antagonism under diverse environmental conditions.

  10. Emergence in China of human disease due to avian influenza A(H10N8)--cause for concern?

    Science.gov (United States)

    To, Kelvin K W; Tsang, Alan K L; Chan, Jasper F W; Cheng, Vincent C C; Chen, Honglin; Yuen, Kwok-Yung

    2014-03-01

    In December 2013, China reported the first human case of avian influenza A(H10N8). A 73-year-old female with chronic diseases who had visited a live poultry market succumbed with community-acquired pneumonia. While human infections with avian influenza viruses are usually associated with subtypes prevalent in poultries, A(H10N8) isolates were mostly found in migratory birds and only recently in poultries. Although not possible to predict whether this single intrusion by A(H10N8) is an accident or the start of another epidemic like the preceding A(H7N9) and A(H5N1), several features suggest that A(H10N8) is a potential threat to humans. Recombinant H10 could attach to human respiratory epithelium, and A(H10N4) virus could cause severe infections in minks and chickens. A(H10N8) viruses contain genetic markers for mammalian adaptation and virulence in the haemagglutinin (A135T, S138A[H3 numbering]), M1(N30D, T215A), NS1(P42S) and PB2(E627K) protein. Studies on this human A(H10N8) isolate will reveal its adaptability to humans. Clinicians should alert the laboratory to test for A(H5,6,7,9,10) viruses in patients with epidemiological exposure in endemic geographical areas especially when human influenza A(H1,3) and B are negative. Vigilant virological and serological surveillance for A(H10N8) in human, poultry and wild bird is important for following the trajectory of this emerging influenza virus. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  11. Binary Classification of a Large Collection of Environmental Chemicals from Estrogen Receptor Assays by Quantitative Structure-Activity Relationship and Machine Learning Methods

    Science.gov (United States)

    ABSTRACT: There are thousands of environmental chemicals subject to regulatory decisions for endocrine disrupting potential. A promising approach to manage this large universe of untested chemicals is to use a prioritization filter that combines in vitro assays with in silico QSA...

  12. Anti-Restriction Protein, KlcAHS, Promotes Dissemination of Carbapenem Resistance

    Directory of Open Access Journals (Sweden)

    Xiaofei Jiang

    2017-05-01

    Full Text Available Carbapenemase-producing Klebsiella pneumoniae (KPC has emerged and spread throughout the world. A retrospective analysis was performed on carbapenem-resistant K. pneumoniae isolated at our teaching hospital during the period 2009–2010, when the initial outbreak occurred. To determine the mechanism(s that underlies the increased infectivity exhibited by KPC, Multilocus Sequence Typing (MLST was conducted. A series of plasmids was also extracted, sequenced and analyzed. Concurrently, the complete sequences of blaKPC−2-harboring plasmids deposited in GenBank were summarized and aligned. The blaKPC−2 and KlcAHS genes in the carbapenem-resistant K. pneumoniae isolates were examined. E. coli strains, carrying different Type I Restriction and Modification (RM systems, were selected to study the interaction between RM systems, anti-RM systems and horizontal gene transfer (HGT. The ST11 clone predominated among 102 carbapenem-resistant K. pneumoniae isolates, all harbored the blaKPC−2 gene; 98% contained the KlcAHS gene. KlcAHS was one of the core genes in the backbone region of most blaKPC−2 carrying plasmids. Type I RM systems in the host bacteria reduced the rate of pHS10842 plasmid transformation by 30- to 40-fold. Presence of the anti-restriction protein, KlcAHS, on the other hand, increased transformation efficiency by 3- to 6-fold. These results indicate that RM systems can significantly restrict HGT. In contrast, KlcAHS can disrupt the RM systems and promote HGT by transformation. These findings suggest that the anti-restriction protein, KlcAHS, represents a novel mechanism that facilitates the increased transfer of blaKPC-2 and KlcAHS-carrying plasmids among K. pneumoniae strains.

  13. QSAR model for human pregnane X receptor (PXR) binding: Screening of environmental chemicals and correlations with genotoxicity, endocrine disruption and teratogenicity

    DEFF Research Database (Denmark)

    Dybdahl, Marianne; Nikolov, Nikolai G.; Wedebye, Eva Bay

    2012-01-01

    The pregnane X receptor (PXR) has a key role in regulating the metabolism and transport of structurally diverse endogenous and exogenous compounds. Activation of PXR has the potential to initiate adverse effects, causing drug–drug interactions, and perturbing normal physiological functions...

  14. The role of retinoic acid receptors and their cognate ligands in reproduction in a context of triorganotin based endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Macejova Dana

    2016-07-01

    Full Text Available Retinoic acid (RA, an active form of vitamin A, regulates the embryonic development, male and female reproduction and induces important effects on the cell development, proliferation, and differentiation. These effects are mediated by the retinoid (RAR and rexinoid nuclear receptors (RXR, which are considered to be a ligand-activated, DNA-binding, trans-acting, and transcription-modulating proteins, involved in a general molecular mechanism responsible for the transcriptional responses in target genes. Organotin compounds are typical environmental contaminants and suspected endocrine disrupting substances. They may affect processes of reproductive system in mammals, predominantly via nuclear receptor signaling pathways. Triorganotins, such as tributyltin chloride (TBTCl and triphenyltin chloride (TPTCl, are capable to bind to RXR molecules, and thus represent potent agonists of RXR subtypes of nuclear receptors not sharing any structural characteristics with endogenous ligands of nuclear receptors. Th is article summarizes selected effects of biologically active retinoids and rexinoids on both male and female reproduction and also deals with the effects of organotin compounds evoking endocrine disrupting actions in reproduction.

  15. Water soluble and efficient amino acid Schiff base receptor for reversible fluorescence turn-on detection of Zn2+ ions: Quantum chemical calculations and detection of bacteria

    Science.gov (United States)

    Subha, L.; Balakrishnan, C.; Natarajan, Satheesh; Theetharappan, M.; Subramanian, Balanehru; Neelakantan, M. A.

    2016-01-01

    An amino acid Schiff base (R) capable of recognizing Zn2+ ions selectively and sensitively in an aqueous medium was prepared and characterized. Upon addition of Zn2+ ions, the receptor exhibits fluorescence intensity enhancements ( 40 fold) at 460 nm (quantum yield, Φ = 0.05 for R and Φ = 0.18 for R-Zn2+) and can be detected by naked eye under UV light. The receptor can recognize the Zn2+ (1.04 × 10- 8 M) selectively for other metal ions in the pH range of 7.5-11. The Zn2+ chelation with R decreases the loss of energy through non-radiative transition and leads to fluorescence enhancement. The binding mode of the receptor with Zn2+ was investigated by 1H NMR titration and further validated by ESI-MS. The elemental color mapping and SEM/EDS analysis were also used to study the binding of R with Zn2+. Density functional theory calculations were carried out to understand the binding mechanism. The receptor was applied as a microbial sensor for Escherichia coli and Staphylococcus aureus.

  16. Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3

    DEFF Research Database (Denmark)

    Schmidt, Johannes; Smith, Nicola J; Christiansen, Elisabeth

    2011-01-01

    given its size. Propionate, however, does not discriminate between FFA2 and the closely related receptor FFA3 (GPR41). To identify FFA2 selective ligands and understand the molecular basis for FFA2 selectivity, a targeted library of small carboxylic acids (SCAs) was examined using holistic, label...

  17. Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Vorrink, Sabine U. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Severson, Paul L. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Kulak, Mikhail V. [Department of Surgery, The University of Iowa, Iowa City, IA (United States); Futscher, Bernard W. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Domann, Frederick E., E-mail: frederick-domann@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Department of Surgery, The University of Iowa, Iowa City, IA (United States)

    2014-02-01

    The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O{sub 2} prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and

  18. Low-temperature thermal decomposition of dioxin-like compounds in fly ash: combination of chemical analysis with in vitro bioassays (EROD and DR-CALUX).

    Science.gov (United States)

    Behnisch, Peter A; Hosoe, Kazunori; Shiozaki, Ken; Ozaki, Hironori; Nakamura, Kazuo; Sakai, Shin-Ichi

    2002-12-01

    To investigate the dechlorination of fly ash during low-temperature treatment under oxygen-deficient conditions (thermocatalyic treatment or Hagenmaier process), six fly ash samples from six different incineration plants were treated in a laboratory experiment or in the actual plant, either under ideal (400 degrees C, 120 min) or intermediate (300 degrees C, 30 min) conditions. The aim of the present study was to confirm the decrease in the I-TEQ (international toxicity equivalency) of polychlorinated dibenzo-p-dioxins/-furans (PCDD/Fs) and coplanar polychlorinated biphenyls (co-PXBs) and, also for the first time, the decrease in the sum of dioxin-like toxicity (bioassay- or bio-TEQ) of all kinds of other dioxin-like Ah receptor agonists (such as PXDD/Fs, PXBs, PXN, X = Br, F) measured by two state-of-the-art cell-based Ah receptor-dependent bioassays: H4IIE-Ethoxy-Resorufin-o-Deethylase (EROD) and H4IIE-luc/DR-Chemical Activated Luciferase expression (DR-CALUX). The treatment efficiency was calculated on the basis of the reduction in the I-TEQ and bio-TED values. For these fly ash samples, the treatment efficiency, as measured by chemical analysis, was higher than 99%, and 85%-99%, in the case of the bio-TED values, indicating that these Ah receptor binding toxic compounds were sufficiently decomposed. Bio-TEQ values for untreated fly ash samples (n = 6) were on average 1.2 times (range 0.7-1.9), for the H4IIE-EROD assay, and 2.8 times (1.1-4.9), for the DR-CALUX assay, higher than I-TEQ values measured by chemical analyses (sum of PCDD/Fs and co-PCBs). In the case of these fly ash samples treated under ideal conditions and therefore low in contaminants, the bio-TEQ values were on average 1.4 times (range 0.9-1.8), for the H4IIE-EROD assay, and 5.1 times (range 1.2-12), for the DR-CALUX assay, higher than the I-TEQ values.

  19. Impact of untreated wastewater on a major European river evaluated with a combination of in vitro bioassays and chemical analysis.

    Science.gov (United States)

    König, Maria; Escher, Beate I; Neale, Peta A; Krauss, Martin; Hilscherová, Klára; Novák, Jiří; Teodorović, Ivana; Schulze, Tobias; Seidensticker, Sven; Kamal Hashmi, Muhammad Arslan; Ahlheim, Jörg; Brack, Werner

    2017-01-01

    Complex mixtures of micropollutants, including pesticides, pharmaceuticals and industrial chemicals emitted by wastewater effluents to European rivers may compromise the quality of these water resources and may pose a risk to ecosystem health and abstraction of drinking water. In the present study, an integrated analytical and bioanalytical approach was applied to investigate the impact of untreated wastewater effluents from the city of Novi Sad, Serbia, into the River Danube. The study was based on three on-site large volume solid phase extracted water samples collected upstream and downstream of the untreated wastewater discharge. Chemical screening with liquid chromatography high resolution mass spectrometry (LC-HRMS) was applied together with a battery of in vitro cell-based bioassays covering important steps of the cellular toxicity pathway to evaluate effects on the activation of metabolism (arylhydrocarbon receptor AhR, peroxisome proliferator activated receptor gamma PPARγ), specific modes of action (estrogen receptor ERα, androgen receptor AR) and adaptive stress responses (oxidative stress, inflammation). Increased effects, significantly changed contamination patterns and higher chemical concentrations were observed downstream of the wastewater discharge. A mass balance approach showed that enhanced endocrine disruption was in good agreement with concentrations of detected hormones, while only a smaller fraction of the effects on xenobiotic metabolism (<1%) and adaptive stress responses (0-12%) could be explained by the detected chemicals. The chemical and effects patterns observed upstream of the discharge point were fairly re-established at about 7 km downstream, demonstrating the enormous dilution capacity of this large river. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Cell specific effects of PCB 126 on aryl hydrocarbone receptors in follicular cells of porcine ovaries

    Energy Technology Data Exchange (ETDEWEB)

    Wojtowicz, A.; Augustowska, K.; Gregoraszczuk, E. [Lab. of Physiology and Toxicology of Reproduction, Dept. of Animal Physiology, Inst. of Zoology, Jagiellonian Univ., Krakow (Poland)

    2004-09-15

    Polychlorinated biphenyles (PCBs) like other endocrine disrupters could interfere with natural hormones by binding to their receptors and thus mimicking the cellular response to them. They are known to possess either estrogenic or antiestrogenic properties. In our previous papers we demonstrated that PCBs are able to disrupt ovarian steroidogenesis. We found that the coplanar PCB 126 caused the decrease in estradiol secretion in whole cultured pig ovarian follicles. PCB 126 congener is structurally related to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since TCDD effects are known to be mediated by aryl hydrocarbone receptors (AhRs), we decided to determine if PCB 126 affects signal transduction pathway activated by these receptors. It has been reported that the functional AhR is present in ovary including oocytes, granulosa and theca cells of rat, mouse, rhesus monkey and human ovary. Moreover, the expression of AhR in the rat ovary appeared to be estrous cycle-dependent, thus suggesting that AhR expression may be regulated by fluctuating hormone levels. This study was designed to investigate the effects of the non-ortho-substituted 3,3',4,4',5-pentachlorobiphenyl (PCB126) on the AhR activation, localization and protein level in pig ovarian follicle cells.

  1. Effect of dioxins on regulation of tyrosine hydroxylase gene expression by aryl hydrocarbon receptor: a neurotoxicology study

    Directory of Open Access Journals (Sweden)

    Akahoshi Eiichi

    2009-06-01

    Full Text Available Abstract Background Dioxins and related compounds are suspected of causing neurological disruption. Epidemiological studies indicated that exposure to these compounds caused neurodevelopmental disturbances such as learning disability and attention deficit hyperactivity disorder, which are thought to be closely related to dopaminergic dysfunction. Although the molecular mechanism of their actions has not been fully investigated, a major participant in the process is aryl hydrocarbon receptor (AhR. This study focused on the effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD exposure on the regulation of TH, a rate-limiting enzyme of dopamine synthesis, gene expression by AhR. Methods N2a-Rβ cells were established by transfecting murine neuroblastoma Neuro2a with the rat AhR cDNA. TH expression induced by TCDD was assessed by RT-PCR and Western blotting. Participation of AhR in TCDD-induced TH gene expression was confirmed by suppressing AhR expression using the siRNA method. Catecholamines including dopamine were measured by high-performance liquid chromatography. A reporter gene assay was used to identify regulatory motifs in the promoter region of TH gene. Binding of AhR with the regulatory motif was confirmed by an electrophoretic mobility shift assay (EMSA. Results Induction of TH by TCDD through AhR activation was detected at mRNA and protein levels. Induced TH protein was functional and its expression increased dopamine synthesis. The reporter gene assay and EMSA indicated that AhR directly regulated TH gene expression. Regulatory sequence called aryl hydrocarbon receptor responsive element III (AHRE-III was identified upstream of the TH gene from -285 bp to -167 bp. Under TCDD exposure, an AhR complex was bound to AHRE-III as well as the xenobiotic response element (XRE, though AHRE-III was not identical to XRE, the conventional AhR-binding motif. Conclusion Our results suggest TCDD directly regulate the dopamine system by TH gene

  2. Contra trading in Bursa Malaysia Securities Berhad: a Sharīʿah and legal appraisal

    Directory of Open Access Journals (Sweden)

    Noor Suhaida Kasri

    2017-07-01

    Full Text Available Purpose - The purpose of this paper is to analyze the practice of contra trading in Bursa Malaysia Securities Berhad. Through a critical examination of the practice, it aims to discuss the issues from the angles of Sharīʿah and Malaysian common law. Design/methodology/approach - The paper uses a qualitative research methodology. The information on the practice of contra trading is obtained through the Bursa Malaysia Securities Berhad’s website and literature as well as series of meetings and discussions held with Bursa Malaysia Securities Berhad. In comprehending and dissecting the Sharīʿah and legal issues, classical along with contemporary Sharīʿah literature including local and international Sharīʿah advisory bodies’ resolutions and standards have been referred to. The Sharīʿah analysis of these issues is further supported by reference to the statute and by-laws of Bursa Malaysia Securities Berhad as well as other related legal literature. Findings - This paper finds that contra trading involves a real sale and purchase of shares; the shares are not taken into the possession of the contra trader, neither physically nor constructively; the liability of shares is not transferred to the contra trader; though the practice of profiting in contra trading may contradict the prohibition on profiting without bearing liability, the permissibility of contra trading could still be argued from the contextual approach of public interest (maṣlaḥah and needs (hājah; and contra trading is not gambling. Research limitations/implications - This paper is limited in its analysis to only Sharīʿah and legal perspectives. It does not cover a thorough empirical and quantitative investigation that would measure the extent of the public needs for contra trading and the real benefits that contra trading brings about to the society in the long run. Such studies will further demonstrate whether contra trading deserves a relaxation from the strict Sharīʿah

  3. Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options.

    Science.gov (United States)

    Teschke, Rolf

    2018-06-01

    Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. Areas covered: This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. Expert opinion: Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.

  4. The Volatility of Indonesia Shari’ah Capital Market Stock Price Toward Macro Economics Variable

    Directory of Open Access Journals (Sweden)

    Helma Malini

    2014-08-01

    Full Text Available Shari’ah stock market is also affected by many highly interrelated economic, social, political andother factor, same as the conventional stock market, the interaction between macroeconomic variablesand Shari’ah stock market creating volatility in the stock price as a response towards severalshocks. The sensitivity of Shari’ah stock market towards shocks happened related with the futureexpectation of micro and macro factor in one country which can be predict or unpredictable.There are six macroeconomic variables that used in this research; inflation, exchange rate, interestrate, dow jones index, crude oil palm price, and FED rate. Using vector error correction model(VECM, the result shows that domestic macroeconomic variables that significantly affect IndonesiaShari’ah compliance for long term, while for international macroeconomic variables the selectedvariable such as FED rate and Dow Jones Index are not significantly affected Indonesia Shari’ahcompliance both in short term and long term. Keywords: Indonesia Shari’ah compliance, Macro Economic Indicators, Impulse Response Function,Stock Price Volatility

  5. Human Infection with Highly Pathogenic Avian Influenza A(H7N9) Virus, China.

    Science.gov (United States)

    Ke, Changwen; Mok, Chris Ka Pun; Zhu, Wenfei; Zhou, Haibo; He, Jianfeng; Guan, Wenda; Wu, Jie; Song, Wenjun; Wang, Dayan; Liu, Jiexiong; Lin, Qinhan; Chu, Daniel Ka Wing; Yang, Lei; Zhong, Nanshan; Yang, Zifeng; Shu, Yuelong; Peiris, Joseph Sriyal Malik

    2017-07-01

    The recent increase in zoonotic avian influenza A(H7N9) disease in China is a cause of public health concern. Most of the A(H7N9) viruses previously reported have been of low pathogenicity. We report the fatal case of a patient in China who was infected with an A(H7N9) virus having a polybasic amino acid sequence at its hemagglutinin cleavage site (PEVPKRKRTAR/GL), a sequence suggestive of high pathogenicity in birds. Its neuraminidase also had R292K, an amino acid change known to be associated with neuraminidase inhibitor resistance. Both of these molecular features might have contributed to the patient's adverse clinical outcome. The patient had a history of exposure to sick and dying poultry, and his close contacts had no evidence of A(H7N9) disease, suggesting human-to-human transmission did not occur. Enhanced surveillance is needed to determine whether this highly pathogenic avian influenza A(H7N9) virus will continue to spread.

  6. PEMBARUAN MASLAḤAH DALAM MAQĀṢID AL- SHARĪ‘AH: TELAAH HUMANISTIS TENTANG AL-KULLIYYĀT AL-KHAMSAH

    Directory of Open Access Journals (Sweden)

    Zaenuddin Mansyur

    2012-06-01

    Full Text Available Abstract:   In order to answer a variety of issues faced by human being in the current era, such as human rights abuses, social disintegration, and terrorism, the renewal of Islamic law in the level of theoretical and practical aspects is very urgent. This paper aims to examine one of the Islamic legal reform efforts, namely to build a more technical understanding of the concept of maṣlaḥah contained in the maqāṣīd sharī‘ah, called the al-kulliyat al-khamsah. Therefore, the concept of maṣlaḥah in ḥifẓ al-dīn is technically defined as al-ḥurriyah al-i‘tiqād (freedom of religion and schools; in ḥifẓ al-nafs as al-karamat al-insān (human being breeding; in ḥifẓ al-nasl as ḥifẓ al-usrah (wholeness and harmony of the family; in ḥifẓ al-māl as al-taḍammun al-insān (social solidarity , and in ḥifẓ al-‘aql as al-ḥuqūq as al-tarbiyāt (increasing human resources quality.Abstrak: Demi menjawab aneka persoalan zaman yang dihadapi manusia era sekarang, seperti penyelewengan terhadap HAM, disintegrasi sosial, dan terorisme, maka pembaharuan hukum Islam dalam tataran teoretis dan praktis urgen dilakukan. Tulisan ini bertujuan untuk mengkaji salah satu upaya pembaruan hukum Islam, yaitu membangun pemahaman yang lebih teknis terhadap konsep maṣlaḥah yang terkandung dalam maqāṣīd sharī‘ah, yang disebut dengan al-kulliyāt al-khamsah. Oleh karena itu, konsep maṣlaḥah dalam ḥifẓu al-dīn secara teknis dimaknai sebagai ḥurriyah al-i‘tiqād (kebebasan untuk beragama dan beraliran; dalam ḥifẓu al-nafs sebagai al-karāmāt al-insān (pemuliaan kemanusiaan; dalam ḥifẓu al-nasl sebagai ḥifẓu al-usrah (keutuhan dan keharmonisan keluarga; dalam ḥifẓu al-māl sebagai al-taḍammun al-insān (solidaritas sosial; dan dalam ḥifẓu al-‘aql sebagai al-ḥuqūq al-tarbiyāt (peningkatan sumber daya manusia.

  7. Marine Inspired 2-(5-Halo-1H-indol-3-yl)-N,N-dimethylethanamines as Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as Part of the Uniquely Marine Chemical Space.

    Science.gov (United States)

    Ibrahim, Mohamed A; El-Alfy, Abir T; Ezel, Kelly; Radwan, Mohamed O; Shilabin, Abbas G; Kochanowska-Karamyan, Anna J; Abd-Alla, Howaida I; Otsuka, Masami; Hamann, Mark T

    2017-08-09

    In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo- N , N -dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1 H -indol-3-yl)- N , N -dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 2-(1 H -indol-3-yl)- N , N -dimethyl-2-oxoacetamide ( 1a ), 2-(5-bromo-1 H -indol-3-yl)- N , N -dimethyl-2-oxoacetamide ( 1d ), 2-(1 H -indol-3-yl)- N , N -dimethylethanamine ( 2a ), 2-(5-chloro-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2c ), 2-(5-bromo-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2d ), and 2-(5-iodo-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2e ) have been shown to possess significant antidepressant-like action, while compounds 2c , 2d , and 2e exhibited potent sedative activity. Compounds 2a , 2c , 2d , and 2e showed nanomolar affinities to serotonin receptors 5-HT 1A and 5-HT₇. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.

  8. Estrogen receptor α and aryl hydrocarbon receptor cross-talk in a transfected hepatoma cell line (HepG2 exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

    Directory of Open Access Journals (Sweden)

    Manuela Göttel

    2014-01-01

    Full Text Available The prototype dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD is known to exert anti-estrogenic effects via activation of the aryl hydrocarbon receptor (AhR by interfering with the regulation of oestrogen homeostasis and the estrogen receptor α (ERα signalling pathway. The AhR/ER cross-talk is considered to play a crucial role in TCDD- and E2-dependent mechanisms of carcinogenesis, though the concerted mechanism of action in the liver is not yet elucidated. The present study investigated TCDD's impact on the transcriptional cross-talk between AhR and ERα and its modulation by 17β-estradiol (E2 in the human hepatoma cell line HepG2, which is AhR-responsive but ERα-negative. Transient transfection assays with co-transfection of hERα and supplementation of receptor antagonists showed anti-estrogenic action of TCDD via down-regulation of E2-induced ERα signaling. In contrast, enhancement of AhR signaling dependent on ERα was observed providing evidence for increased cytochrome P450 (CYP induction to promote E2 metabolism. However, relative mRNA levels of major E2-metabolizing CYP1A1 and 1B1 and the main E2-detoxifying catechol-O-methyltransferase were not affected by the co-treatments. This study provides new evidence of a TCDD-activated AhR-mediated molecular AhR/ERα cross-talk mechanism at transcriptional level via indirect inhibition of ERα and enhanced transcriptional activity of AhR in HepG2 cells.

  9. Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB

    International Nuclear Information System (INIS)

    Zhang, Shaojie; Patel, Ananddeep; Chu, Chun; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E.; Moorthy, Bhagavatula; Shivanna, Binoy

    2015-01-01

    Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Activation of the aryl hydrocarbon receptor (AhR) protects adult and newborn mice against hyperoxic lung injury by mediating increases in the expression of phase I (cytochrome P450 (CYP) 1A) and phase II (NADP(H) quinone oxidoreductase (NQO1)) antioxidant enzymes (AOE). AhR positively regulates the expression of RelB, a component of the nuclear factor-kappaB (NF-κB) protein that contributes to anti-inflammatory processes in adult animals. Whether AhR regulates the expression of AOE and RelB, and protects fetal primary human lung cells against hyperoxic injury is unknown. Therefore, we tested the hypothesis that AhR-deficient fetal human pulmonary microvascular endothelial cells (HPMEC) will have decreased RelB activation and AOE, which will in turn predispose them to increased oxidative stress, inflammation, and cell death compared to AhR-sufficient HPMEC upon exposure to hyperoxia. AhR-deficient HPMEC showed increased hyperoxia-induced reactive oxygen species (ROS) generation, cleavage of poly(ADP-ribose) polymerase (PARP), and cell death compared to AhR-sufficient HPMEC. Additionally, AhR-deficient cell culture supernatants displayed increased macrophage inflammatory protein 1α and 1β, indicating a heightened inflammatory state. Interestingly, loss of AhR was associated with a significantly attenuated CYP1A1, NQO1, superoxide dismutase 1(SOD1), and nuclear RelB protein expression. These findings support the hypothesis that decreased RelB activation and AOE in AhR-deficient cells is associated with increased hyperoxic injury compared to AhR-sufficient cells. - Highlights: • AhR deficiency potentiates oxygen toxicity in human fetal lung cells. • Deficient AhR signaling increases hyperoxia-induced cell death. • AhR deficiency increases hyperoxia-induced ROS generation and inflammation. • Anti-oxidant enzyme levels are attenuated in AhR-deficient lung cells

  10. Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shaojie; Patel, Ananddeep; Chu, Chun; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E.; Moorthy, Bhagavatula; Shivanna, Binoy, E-mail: shivanna@bcm.edu

    2015-07-15

    Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Activation of the aryl hydrocarbon receptor (AhR) protects adult and newborn mice against hyperoxic lung injury by mediating increases in the expression of phase I (cytochrome P450 (CYP) 1A) and phase II (NADP(H) quinone oxidoreductase (NQO1)) antioxidant enzymes (AOE). AhR positively regulates the expression of RelB, a component of the nuclear factor-kappaB (NF-κB) protein that contributes to anti-inflammatory processes in adult animals. Whether AhR regulates the expression of AOE and RelB, and protects fetal primary human lung cells against hyperoxic injury is unknown. Therefore, we tested the hypothesis that AhR-deficient fetal human pulmonary microvascular endothelial cells (HPMEC) will have decreased RelB activation and AOE, which will in turn predispose them to increased oxidative stress, inflammation, and cell death compared to AhR-sufficient HPMEC upon exposure to hyperoxia. AhR-deficient HPMEC showed increased hyperoxia-induced reactive oxygen species (ROS) generation, cleavage of poly(ADP-ribose) polymerase (PARP), and cell death compared to AhR-sufficient HPMEC. Additionally, AhR-deficient cell culture supernatants displayed increased macrophage inflammatory protein 1α and 1β, indicating a heightened inflammatory state. Interestingly, loss of AhR was associated with a significantly attenuated CYP1A1, NQO1, superoxide dismutase 1(SOD1), and nuclear RelB protein expression. These findings support the hypothesis that decreased RelB activation and AOE in AhR-deficient cells is associated with increased hyperoxic injury compared to AhR-sufficient cells. - Highlights: • AhR deficiency potentiates oxygen toxicity in human fetal lung cells. • Deficient AhR signaling increases hyperoxia-induced cell death. • AhR deficiency increases hyperoxia-induced ROS generation and inflammation. • Anti-oxidant enzyme levels are attenuated in AhR-deficient lung cells

  11. Case of seasonal reassortant a(H1N2) influenza virus infection, the Netherlands, March 2018

    NARCIS (Netherlands)

    Meijer, A. (Adam); C. Swaan (Corien); Voerknecht, M. (Martin); E. Jusic (Edin); van den Brink, S. (Sharon); Wijsman, L.A. (Lisa A.); A.C.G. Voordouw (Bettie); G.A. Donker (Gé); Sleven, J. (Jacqueline); Dorigo-Zetsma, W.W. (Wendelien W.); S. Svraka-Latifovic (Sanela); M. van Boven (Michiel); Haverkate, M.R. (Manon R.); A. Timen (Aura); J.T. van Dissel (Jaap); M.P.G. Koopmans D.V.M. (Marion); T.M. Bestebroer (Theo); R.A.M. Fouchier (Ron)

    2018-01-01

    textabstractA seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general

  12. Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

    NARCIS (Netherlands)

    Meijer, A.; Swaan, C.M.; Voerknecht, M.; Jusic, E.; Brink, S. van den; Wijsman, L.A.; Voordouw, B.C.G.; Donker, G.A.; Sleven, J.; Dorigo-Zetsma, W.W.; Svraka, S.; Boven, M. van; Haverkate, M.R.; Timen, A.; Dissel, J.T. van; Koopmans, M.P.G.; Besteboer, T.M.; Fouchier, R.A.M.

    2018-01-01

    A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general

  13. Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

    NARCIS (Netherlands)

    Meijer, Adam; Swaan, Corien M; Voerknecht, Martin; Jusic, Edin; van den Brink, Sharon; Wijsman, Lisa A; Voordouw, Bettie Cg; Donker, Gé A; Sleven, Jacqueline; Dorigo-Zetsma, Wendelien W; Svraka, Sanela; van Boven, Michiel; Haverkate, Manon R; Timen, Aura; van Dissel, Jaap T; Koopmans, Marion Pg; Bestebroer, Theo M; Fouchier, Ron Am

    A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general

  14. Preliminary Epidemiology of Human Infections with Highly Pathogenic Avian Influenza A(H7N9) Virus, China, 2017.

    Science.gov (United States)

    Zhou, Lei; Tan, Yi; Kang, Min; Liu, Fuqiang; Ren, Ruiqi; Wang, Yali; Chen, Tao; Yang, Yiping; Li, Chao; Wu, Jie; Zhang, Hengjiao; Li, Dan; Greene, Carolyn M; Zhou, Suizan; Iuliano, A Danielle; Havers, Fiona; Ni, Daxin; Wang, Dayan; Feng, Zijian; Uyeki, Timothy M; Li, Qun

    2017-08-01

    We compared the characteristics of cases of highly pathogenic avian influenza (HPAI) and low pathogenic avian influenza (LPAI) A(H7N9) virus infections in China. HPAI A(H7N9) case-patients were more likely to have had exposure to sick and dead poultry in rural areas and were hospitalized earlier than were LPAI A(H7N9) case-patients.

  15. Specific binding of prostaglandin E2 to membrane preparations from human skin: receptor modulation by UVB-irradiation and chemical agents

    International Nuclear Information System (INIS)

    Lord, J.T.; Ziboh, V.A.

    1979-01-01

    Human skin membranes bind prostaglandin E2 (PGE2) with high affinity and specificity. This binding is inhibited by trypsin or heat treatment suggesting that PGE2 receptors have protein components. Exposure of the membranes to ultraviolet irradiation (UVB) resulted in the loss of the membrane binding capacity for PGE2. This UVB-inhibitory effect could be prevented by a known protein sulfhydryl-oxidizing agent and a known lipid anti-oxidant

  16. Assessment of energetic costs of AhR activation by β-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis

    International Nuclear Information System (INIS)

    Nault, Rance; Abdul-Fattah, Hiba; Mironov, Gleb G.; Berezovski, Maxim V.; Moon, Thomas W.

    2013-01-01

    Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist β-naphthoflavone (βNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesis rates, Na + /K + -ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1 μM βNF for 48 h did not alter hepatocyte AEC, protein synthesis, or Na + /K + -ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. - Highlights: • Energetic costs of AhR activation by βNF was examined in rainbow trout hepatocytes. • Metabolic flux analysis was performed on a fish cell preparation for the first time. • Exposure to βNF led to sparing of glycogen reserves and altered enzyme activities. • Adenylate energy charge was maintained despite temporal changes in metabolism

  17. Assessment of energetic costs of AhR activation by β-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis

    Energy Technology Data Exchange (ETDEWEB)

    Nault, Rance, E-mail: naultran@msu.edu [Ottawa-Carleton Institute of Biology, Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada); Abdul-Fattah, Hiba [Ottawa-Carleton Institute of Biology, Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada); Mironov, Gleb G.; Berezovski, Maxim V. [Ottawa-Carleton Institute of Biology, Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada); Department of Chemistry, University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada); Moon, Thomas W. [Ottawa-Carleton Institute of Biology, Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada)

    2013-08-15

    Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist β-naphthoflavone (βNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesis rates, Na{sup +}/K{sup +}-ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1 μM βNF for 48 h did not alter hepatocyte AEC, protein synthesis, or Na{sup +}/K{sup +}-ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. - Highlights: • Energetic costs of AhR activation by βNF was examined in rainbow trout hepatocytes. • Metabolic flux analysis was performed on a fish cell preparation for the first time. • Exposure to βNF led to sparing of glycogen reserves and altered enzyme activities. • Adenylate energy charge was maintained despite temporal changes in metabolism.

  18. Part I. Naltrexone-derived conjugate addition ligands for opioid receptors. Part II. Chemical and enantioselective aspects of the metabolism of verapamil

    International Nuclear Information System (INIS)

    Olsen, L.D.

    1987-01-01

    Selective chemoaffinity ligands to aid in identification and purification of opioid receptor subtypes were prepared from 6α- and 6β-naltrexol, obtained stereoselectively from the μ-receptor antagonist naltrexone. The targets were the 6α- and 6β-methacrylate ethers and 6α- and 6β-methacrylate esters prepared from reaction of 6α- and 6β-naltrexol with methyl α-(bromomethyl)acrylate or methacryloyl chloride. Of three methacrylate derivatives, the 6α-ether was the most potent in an opioid receptor binding assay with [ 3 H]-naltrexone. In the presence of sodium ion, preincubation of the 6α-ether resulted in recovery of about 60% of original [ 3 H]-naltrexone binding suggesting some irreversible effects. The methacrylate esters precipitated withdrawal in morphine dependent monkeys. The enantiomers of verapamil, a calcium channel antagonist, have different pharmacological and pharmacokinetic properties. The oxidative metabolism of verapamil was studied in rat and human liver microsomes and in man after a single oral dose

  19. Part I. Naltrexone-derived conjugate addition ligands for opioid receptors. Part II. Chemical and enantioselective aspects of the metabolism of verapamil

    Energy Technology Data Exchange (ETDEWEB)

    Olsen, L.D.

    1987-01-01

    Selective chemoaffinity ligands to aid in identification and purification of opioid receptor subtypes were prepared from 6..cap alpha..- and 6..beta..-naltrexol, obtained stereoselectively from the ..mu..-receptor antagonist naltrexone. The targets were the 6..cap alpha..- and 6..beta..-methacrylate ethers and 6..cap alpha..- and 6..beta..-methacrylate esters prepared from reaction of 6..cap alpha..- and 6..beta..-naltrexol with methyl ..cap alpha..-(bromomethyl)acrylate or methacryloyl chloride. Of three methacrylate derivatives, the 6..cap alpha..-ether was the most potent in an opioid receptor binding assay with (/sup 3/H)-naltrexone. In the presence of sodium ion, preincubation of the 6..cap alpha..-ether resulted in recovery of about 60% of original (/sup 3/H)-naltrexone binding suggesting some irreversible effects. The methacrylate esters precipitated withdrawal in morphine dependent monkeys. The enantiomers of verapamil, a calcium channel antagonist, have different pharmacological and pharmacokinetic properties. The oxidative metabolism of verapamil was studied in rat and human liver microsomes and in man after a single oral dose.

  20. A Modified AH-FDTD Unconditionally Stable Method Based on High-Order Algorithm

    Directory of Open Access Journals (Sweden)

    Zheng Pan

    2017-01-01

    Full Text Available The unconditionally stable method, Associated-Hermite FDTD, has attracted more and more attentions in computational electromagnetic for its time-frequency compact property. Because of the fewer orders of AH basis needed in signal reconstruction, the computational efficiency can be improved further. In order to further improve the accuracy of the traditional AH-FDTD, a high-order algorithm is introduced. Using this method, the dispersion error induced by the space grid can be reduced, which makes it possible to set coarser grid. The simulation results show that, on the condition of coarse grid, the waveforms obtained from the proposed method are matched well with the analytic result, and the accuracy of the proposed method is higher than the traditional AH-FDTD. And the efficiency of the proposed method is higher than the traditional FDTD method in analysing 2D waveguide problems with fine-structure.

  1. Novel archaeal plasmid pAH1 and its interactions with the lipothrixvirus AFV1

    DEFF Research Database (Denmark)

    Basta, Tamara; Smyth, John; Forterre, Patrick

    2009-01-01

    . Although nucleotide sequence comparisons revealed extensive intergenomic exchange during the evolution of archaeal conjugative plasmids, pAH1 was shown to be stably maintained suggesting that the host system is suitable for studying plasmid-virus interactions. AFV1 infection and propagation leads to a loss...... of the circular form of pAH1 and this effect correlates positively with the increase in the intracellular quantity of AFV1 DNA. We infer that the virus inhibits plasmid replication since no pAH1 degradation was observed. This mechanism of archaeal viral inhibition of plasmid propagation is not observed...... in bacteria where relevant bacteriophages either are dependent on a conjugative plasmid for successful infection or are excluded by a resident plasmid....

  2. Identification and simulation evaluation of an AH-64 helicopter hover math model

    Science.gov (United States)

    Schroeder, J. A.; Watson, D. C.; Tischler, M. B.; Eshow, M. M.

    1991-01-01

    Frequency-domain parameter-identification techniques were used to develop a hover mathematical model of the AH-64 Apache helicopter from flight data. The unstable AH-64 bare-airframe characteristics without a stability-augmentation system were parameterized in the convectional stability-derivative form. To improve the model's vertical response, a simple transfer-function model approximating the effects of dynamic inflow was developed. Additional subcomponents of the vehicle were also modeled and simulated, such as a basic engine response for hover and the vehicle stick dynamic characteristics. The model, with and without stability augmentation, was then evaluated by AH-64 pilots in a moving-base simulation. It was the opinion of the pilots that the simulation was a satisfactory representation of the aircraft for the tasks of interest. The principal negative comment was that height control was more difficult in the simulation than in the aircraft.

  3. An Exploratory Study of the Rhetoric in CSR Reports: A Comparison of Shari’ah Compliant Company and Non –Shari’ah Compliant Company in Malaysia

    Directory of Open Access Journals (Sweden)

    Abdul Razak Rafizan

    2017-01-01

    Full Text Available This paper advances previous research in corporate social reporting (CSR by using a taxonomy of five distinct rhetorical strategies to examine any differences in term of type of ethical categories and to identify moral attitudes towards different societal activities between Shari’ah compliant company Bank Islam Malaysia Berhad (BIMB and Non-Shari’ah compliant company Malayan Banking Berhad (Maybank. The data is analyzed using content analysis. The findings revealed that there are different rhetoric applied in both types of companies such as Agency (profit, Benefit (collective welfare, Compliance (law and contracts, Duty and Ethos (virtue. In term of moral attitudes, both types of companies disclosed relatively similar behaviour and commitment towards CSR. This research is the first of its kind to be conducted in Malaysia by using this new approach and will contribute new insights to existing CSR literatures in Malaysia.

  4. Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Le Vee, Marc; Jouan, Elodie; Lecureur, Valérie [Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes (France); Fardel, Olivier, E-mail: olivier.fardel@univ-rennes1.fr [Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes (France); Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 35033 Rennes (France)

    2016-01-01

    The heterodimeric L-type amino acid transporter (LAT) 1/CD98hc is overexpressed in lung cancers with a poor prognosis factor. Factors that contribute to LAT1/CD98hc overexpression in lung cells remain however to be determined, but the implication of atmospheric pollution can be suspected. The present study was therefore designed to analyze the effects of diesel exhaust particle (DEP) extract (DEPe) on LAT1/CD98hc expression in bronchial epithelial BEAS-2B cells. Exposure to DEPe up-regulated LAT1 and CD98hc mRNA levels in a concentration-dependent manner, with DEPe EC{sub 50} values (around 0.2 μg/mL) relevant to environmental situations. DEPe concomitantly induced LAT1/CD98hc protein expression and LAT1-mediated leucine accumulation in BEAS-2B cells. Inhibition of the aryl hydrocarbon receptor (AhR) pathway through the use of a chemical AhR antagonist or the siRNA-mediated silencing of AhR expression was next found to prevent DEPe-mediated induction of LAT1/CD98hc, indicating that this regulation depends on AhR, known to be activated by major chemical DEP components like polycyclic aromatic hydrocarbons. DEPe exposure was finally shown to induce mRNA expression and activity of matrix metalloproteinase (MMP)-2 in BEAS-2B cells, in a CD98hc/focal adhesion kinase (FAK)/extracellular regulated kinase (ERK) manner, thus suggesting that DEPe-mediated induction of CD98hc triggers activation of the integrin/FAK/ERK signaling pathway known to be involved in MMP-2 regulation. Taken together, these data demonstrate that exposure to DEPe induces functional overexpression of the amino acid transporter LAT1/CD98hc in lung cells. Such a regulation may participate to pulmonary carcinogenic effects of DEPs, owing to the well-documented contribution of LAT1 and CD98hc to cancer development. - Highlights: • The amino acid transporter LAT1/CD98hc is up-regulated in DEPe-treated lung cells. • The aryl hydrocarbon receptor is involved in DEPe-triggered induction of LAT1/CD98hc.

  5. Novel reassortant influenza A(H1N2) virus derived from A(H1N1)pdm09 virus isolated from swine, Japan, 2012.

    Science.gov (United States)

    Kobayashi, Miho; Takayama, Ikuyo; Kageyama, Tsutomu; Tsukagoshi, Hiroyuki; Saitoh, Mika; Ishioka, Taisei; Yokota, Yoko; Kimura, Hirokazu; Tashiro, Masato; Kozawa, Kunihisa

    2013-12-01

    We isolated a novel influenza virus A(H1N2) strain from a pig on January 13, 2012, in Gunma Prefecture, Japan. Phylogenetic analysis showed that the strain was a novel type of double-reassortant virus derived from the swine influenza virus strains H1N1pdm09 and H1N2, which were prevalent in Gunma at that time.

  6. Penyelesaian Sengketa antara Bank Sharî‘ah dengan Nasabah Bermasalah melalui Badan Arbitrase Sharî‘ah Nasional (BASYARNAS menurut UU No. 30 tahun 1999

    Directory of Open Access Journals (Sweden)

    Sulistyowati Sulistyowati

    2015-09-01

    Full Text Available This study deals with dispute settlement between Bank Syari’ah and its customers through the National Shari’ah Arbitration Board (BASYARNAS. It focuses to elaborate the procedures of dispute settlement between Bank Syari’ah and its customers of financing from the perspective of Islamic law according to Bill No. 30/1999 above law No. 30 year 1999. Based on procedures as mentioned in the bill with regard to arbitration and alternative dispute resolution, Basyarnas, in proofing and resolving cases, has fulfilled the procedures and satisfied the conflicting parties with justice, so there is no need to appeal and reconsideration. This means that Basyarnas has conducted dispute resolution according to the existing procedures. The dispute settlement has also been in accordance with the Qur’ân and other Islamic legal rules which consist of the principles of power and mandate applied by the arbitrator in deciding and resolving the dispute. The board—as an independent institution—has setttled the disputes on the basis of justice for all parties, rejected the act of bribery since the cost is measurable. In addition, Basyarnas also gives strong emphasis on the principle of equality, friendship, consistence and response-bility in resolving disputes.

  7. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  8. Month of the Year and Pre- Holiday Effects In Indonesia and Malaysia Shari’ah Compliance

    Directory of Open Access Journals (Sweden)

    Helma Malini

    2014-01-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} This paper investigates the existence of two anomalies in Indonesia and Malaysia Shari’ah compliance; the month of the year and pre-holiday effect, and their implication for stock market efficiency. Investing in Shari’ah compliant is different from investing in conventional stock. Conventional stock market followed the capital market set of rules and law, while Shari’ah follows not only followed the capital market set of laws but also the Islamic principles. Most of the previous studies investigated issues related to the conventional stock market, this study take one step further by investigating issue related to Shari’ah compliant instrument and make comparison between both Shari’ah compliance stock market in Indonesia and Malaysia. We document high and significant returns in month and pre-holiday in Indonesia and Malaysia stock market that represent by the Shari’ah compliance. Our result indicate that the month of the year effect is prevalent in Indonesia and Malaysia Shari’ah compliance.   Keywords: Calendar effects, Indonesia and Malaysia Shari’ah compliance, Month of the year and pre-holiday effects

  9. A purely infinite AH-algebra and an application to AF-embeddability

    OpenAIRE

    Rordam, Mikael

    2002-01-01

    We show that there exists a purely infinite AH-algebra. The AH-algebra arises as an inductive limit of C*-algebras of the form C_0([0,1),M_k) and it absorbs the Cuntz algebra O_\\infty tensorially. Thus one can reach an O_\\infty-absorbing C*-algebra as an inductive limit of the finite and elementary C*-algebras C_0([0,1),M_k). As an application we give a new proof of a recent theorem of Ozawa that the cone over any separable exact C*-algebra is AF-embeddable, and we exhibit a concrete AF-algeb...

  10. Influenza A/H1N1 Severe Pneumonia: Novel Morphocytological Findings in Bronchoalveolar Lavage

    Directory of Open Access Journals (Sweden)

    Paola Faverio

    2014-01-01

    Full Text Available We present the results of bronchoalveolar lavage (BAL performed in three patients with severe influenza A/H1N1 pneumonia complicated by acute respiratory distress syndrome (ARDS. Light microscopy analysis of BAL cytocentrifugates showed the presence of characteristic large, mononuclear, plasmoblastic/plasmocytoid-like cells never described before. Via transmission electron microscopy, these cells were classified as atypical type II pneumocytes and some of them showed cytoplasmic vesicles and inclusions. We concluded that plasmoblastic/plasmocytoid-like type II pneumocytes might represent a morphologic marker of A/H1N1 influenza virus infection as well as reparative cellular activation after diffuse alveolar damage.

  11. Influenza A(H10N7) Virus in Dead Harbor Seals, Denmark

    DEFF Research Database (Denmark)

    Krog, Jesper Schak; Hansen, Mette Sif; Holm, Elisabeth

    2015-01-01

    Since April 2014, an outbreak of influenza in harbor seals has been ongoing in northern Europe. In Denmark during June-August, 152 harbor seals on the island of Anholt were found dead from severe pneumonia. We detected influenza A(H10N7) virus in 2 of 4 seals examined.......Since April 2014, an outbreak of influenza in harbor seals has been ongoing in northern Europe. In Denmark during June-August, 152 harbor seals on the island of Anholt were found dead from severe pneumonia. We detected influenza A(H10N7) virus in 2 of 4 seals examined....

  12. Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals.

    Science.gov (United States)

    Park, Joo-Hung; Lee, Jeong-Min; Lee, Eun-Jin; Kim, Da-Jeong; Hwang, Won-Bhin

    2018-04-01

    Various amino acids regulate cell growth and differentiation. In the present study, we examined the ability of HT-29 cells to differentiate into goblet cells in RPMI and DMEM which are largely different in the amounts of numerous amino acids. Most of the HT-29 cells differentiated into goblet cells downregulating the stem cell marker Lgr5 when cultured in DMEM, but remained undifferentiated in RPMI. The goblet cell differentiation in DMEM was inhibited by 1-methyl-tryptophan (1-MT), an inhibitor of indoleamine 2,3 dioxygenase-1 which is the initial enzyme in tryptophan metabolism along the kynurenine (KN) pathway, whereas tryptophan and KN induced goblet cell differentiation in RPMI. The levels of Notch1 and its activation product Notch intracytoplasmic domain in HT-29 cells were lower in DMEM than those in RPMI and were increased by 1-MT in both media. HT-29 cells grown in both media expressed β-catenin at the same level on day 2 when goblet cell differentiation was not observed. β-catenin expression, which was increased by 1-MT in both media, was decreased by KN. DMEM reduced Hes1 expression while enhancing Hath1 expression. Finally, aryl hydrocarbon receptor (AhR) activation moderately induced goblet cell differentiation. Our results suggest that KN promotes goblet cell differentiation by regulating Wnt, Notch, and AhR signals and expression of Hes1 and Hath1.

  13. A Non-imaging High Throughput Approach to Chemical Library Screening at the Unmodified Adenosine-A3 Receptor in Living Cells

    Directory of Open Access Journals (Sweden)

    Maria Augusta Arruda

    2017-12-01

    Full Text Available Recent advances in fluorescent ligand technology have enabled the study of G protein-coupled receptors in their native environment without the need for genetic modification such as addition of N-terminal fluorescent or bioluminescent tags. Here, we have used a non-imaging plate reader (PHERAstar FS to monitor the binding of fluorescent ligands to the human adenosine-A3 receptor (A3AR; CA200645 and AV039, stably expressed in CHO-K1 cells. To verify that this method was suitable for the study of other GPCRs, assays at the human adenosine-A1 receptor, and β1 and β2 adrenoceptors (β1AR and β2AR; BODIPY-TMR-CGP-12177 were also carried out. Affinity values determined for the binding of the fluorescent ligands CA200645 and AV039 to A3AR for a range of classical adenosine receptor antagonists were consistent with A3AR pharmacology and correlated well (R2 = 0.94 with equivalent data obtained using a confocal imaging plate reader (ImageXpress Ultra. The binding of BODIPY-TMR-CGP-12177 to the β1AR was potently inhibited by low concentrations of the β1-selective antagonist CGP 20712A (pKi 9.68 but not by the β2-selective antagonist ICI 118551(pKi 7.40. Furthermore, in experiments conducted in CHO K1 cells expressing the β2AR this affinity order was reversed with ICI 118551 showing the highest affinity (pKi 8.73 and CGP20712A (pKi 5.68 the lowest affinity. To determine whether the faster data acquisition of the non-imaging plate reader (~3 min per 96-well plate was suitable for high throughput screening (HTS, we screened the LOPAC library for inhibitors of the binding of CA200645 to the A3AR. From the initial 1,263 compounds evaluated, 67 hits (defined as those that inhibited the total binding of 25 nM CA200645 by ≥40% were identified. All compounds within the library that had medium to high affinity for the A3AR (pKi ≥6 were successfully identified. We found three novel compounds in the library that displayed unexpected sub-micromolar affinity

  14. Distribution of the P2X2 receptor and chemical coding in ileal enteric neurons of obese male mice (ob/ob)

    Science.gov (United States)

    Mizuno, Márcia Sanae; Crisma, Amanda Rabello; Borelli, Primavera; Schäfer, Bárbara Tavares; Silveira, Mariana Póvoa; Castelucci, Patricia

    2014-01-01

    AIM: To investigate the colocalization, density and profile of neuronal areas of enteric neurons in the ileum of male obese mice. METHODS: The small intestinal samples of male mice in an obese group (OG) (C57BL/6J ob/ob) and a control group (CG) (+/+) were used. The tissues were analyzed using a double immunostaining technique for immunoreactivity (ir) of the P2X2 receptor, nitric oxide synthase (NOS), choline acetyl transferase (ChAT) and calretinin (Calr). Also, we investigated the density and profile of neuronal areas of the NOS-, ChAT- and Calr-ir neurons in the myenteric plexus. Myenteric neurons were labeled using an NADH-diaphorase histochemical staining method. RESULTS: The analysis demonstrated that the P2X2 receptor was expressed in the cytoplasm and in the nuclear and cytoplasmic membranes only in the CG. Neuronal density values (neuron/cm2) decreased 31% (CG: 6579 ± 837; OG: 4556 ± 407) and 16.5% (CG: 7796 ± 528; OG: 6513 ± 610) in the NOS-ir and calretinin-ir neurons in the OG, respectively (P < 0.05). Density of ChAT-ir (CG: 6200 ± 310; OG: 8125 ± 749) neurons significantly increased 31% in the OG (P < 0.05). Neuron size studies demonstrated that NOS, ChAT, and Calr-ir neurons did not differ significantly between the CG and OG groups. The examination of NADH-diaphorase-positive myenteric neurons revealed an overall similarity between the OG and CG. CONCLUSION: Obesity may exert its effects by promoting a decrease in P2X2 receptor expression and modifications in the density of the NOS-ir, ChAT-ir and CalR-ir myenteric neurons. PMID:25320527

  15. Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring

    International Nuclear Information System (INIS)

    Takagi, Hironori; Shibutani, Makoto; Lee, Kyoung-Youl; Masutomi, Naoya; Fujita, Haruka; Inoue, Kaoru; Mitsumori, Kunitoshi; Hirose, Masao

    2005-01-01

    We have previously examined the impact of perinatal exposure to ethinylestradiol (EE), methoxychlor (MXC), diisononyl phthalate (DINP), and genistein (GEN) in maternal diet on rat offspring, and found developmental and/or reproductive toxicity with 0.5 ppm EE, 1200 ppm MXC, and 20,000 ppm DINP. Although the toxicological profile with MXC was similar to the EE case, the population changes in pituitary hormone-producing cells totally differed between the two cases, changes being evident from 240 ppm with MXC. In the present study, to assess the impact of these agents on brain sexual differentiation, region-specific mRNA expression of estrogen receptors (ER) α and β, the progesterone receptor (PR), gonadotrophin-releasing hormone, steroid receptor coactivators (SRC)-1 and -2, and calbindin-D in microdissected hypothalamic medial preoptic areas (MPOAs) at postnatal day 10 was first analyzed in rats exposed to 0.5 ppm-EE from gestational day 15 by real-time RT-PCR. Sexually dimorphic expression of ERα and PR was noted with predominance in females and males, respectively, EE up-regulating SRC-1 in males and ERβ and PR in females. Next, we similarly examined expression changes of ERα and β, PR, and SRC-1 in animals exposed to MXC at 24, 240, and 1200 ppm, DINP at 4000 and 20,000 ppm, and GEN at 1000 ppm. MXC at 1200 ppm down- and up-regulated PR in males and females, respectively, and DINP at 20,000 ppm down-regulated PR in females, while GEN did not exert any clear effects. The results thus suggest that agents causing developmental and/or reproductive abnormalities in later life may affect hypothalamic PR expression during the exposure period in early life

  16. Integrated in silico and in vivo approaches to investigate effects of BDE-99 mediated by the nuclear receptors on developing zebrafish.

    Science.gov (United States)

    Zhang, Li; Jin, Yaru; Han, Zhihua; Liu, Hongling; Shi, Laihao; Hua, Xiaoxue; Doering, Jon A; Tang, Song; Giesy, John P; Yu, Hongxia

    2018-03-01

    One of the most abundant polybrominated diphenyl ethers (PBDEs) is 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), which persists and potentially bioaccumulates in aquatic wildlife. Previous studies in mammals have shown that BDE-99 affects development and disrupts certain endocrine functions through signaling pathways mediated by nuclear receptors. However, fewer studies have investigated the potential of BDE-99 to interact with nuclear receptors in aquatic vertebrates such as fish. In the present study, interactions between BDE-99 and nuclear receptors were investigated by in silico and in vivo approaches. This PBDE was able to dock into the ligand-binding domain of zebrafish aryl hydrocarbon receptor 2 (AhR2) and pregnane X receptor (PXR). It had a significant effect on the transcriptional profiles of genes associated with AhR or PXR. Based on the developed cytoscape of all zebrafish genes, it was also inferred that AhR and PXR could interact via cross-talk. In addition, both the in silico and in vivo approaches found that BDE-99 affected peroxisome proliferator-activated receptor alpha (PPARα), glucocorticoid receptor, and thyroid receptor. Collectively, our results demonstrate for the first time detailed in silico evidence that BDE-99 can bind to and interact with zebrafish AhR and PXR. These findings can be used to elaborate the molecular mechanism of BDE-99 and guide more objective environmental risk assessments. Environ Toxicol Chem 2018;37:780-787. © 2017 SETAC. © 2017 SETAC.

  17. Anti-phase synchronization of influenza A/H1N1 and A/H3N2 in Hong Kong and countries in the North Temperate Zone

    Directory of Open Access Journals (Sweden)

    Alice P.Y. Chiu

    2018-01-01

    Conclusions: These results are novel in identifying anti-phase synchronization in influenza A subtypes in Hong Kong and the NTZ. These findings should inform public health preparedness for future epidemics of A/H3N2, which are typically more severe than those of A/H1N1.

  18. Mortality burden of the 2009 A/H1N1 influenza pandemic in France: comparison to seasonal influenza and the A/H3N2 pandemic.

    Directory of Open Access Journals (Sweden)

    Magali Lemaitre

    Full Text Available BACKGROUND: The mortality burden of the 2009 A/H1N1 pandemic remains unclear in many countries due to delays in reporting of death statistics. We estimate the age- and cause-specific excess mortality impact of the pandemic in France, relative to that of other countries and past epidemic and pandemic seasons. METHODS: We applied Serfling and Poisson excess mortality approaches to model weekly age- and cause-specific mortality rates from June 1969 through May 2010 in France. Indicators of influenza activity, time trends, and seasonal terms were included in the models. We also reviewed the literature for country-specific estimates of 2009 pandemic excess mortality rates to characterize geographical differences in the burden of this pandemic. RESULTS: The 2009 A/H1N1 pandemic was associated with 1.0 (95% Confidence Intervals (CI 0.2-1.9 excess respiratory deaths per 100,000 population in France, compared to rates per 100,000 of 44 (95% CI 43-45 for the A/H3N2 pandemic and 2.9 (95% CI 2.3-3.7 for average inter-pandemic seasons. The 2009 A/H1N1 pandemic had a 10.6-fold higher impact than inter-pandemic seasons in people aged 5-24 years and 3.8-fold lower impact among people over 65 years. CONCLUSIONS: The 2009 pandemic in France had low mortality impact in most age groups, relative to past influenza seasons, except in school-age children and young adults. The historical A/H3N2 pandemic was associated with much larger mortality impact than the 2009 pandemic, across all age groups and outcomes. Our 2009 pandemic excess mortality estimates for France fall within the range of previous estimates for high-income regions. Based on the analysis of several mortality outcomes and comparison with laboratory-confirmed 2009/H1N1 deaths, we conclude that cardio-respiratory and all-cause mortality lack precision to accurately measure the impact of this pandemic in high-income settings and that use of more specific mortality outcomes is important to obtain reliable

  19. Scoring and ranking of metabolic trees to computationally prioritize chemicals for testing using fit-for-purpose in vitro estrogen receptor assay

    Science.gov (United States)

    Increasing awareness about endocrine disrupting chemicals (EDCs) in the environment has driven concern about their potential impact on human health and wildlife. Tens of thousands of natural and synthetic xenobiotics are presently in commerce with little to no toxicity data and t...

  20. The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects.

    Directory of Open Access Journals (Sweden)

    Iana H Haralambieva

    Full Text Available Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly.We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles - TREC content, peripheral white blood cell telomerase - TERT expression and CD28 expression on T cells and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination.TERT activity (TERT mRNA expression was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025. TREC levels were positively correlated with the baseline and early (Day 3 influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively. The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28 was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively.Our data suggest that influenza-specific humoral immunity is significantly influenced by

  1. Effectiveness of A(H1N1)pdm09 influenza vaccine in adults recommended for annual influenza vaccination.

    NARCIS (Netherlands)

    Gefenaite, G.; Tacken, M.; Bos, J.; Stirbu-Wagner, I.; Korevaar, J.C.; Stolk, R.P.; Wolters, B.; Bijl, M.; Postma, M.J.; Wilschut, J.; Nichol, K.L.; Hak, E.

    2013-01-01

    Introduction: Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we conducted a study in the adults belonging to the risk groups to assess the A(H1N1)pdm09 MF59-adjuvanted influenza vaccine effectiveness. Methods: VE against influenza and/or pneumonia was

  2. IEEE 802.11ah: A Technology to Face the IoT Challenge.

    Science.gov (United States)

    Baños-Gonzalez, Victor; Afaqui, M Shahwaiz; Lopez-Aguilera, Elena; Garcia-Villegas, Eduard

    2016-11-22

    Since the conception of the Internet of things (IoT), a large number of promising applications and technologies have been developed, which will change different aspects in our daily life. This paper explores the key characteristics of the forthcoming IEEE 802.11ah specification. This future IEEE 802.11 standard aims to amend the IEEE 802.11 legacy specification to support IoT requirements. We present a thorough evaluation of the foregoing amendment in comparison to the most notable IEEE 802.11 standards. In addition, we expose the capabilities of future IEEE 802.11ah in supporting different IoT applications. Also, we provide a brief overview of the technology contenders that are competing to cover the IoT communications framework. Numerical results are presented showing how the future IEEE 802.11ah specification offers the features required by IoT communications, thus putting forward IEEE 802.11ah as a technology to cater the needs of the Internet of Things paradigm.

  3. Pandemic influenza A/H1N1 virus incursion into Africa: countries ...

    African Journals Online (AJOL)

    Pandemic influenza A/H1N1 virus incursion into Africa: countries, hosts and ... features are important for planning control measures between countries and to ... in humans, infections in pigs earlier reported in America, Europe and Asia were ...

  4. Inhibition of Vibrio anguillarum by Pseudomonas fluorescens AH2, a possible probiotic treatment of fish

    DEFF Research Database (Denmark)

    Gram, Lone; Melchiorsen, Jette; Spanggaard, Bettina

    1999-01-01

    To study the possible use of probiotics in fish farming, we evaluated the in vitro and in vivo antagonism of antibacterial strain Pseudomonas fluorescens strain AH2 against the fish- pathogenic bacterium Vibrio anguillarum. As iron is important in virulence and bacterial interactions, the effect....... fluorescens AH2 inhibited the growth of V. anguillarum during coculture, independently of the iron concentration, when the initial count of the antagonist was 100 to 1,000 times greater that of the fish pathogen. These in vitro results were successfully repeated in vivo. A probiotic effect in vivo was tested...... by exposing rainbow trout (Oncorynchus mykiss Walbaum) to P. fluorescens AH2 at a density of 10(5) CFU/ml for 5 days before a challenge with V. anguillarum at 10(4) to 10(5) CFU/ml for 1 h. Some fish were also exposed to P. fluorescens AH2 at 10(7) CFU/ml during the 1-h infection. The combined probiotic...

  5. Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus. [Mice

    Energy Technology Data Exchange (ETDEWEB)

    Nebert, D.W.; Levitt, R.C.; Jensen, N.M.; Lambert, G.H.; Felton, J.S.

    1977-01-01

    The balance between cytochrome(s) P/sub 1/-450 and other forms of P-450 in the liver, and probably many nonhepatic tissues as well, appears to be important in the toxicity, carcinogenicity, mutagenicity, and teratogenicity of numerous compounds. Thus, allelic differences in a single gene--the Ah locus-- can have profound effects on the susceptibility of mice to drug toxicity and cancer. There is evidence for the Ah lous in the human. Striking increases in the incidence of stillborns, reorptions,and malformations caused by 3-methylcholanthrene or 7,12-dimethylbenz(a)anthracene were observed in the aromatic hydrocarbon responsive C57BL/6N,C3H/HeN, and BALB/cAnN inbred strains, compared with the genetically nonresponsive AKR/N. These data suggest that an association exists between the Ah locus and teratogenesis. Although numerous teratogenic differences among inbred mouse strains have been previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance, on the basis of known differences in polycyclic hydrocarbon metabolism regulated by the Ah locus.

  6. HOW SHOULD SHARI’AH PRINCIPLES BE APPLIED IN MODERN COMPANY?

    Directory of Open Access Journals (Sweden)

    Burhanuddin Susamto

    2012-06-01

    Full Text Available The purpose of this study is to show why the modern business institution (company should be Islamized, and to suggest ways in which shari’ah principles can be applied in the company. To achieve this purpose, we should understand how company be islamized in comprehensive and integrated  manner through the Islamic law perspective, with the contemporary issues like underlying contract of company,  legal entity, and the concept of liability. The resolution of these issues is important to assert that shari’ah principles could be applied in the modern company by integrating approach. An integrating approach in the treating of these issues has, however, been lacking, nor has it been subjected to a thorough legal analysis through the principles of Islamic business law.   Tujuan dari pembahasan ini adalah untuk menunjukkan bahwa institusi bisnis modern (perusahaan harus diislamisasi, dan member masukan cara-cara bagimana prinsip- prinsip shari’ah dapat ditetapkan dalam perusahaan. Untuk mencapai tujuan ini, kita perlu memahami bagaimana perusahaan diislamisasi secara menyeluruh dan terintegrasi melalui perspektif hukum Islam terhadap persoalan kontemporer, seperti landasan kontrak perusahaan, badan hukum, dan konsep liabilitas. Solusi dari persoalan ini sangat penting untuk   menegaskan bahwa prinsip-prinsip shari’ah dapat ditetapkan pada perusahaan modern melalui pendekatan integrasi. Bagaimanapun, pendekatan integrasi dalam menyikapi persoalan ini jarang dilakukan, disamping tidak menjadi tema analisis melalui prinsip-prinsip hukum bisnis Islami.

  7. Outcomes of influenza A(H1N1)pdm09 virus infection

    DEFF Research Database (Denmark)

    Lynfield, Ruth; Davey, Richard; Dwyer, Dominic E

    2014-01-01

    BACKGROUND: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were...

  8. The Influenza A(H1N1)v Pandemic : An Exploratory System Dynamics Approach

    NARCIS (Netherlands)

    Pruyt, E.; Hamarat, C.

    2010-01-01

    This paper presents a small exploratory System Dynamics model related to the dynamics of the 2009 flu pandemic, also known as the Mexican flu, swine flu, or A(H1N1)v. The model was developed in May 2009 in order to quickly foster understanding about the possible dynamics of this new flu variant and

  9. Influenza AH1N2 Viruses, United Kingdom, 2001?02 Influenza Season

    OpenAIRE

    Ellis, Joanna S.; Alvarez-Aguero, Adriana; Gregory, Vicky; Lin, Yi Pu; Hay, A.; Zambon, Maria C.

    2003-01-01

    During the winter of 2001?02, influenza AH1N2 viruses were detected for the first time in humans in the U.K. The H1N2 viruses co-circulated with H3N2 viruses and a very small number of H1N1 viruses and were isolated in the community and hospitalized patients, predominantly from children

  10. Outbreak of pandemic influenza A/H1N1 2009 in Nepal.

    Science.gov (United States)

    Adhikari, Bal Ram; Shakya, Geeta; Upadhyay, Bishnu Prasad; Prakash Kc, Khagendra; Shrestha, Sirjana Devi; Dhungana, Guna Raj

    2011-03-23

    The 2009 flu pandemic is a global outbreak of a new strain of H1N1 influenza virus. Pandemic influenza A (H1N1) 2009 has posed a serious public health challenge world-wide. Nepal has started Laboratory diagnosis of Pandemic influenza A/H1N1 from mid June 2009 though active screening of febrile travellers with respiratory symptoms was started from April 27, 2009. Out of 609 collected samples, 302 (49.6%) were Universal Influenza A positive. Among the influenza A positive samples, 172(28.3%) were positive for Pandemic influenza A/H1N1 and 130 (21.3%) were Seasonal influenza A. Most of the pandemic cases (53%) were found among young people with ≤ 20 years. Case Fatality Ratio for Pandemic influenza A/H1N1 in Nepal was 1.74%. Upon Molecular characterization, all the isolated pandemic influenza A/H1N1 2009 virus found in Nepal were antigenically and genetically related to the novel influenza A/CALIFORNIA/07/2009-LIKE (H1N1)v type. The Pandemic 2009 influenza virus found in Nepal were antigenically and genetically related to the novel A/CALIFORNIA/07/2009-LIKE (H1N1)v type.

  11. A Challenge for Social Studies Educators: Teaching about Islam, "Jihad," and "Shari'ah" Law

    Science.gov (United States)

    Moore, James R.

    2012-01-01

    In this article, the author investigates the controversial curricular and instructional aspects of teaching about Islam in social studies courses. Specifically, the author discusses pedagogically sound approaches to teaching about "jihad" and "Shari'ah" law, two of the most important and controversial concepts in Islam that often generate intense…

  12. 'Urf / 'Adah (Custom) : An Ancillary Mechanism in Shari'ah | Salisu ...

    African Journals Online (AJOL)

    According to the legal maxim in Islamic legislative system, custom ('Urf / 'Adah) is said to be authoritative (al-'adah Muhakkamah). Thus, right from the inception of Islam, it has been playing a decisive role in the dispensation of Shari'ah. Indeed, medieval and modern works in Islamic jurisprudence ('Usul al-Fiqh) are replete ...

  13. Shari’ah-Compliant E-Commerce Models and Consumer Trust

    Directory of Open Access Journals (Sweden)

    Muhammad Kholifatul I Ardiansyah

    2016-07-01

    Full Text Available This study is aimed at finding out the real picture of Shari’ah-compliant E-commerce model and consumer trust in e-commerce today, analyzing its drawbacks, and finding out how they influence each other. Shari'ah-compliant E-commerce model is a model that describes how e-commerce should run in accordance with the provisions of the Shari’ah. Broadly speaking, e-commerce in the perspective of Shari’ah must comply with some rules, namely: 1. the form of the offer and transaction agreement; 2. the transacting parties (buyers and sellers; 3. Objects and prices in the transaction; 4. Free from major prohibitions in transactions. The sample in this study is Indonesian citizen who are consumers of e-commerce. This research uses descriptive and statistical methods with multiple linear regression model. This model is considered relevant and good to be studied in order to enlighten how e-commerce is currently in the perspective of IslamDOI: 10.15408/aiq.v8i2.2913

  14. Influenza A(H9N2) Virus, Myanmar, 2014-2015.

    Science.gov (United States)

    Lin, Thant Nyi; Nonthabenjawan, Nutthawan; Chaiyawong, Supassama; Bunpapong, Napawan; Boonyapisitsopa, Supanat; Janetanakit, Taveesak; Mon, Pont Pont; Mon, Hla Hla; Oo, Kyaw Naing; Oo, Sandi Myint; Mar Win, Mar; Amonsin, Alongkorn

    2017-06-01

    Routine surveillance of influenza A virus was conducted in Myanmar during 2014-2015. Influenza A(H9N2) virus was isolated in Shan State, upper Myanmar. Whole-genome sequencing showed that H9N2 virus from Myanmar was closely related to H9N2 virus of clade 4.2.5 from China.

  15. Physical Parameters of the Overcontact Binary AH Cnc in the Old Open Cluster M 67

    NARCIS (Netherlands)

    Yakut, K.; Aerts, C.C.

    2006-01-01

    We present a photometric study of the overcontact binary AH Cnc. The CCD observations were done with the Russian-Turkish 1.5 m telescope and the light-curve was solved with the Wilson-Devinney code. The physical parameters of the components have been deduced as M1 = 1.22 Msun,

  16. Architectuur als beschavingsideaal : Het bezield modernisme van A.H. Wegerif

    NARCIS (Netherlands)

    Thomas, H.

    2014-01-01

    Architecture as civilizing ideal - The inspired modernism of A.H. Wegerif Ahazuerus Hendrikus (Henk) Wegerif was born in Apeldoorn on 13th of April 1888, the son of Gerrit Wegerif and Elsje Breman. Both his father and grandfather were building contractors, as was his paternal uncle, Chris Wegerif.

  17. Syari’ah, Fiqih dan Sebuah Perspektif tentang Tarjîh

    Directory of Open Access Journals (Sweden)

    Miftahul Huda

    2014-01-01

    Full Text Available This paper takes into account the very fact that Syari’ah has been a subject of controversy over centuries. Its interpretation in the form of fiqh (Islamic jurisprudence is a strong indication that Syari’ah is not immune from personal subjectivication. Fiqh is quite personal whereby a jurist would read the message of Syari’ah and attempt to give his personal and subjective interpretation of it. Nonetheless, the paper is also of the argument that this controversy is in itself a source of the dynamics of Syari’ah. It is due to this controversy–otherwise known as the legal dispute- that fiqh is capable of being developed over times. Some substances of fiqh are responses to the opposing views on some issues. Not less important than this is to delve into the factors that triggered such controversy and dispute. The paper speaks of three factors, namely the nature of subject-matter, the way the jurists interpret it, and the social circumstances that surround the jurists and help shape their way of thinking. The first is epistemological, the second methodological, whereas the third to sociological. The three factors are inter-related and form as it were the comprehensive legal products which the Muslims currently inherited. The Tarjih in the meantime, is a form of a legal product, which serves both as a social and intellectual modality for the Muslims in their daily lives.

  18. Outbreak of pandemic influenza A/H1N1 2009 in Nepal

    Directory of Open Access Journals (Sweden)

    Shrestha Sirjana

    2011-03-01

    Full Text Available Abstract Background The 2009 flu pandemic is a global outbreak of a new strain of H1N1 influenza virus. Pandemic influenza A (H1N1 2009 has posed a serious public health challenge world-wide. Nepal has started Laboratory diagnosis of Pandemic influenza A/H1N1 from mid June 2009 though active screening of febrile travellers with respiratory symptoms was started from April 27, 2009. Results Out of 609 collected samples, 302 (49.6% were Universal Influenza A positive. Among the influenza A positive samples, 172(28.3% were positive for Pandemic influenza A/H1N1 and 130 (21.3% were Seasonal influenza A. Most of the pandemic cases (53% were found among young people with ≤ 20 years. Case Fatality Ratio for Pandemic influenza A/H1N1 in Nepal was 1.74%. Upon Molecular characterization, all the isolated pandemic influenza A/H1N1 2009 virus found in Nepal were antigenically and genetically related to the novel influenza A/CALIFORNIA/07/2009-LIKE (H1N1v type. Conclusion The Pandemic 2009 influenza virus found in Nepal were antigenically and genetically related to the novel A/CALIFORNIA/07/2009-LIKE (H1N1v type.

  19. Outdoor Long-Range WLANs : A Lesson for IEEE 802.11ah

    NARCIS (Netherlands)

    Aust, Stefan; Venkatesha Prasad, R.; Niemegeers, Ignas G M M

    2015-01-01

    Several service applications have been reported by many who proposed the use of wireless LANs (WLANs) over a wide variety of outdoor deployments. In particular, the upcoming IEEE 802.11ah WLAN protocol will enable a longer transmission range between WLAN access points (APs) and stations (STAs) up to

  20. REINTERPRETASI PRINSIP KAFĀ’AH SEBAGAI NILAI DASAR DALAM POLA RELASI SUAMI ISTRI

    Directory of Open Access Journals (Sweden)

    Siti Jahroh

    2016-09-01

    Full Text Available Symptoms of domestic violence that occurs in marriage is due to the absence of equality or what is often called kafa>’ah in the fiqh al-muna>kah}ah between the prospective husband and wife. In this case the position of husband to wife is not equal, either in economic, social, education, culture, race/ethnicity, ancestry or religious level. Husband’s position which is not equivalent (as kufu>’ with his wife or vice versa, often triggers dispute between the two. Ongoing dispute, then followed by hurting words, beatings or physical abuse, irresponsible behavior, don’t meet the economic or biological needs, marry again, and even can also lead to a sadistic action or killing. In this perspective the author considers that if the value embodied in the kafa>‘ah concept is understood correctly and properly, it’ll actually give a positive chance to prevent domestic violence crime especially in the context of the relationship between husband and wife. [Gejala Kekerasan Dalam Rumah Tangga (KDRT yang terjadi dalam perkawinan, salah satunya disebabkan tidak adanya kesetaraan atau yang sering disebut dalam fiqh al-munâkahah dengan istilah kafa>’ah antara calon suami dengan calon istri. Dalam hal ini posisi suami dengan istri yang tidak setara, baik setara secara ekonomi, sosial, pendidikan, kultur, ras/suku, keturunan maupun tingkat keberagamaan. Posisi suami yang tidak setara (se-kufu’ dengan istrinya ataupun sebaliknya, sering kali memicu perselisihan di antara keduanya. Perselisihan yang terus-menerus, kemudian diiringi dengan kata-kata yang menyakitkan, tindak pemukulan atau penganiayaan fisik, perilaku yang tidak bertanggung jawab, tidak memenuhi kebutuhan ekonomis atau biologis, kawin lagi, bahkan dapat pula menjurus pada tindakan sadisme dengan menyengsarakan atau menghilangkan nyawa. Dalam perspektif inilah penulis memandang bahwa nilai yang terkandung dalam konsep kafa>’ah jika dipahami dengan tepat dan benar sebenarnya berpeluang

  1. MENGGAGAS PAYUNG HUKUM BAITUL MAAL WATTANWIL (BMT SEBAGAI KOPERASI SYARI’AH DALAM BINGKAI IUS CONSTITUENDUM

    Directory of Open Access Journals (Sweden)

    Elfa Murdiana

    2016-12-01

    Full Text Available Baitul Maal Wat Tanwil (BMT merupakan lembaga keuangan mikro syari’ah yang secara faktual telah memberikan pengaruh positif terhadap berlangsungnya pembangunan ekonomi di Indonesia. BMT sebagai koperasi syari’ah berada di bawah naungan Dinas Koperasi, konsekuensinya , segala aktivitas keuangan yang terjadi dilindungi oleh kebijakan Undang-undang Koperasi. Namun secara faktual keberadaan UU Koperasi justru belum mampu memberikan dasar hukum yang sesuai dengan praktik BMT yang ada. Oleh karenanya pembentukan aturan hukum yang pasti merupakan hal yang tak bisa ditunda lagi mengingat keberadaan BMT kian tumbuh dan semakin berkembang baik dari aspek jumlah maupun permodalannya. Dengan dibatalkannya UU Koperasi No.17 Tahun 2012 maka perlu bagi BMT memiliki aturan hukum tersendiri sebagai payung hukum bagi aktivitas BMT sebab Koperasi dan BMT (yang disejajarkan dengan Koperasi Syari’ah berbeda secara operasional dan prinsip. Oleh karenanya pembentukan Undang-Undang Koperasi Syari’ah sebagai dasar Hukum BMT harus segera dilaksanakan. Dalam rangka pembentukan UU Koperasi Syari’ah dalam kerangka Ius Constituendum  maka hendaknya perlu diperhatikan 3 nilai dasar , nilai dasar tersebut adalah: pertama Nilai Keadilan yang mendasari secara filosofis terbentuknya suatu aturan hukum ( Filosofiche Geltung dimana dasar ini merupakan suatu landasan ideal yang mengandung cita-cita kolektif masyarakat tentang nilai luhur yang  terkandung dalam Pancasila dan UUD 1945. Kedua adalah nilai kemanfaatan yang mendasari secara sosiologis ( soziologische geltung agar hukum memiliki kekuatan berlaku dimasyarakat. Ketika adalah nilai kepastian yang lahir sebagai dasar yuridis suatu aturan hukum( Juridische Geltung, dasar ini terkait dengan  persyaratan formal pembentukan suatu peraturan selanjutnya Landasan politis artinya bahwa keberadaan suatu aturan hukum merupakan suatu upaya menuangkan cita-cita kolektif masyarakat Indonesia dalam suatu aturan hukum melalui

  2. A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling.

    Science.gov (United States)

    Miret, Noelia; Rico-Leo, Eva; Pontillo, Carolina; Zotta, Elsa; Fernández-Salguero, Pedro; Randi, Andrea

    2017-11-01

    Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR-/- models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05μM HCB induced cell migration and TGF-β1 signaling, whereas 5μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR+/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR+/+ mice. Primary culture of mammary epithelial cells from AhR+/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5μM). Interestingly, AhR-/- mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds. Copyright © 2017. Published by Elsevier Inc.

  3. Changes in flip/flop splicing of astroglial AMPA receptors in human temporal lobe epilepsy.

    Science.gov (United States)

    Seifert, Gerald; Schröder, Wolfgang; Hinterkeuser, Stefan; Schumacher, Thekla; Schramm, Johannes; Steinhäuser, Christian

    2002-01-01

    Recent data suggested a role for glial cells in epilepsy. This study sought to identify and functionally characterize AMPA receptors expressed by astrocytes in human hippocampal tissue resected from patients with intractable temporal lobe epilepsy. Patch-clamp and fast application methods were combined to investigate astrocytes in situ and after fresh isolation from the stratum radiatum of the hippocampal CA1 subfield. Relying on presurgical and histopathologic analysis, we divided human specimens into two groups, Ammon's horn sclerosis (AHS) and lesion-associated epilepsy. Fast application of glutamate and kainate evoked receptor currents in all cells studied. Reversal-potential analysis revealed an intermediate Ca2+ permeability of the receptor channels that did not vary between the two groups of patients. However, preapplication of the AMPA receptor-specific modulator, cyclothiazide, disclosed differences in flip-flop splicing. This treatment considerably enhanced the receptor conductance, with potentiation being significantly stronger in cells from AHS specimens compared with lesion-associated cells, suggesting upregulation of AMPA receptor flip splice variants in astrocytes of the sclerotic tissue. Compelling evidence has been accumulated showing direct and rapid signaling between neurons and glial cells. Our data suggest that in AHS patients, neuronally released glutamate will lead to an enhanced and prolonged depolarization of astrocytes, which might be involved in seizure generation and spread in this particular condition of human temporal lobe epilepsy.

  4. Influence of substitution of the proton donor and proton acceptor abilities of molecules. 1. The development method of definition proton donor and proton acceptor abilities A-H containing molecules

    International Nuclear Information System (INIS)

    Nurulloev, M.; Narziev, B.N.; Islomov, Z.; Fayzieva, M.

    2005-01-01

    The influence of nature of the assistant is investigated in work, it is quantity and a site on proton donor and proton acceptor abilities. A-H containing organic connections and ways, of definition of these abilities are developed by the method, of IR spectroscopy. It is developed model and it offered a technique of definition of these abilities. It is shown that the proton donor and proton acceptor is abilities of molecules as constants, are one of individual physical and chemical characteristics A-H of containing organic connections. These sizes determine the abilities of molecules, to form the intermolecular hydrogen connections, disabilities of the H-complexes formed in condensed, environments concerning to the non replaced molecule

  5. A study of analysis PB1-F2 protein of Influenza Viruses A/H1N1pdm09, A/ H3N2, and A/H5N1

    Directory of Open Access Journals (Sweden)

    Hana Apsari Pawestri

    2016-07-01

    Full Text Available Abstrak Tujuan. Protein PB1-F2 (polymerase basic 1-frame 2 adalah protein terbaru yang ditemukan pada virus Influenza dan telah terbukti berperan dalam induksi kematian sel dan patogenitas. Tujuan dari tulisan ini adalah untuk menganalisis protein PB1-F2 pada virus Influenza A/H5N1 dan A/H1N1pdm09. Metode. Kami melakukan pencarian data yang relevan yaitu sekuens gen virus Influenza A/H5N1 dan A/H1N1pdm09 dari Gen Bank National Center for Biotechnology Information (NCBI selama tahun 1997-2015. Data yang digunakan adalah data sekuens nukleotida gen PB1 (polymerase basic1 virus influenza A/H5N1 dan A/H1N1pdm09. Kemudian dilakukan analisis alignment untuk mengetahui variasi protein dan mutasi yang berhubungan dengan patogenitas dan virulensi. Hasil. Kami melakukan penelitian terhadap sekuens PB1-F2 sebanyak 3262 influenza A/H5N1 dan 2472 Influenza A/H1N1pdm09. Hasil analisis menunjukkan bahwa semua sekuens A/H5N1 memiliki panjang yang penuh sebanyak 90 asam amino, kecuali influenza pandemi 2009 hanya memiliki panjang 87 asam amino. Kemudian, ditemukan mutasi yang berhubungan dengan virulensi yang ditunjukan dengan perubahan asam amino Asparagin (N menjadi Serin (S. Mutasi tersebut terjadi pada Influenza A/H5N1 sebanyak 8.5% dan Influenza A/H1N1pdm09 sebanyak 0.5%. Kesimpulan. Ditemukan beberapa variasi panjang asam amino dan mutasi penting pada sekuens PB1-F2 dari subtipe yang berbeda yaitu influenza A/H5N1 dan A/H1N1pdm09  yang mengindikasikan seleksi spesifik karena introduksi dan adaptasi terhadap inang yang berbeda. Diperlukan penelitian lanjutan untuk lebih memahami variasi dan kontribusi protein PB1-F2 tersebut terhadap virulensi dan patogenitas virus Influenza. Kata kunci : Patogenesis, Virus Influenza, Protein  PB1-F2 Abstract Aim. Influenza virus PB1-F2 (polymerase basic 1-frame 2 protein is a novel protein previously shown to be involved in cell death induction and pathogenesis. Here we analysis the PB1-F2 protein of Influenza virus A/H

  6. A study of analysis PB1-F2 protein of Influenza Viruses A/H1N1pdm09, A/ H3N2, and A/H5N1

    Directory of Open Access Journals (Sweden)

    Hana Apsari Pawestri

    2016-07-01

    Full Text Available Abstrak Tujuan. Protein PB1-F2 (polymerase basic 1-frame 2 adalah protein terbaru yang ditemukan pada virus Influenza dan telah terbukti berperan dalam induksi kematian sel dan patogenitas. Tujuan dari tulisan ini adalah untuk menganalisis protein PB1-F2 pada virus Influenza A/H5N1 dan A/H1N1pdm09. Metode. Kami melakukan pencarian data yang relevan yaitu sekuens gen virus Influenza A/H5N1 dan A/H1N1pdm09 dari Gen Bank National Center for Biotechnology Information (NCBI selama tahun 1997-2015. Data yang digunakan adalah data sekuens nukleotida gen PB1 (polymerase basic1 virus influenza A/H5N1 dan A/H1N1pdm09. Kemudian dilakukan analisis alignment untuk mengetahui variasi protein dan mutasi yang berhubungan dengan patogenitas dan virulensi. Hasil. Kami melakukan penelitian terhadap sekuens PB1-F2 sebanyak 3262 influenza A/H5N1 dan 2472 Influenza A/H1N1pdm09. Hasil analisis menunjukkan bahwa semua sekuens A/H5N1 memiliki panjang yang penuh sebanyak 90 asam amino, kecuali influenza pandemi 2009 hanya memiliki panjang 87 asam amino. Kemudian, ditemukan mutasi yang berhubungan dengan virulensi yang ditunjukan dengan perubahan asam amino Asparagin (N menjadi Serin (S. Mutasi tersebut terjadi pada Influenza A/H5N1 sebanyak 8.5% dan Influenza A/H1N1pdm09 sebanyak 0.5%. Kesimpulan. Ditemukan beberapa variasi panjang asam amino dan mutasi penting pada sekuens PB1-F2 dari subtipe yang berbeda yaitu influenza A/H5N1 dan A/H1N1pdm09  yang mengindikasikan seleksi spesifik karena introduksi dan adaptasi terhadap inang yang berbeda. Diperlukan penelitian lanjutan untuk lebih memahami variasi dan kontribusi protein PB1-F2 tersebut terhadap virulensi dan patogenitas virus Influenza. Kata kunci : Patogenesis, Virus Influenza, Protein  PB1-F2 Abstract Aim. Influenza virus PB1-F2 (polymerase basic 1-frame 2 protein is a novel protein previously shown to be involved in cell death induction and pathogenesis. Here we analysis the PB1-F2 protein of Influenza virus A/H

  7. Effectiveness of the influenza a(H1N1)PDM09 vaccine in adults recommended for annual influenza vaccination : A case-control study

    NARCIS (Netherlands)

    Gefenaite, Giedre; Tacken, Margot; Bos, Jens; Stirbu-Wagner, Irina; Korevaar, Joke C.; Stolk, Ronald P.; Wolters, Bert; Bijl, Marc; Postma, Maarten J.; Wilschut, Jan; Nichol, Kristin L.; Hak, Eelko

    Background: Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we aimed to assess the effectiveness of MF59-adjuvanted A(H1N1)pdm09 vaccine in a matched case-control study. Objectives: We aimed to assess the effectiveness of MF59- adjuvanted A(H1N1)pdm09

  8. Pengaruh Sistem Waralaba Terhadap Retail Kecil Di Ponorogo Tinjauan Maṣlaḥah

    Directory of Open Access Journals (Sweden)

    Siti Wulandari

    2016-05-01

    Full Text Available Abstract: One of the indications of the acceleration of economic progress in Ponorogo is the rapid development of the real sectors, especially the proliferation of modern businesses using the franchise system. Therefore, small retail businesses today are facing new competitors with huge capital and reliability of modern management. This study tries to find out the impact of the franchise system invasion to the existence of small retails, and how it affects the maṣlaḥah (safety of small retails in Ponorogo. This study uses the theory of maqāṣid al-sharīah in the aspects of ḥifẓ al-māl to analyze the sustainability of small retail businesses amid the proliferation of franchise businesses. Maṣlāḥah is thinking about the advantages and disadvantages on the basis of religious teachings by thinking about priorities and side with the community (al-maṣlaḥah al-'āmah. The results of this study found out the threat of franchise trading system to the existence of small retails. Therefore, the maṣlaḥah for small retail of businesses means the realization of the safety from the expansion of large investors, such as monopoly. Abstrak: Salah satu indikator meningkatnya laju perekonomian Kabupaten Ponorogo ditandai dengan pesatnya perkembangan sektor riil terutama dengan menjamurnya berbagai jenis toko-roko modern (khususnya dengan sistem waralaba yang terus bertambah jumlahnya. Lalu bagaimana dengan para pebisnis retail kecil yang kebanyakan mereka memiliki usaha dengan modal yang tidak terlalu besar. Penelitian ini berupaya mengetahui adakah  pengaruh yang terjadi akibat adanya toko-toko dengan sistem waralaba terhadap eksistensi retail kecil, serta adakah pengaruhnya terhadap kemaslahatan retail kecil yang ada di Ponorogo. Penelitian ini menggunakan teori keberlangsungan usaha yang dikaitkan dengan maqāsid al-shar’īah  aspek kemaslahatan hifz al-māl untuk menguji pengaruh kemaslahatan retail kecil dengan adanya bisnis

  9. Novel avian-origin human influenza A(H7N9) can be transmitted between ferrets via respiratory droplets.

    Science.gov (United States)

    Xu, Lili; Bao, Linlin; Deng, Wei; Dong, Libo; Zhu, Hua; Chen, Ting; Lv, Qi; Li, Fengdi; Yuan, Jing; Xiang, Zhiguang; Gao, Kai; Xu, Yanfeng; Huang, Lan; Li, Yanhong; Liu, Jiangning; Yao, Yanfeng; Yu, Pin; Li, Xiyan; Huang, Weijuan; Zhao, Xiang; Lan, Yu; Guo, Junfeng; Yong, Weidong; Wei, Qiang; Chen, Honglin; Zhang, Lianfeng; Qin, Chuan

    2014-02-15

    The outbreak of human infections caused by novel avian-origin influenza A(H7N9) in China since March 2013 underscores the need to better understand the pathogenicity and transmissibility of these viruses in mammals. In a ferret model, the pathogenicity of influenza A(H7N9) was found to be less than that of an influenza A(H5N1) strain but comparable to that of 2009 pandemic influenza A(H1N1), based on the clinical signs, mortality, virus dissemination, and results of histopathologic analyses. Influenza A(H7N9) could replicate in the upper and lower respiratory tract, the heart, the liver, and the olfactory bulb. It is worth noting that influenza A(H7N9) exhibited a low level of transmission between ferrets via respiratory droplets. There were 4 mutations in the virus isolated from the contact ferret: D678Y in the gene encoding PB2, R157K in the gene encoding hemagglutinin (H3 numbering), I109T in the gene encoding nucleoprotein, and T10I in the gene encoding neuraminidase. These data emphasized that avian-origin influenza A(H7N9) can be transmitted between mammals, highlighting its potential for human-to-human transmissibility.

  10. Anti hyperglycaemic study of natural inhibitors for Insulin receptor.

    Science.gov (United States)

    Chatterjee, Subhojyoti; Narasimhaiah, Akshaya Lakshmi; Kundu, Sanjay; Anand, Santosh

    2012-01-01

    Diabetes is a metabolic disorder associated with either improper functioning of the beta-cells or wherein cells fail to use insulin properly. Insulin, the principal hormone regulates uptake of glucose from the blood into most of the cells except central nervous system. Therefore, deficiency of insulin or the insensitivity of its receptors plays a key role in all forms of diabetes. In the present work, attempt has been made to find out plant sources which show anti hyperglycaemic activity (AhG) (i.e. compounds that bring down the blood glucose level in the body). Ayurvedic plants showing AhG activity formed the basis of our study by using the platform of Computer Aided Drug Designing (CADD). Among 600 plants showing AhG activity, 500 compounds were selected and screened, out of which 243 compounds showed drug likeness property that can be used as therapeutic ligand/drug. Initial screening of such compounds was done based on their drug likeness or biochemical properties. Dynamic interaction of these molecules was captured through Protein-Ligand study. It also gave an insight of the binding pockets involved. Bench marking of all the parameters were done using the diabetic inhibitor drug, Glipizide. Pharmacokinetic studies of the compounds such as Aloins, Capparisine, Funiculosin and Rhein exhibited less toxicity on various levels of the body. As a conclusion these ligands can lay a foundation for a better anti-diabetic therapy. AhG - Anti hyperglycaemic, CADD - Computer Aided Drug Designing.

  11. Application of Sharī‘ah contracts in contemporary Islamic finance: A maqāṣid perspective

    Directory of Open Access Journals (Sweden)

    Younes Soualhi

    2015-12-01

    Full Text Available This research exposes the underlying maqāṣid embedded in Sharī‘ah contracts as applied in Islamic banking and finance. It addresses the problem of not observing maqāṣid in nominated and combined Sharī‘ah contracts as well as the problem of not sufficiently imbuing maqāṣid in products developed by Islamic financial institutions. As a benchmark of the maqāṣid of wealth, the research adopts Ibn ‘Āshūr’s classification of maqāṣid to evaluate the conformity of Sharī‘ah contracts to Maqāṣid al-Sharī‘ah namely, justice, circulation, transparency, and firmness. The study focuses on three markets related to the application of Sharī‘ah contracts, namely, banking, Islamic capital market, and takāful. The study concludes that, by and large, the application of Sharī‘ah contracts has observed Maqāṣid al-Sharī‘ah during its development and initial application stages of Islamic finance products; however, offering such products in the market has raised economic questions as to their viability and economic values. In addition, the malpractice of some Sharī‘ah contracts has long raised concerns as to the maqāṣid compliance of such products. The research recommends a de-sophistication of Islamic financial engineering to minimise the possibility of convergence with conventional finance. The research also emphasises product differentiation based on less complicated combined Sharī‘ah contracts.

  12. [Differences in oligomerization of nucleocapsid protein of epidemic human influenza A(H1N1), A(H1N2) and B viruses].

    Science.gov (United States)

    Prokudina, E N; Semenova, N P; Chumakov, V M; Burtseva, E I; Slepushkin, A N

    2003-01-01

    A comparative analysis of involving the nucleocapsid protein (NP) into shaping-up of SDS-resistant oligomers was carried out presently in circulating epidemic strains of human influenza, viruses A and B. The study results of viral isolates obtained from clinical samples and recent standard strains revealed that the involvement of NP in the SDS-resistant oligomers, which are different in various subtypes of influenza A viruses. According to this sign, the human viruses A(9H3N2) are close to the avian ones, in which, as proved by us previously, virtually the entire NP transforms itself into the oligomers resistant to SDS. About 10-20% of NP are involved in shaping-up the virus influenza A(H1N1) of SDS-resistant oligomers. No SDS-resistant NP-oligomers were detected in influenza of type B. It is suggested that the prevalence of human viruses A(H3N2) in NP-oligomers are the peculiarities of NP structure and of the presence of the PB1 protein from avian influenza virus.

  13. Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

    Science.gov (United States)

    Meijer, Adam; Swaan, Corien M; Voerknecht, Martin; Jusic, Edin; van den Brink, Sharon; Wijsman, Lisa A; Voordouw, Bettie Cg; Donker, Gé A; Sleven, Jacqueline; Dorigo-Zetsma, Wendelien W; Svraka, Sanela; van Boven, Michiel; Haverkate, Manon R; Timen, Aura; van Dissel, Jaap T; Koopmans, Marion Pg; Bestebroer, Theo M; Fouchier, Ron Am

    2018-04-01

    A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.

  14. Induction of a chloracne phenotype in an epidermal equivalent model by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on aryl hydrocarbon receptor activation and is not reproduced by aryl hydrocarbon receptor knock down.

    Science.gov (United States)

    Forrester, Alison R; Elias, Martina S; Woodward, Emma L; Graham, Mark; Williams, Faith M; Reynolds, Nick J

    2014-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent activator of the aryl hydrocarbon receptor (AhR) and causes chloracne in humans. The pathogenesis and role of AhR in chloracne remains incompletely understood. To elucidate the mechanisms contributing to the development of the chloracne-like phenotype in a human epidermal equivalent model and identify potential biomarkers. Using primary normal human epidermal keratinocytes (NHEK), we studied AhR activation by XRE-luciferase, AhR degradation and CYP1A1 induction. We treated epidermal equivalents with high affinity TCDD or two non-chloracnegens: β-naphthoflavone (β-NF) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Using Western blotting and immunochemistry for filaggrin (FLG), involucrin (INV) and transglutaminase-1 (TGM-1), we compared the effects of the ligands on keratinocyte differentiation and development of the chloracne-like phenotype by H&E. In NHEKs, activation of an XRE-luciferase and CYP1A1 protein induction correlated with ligand binding affinity: TCDD>β-NF>ITE. AhR degradation was induced by all ligands. In epidermal equivalents, TCDD induced a chloracne-like phenotype, whereas β-NF or ITE did not. All three ligands induced involucrin and TGM-1 protein expression in epidermal equivalents whereas FLG protein expression decreased following treatment with TCDD and β-NF. Inhibition of AhR by α-NF blocked TCDD-induced AhR activation in NHEKs and blocked phenotypic changes in epidermal equivalents; however, AhR knock down did not reproduce the phenotype. Ligand-induced CYP1A1 and AhR degradation did not correlate with their chloracnegenic potential, indicating that neither CYP1A1 nor AhR are suitable biomarkers. Mechanistic studies showed that the TCDD-induced chloracne-like phenotype depends on AhR activation whereas AhR knock down did not appear sufficient to induce the phenotype. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier

  15. Fabrication and evaluation of 100 Ah cylindrical lithium ion battery for electric vehicle applications

    Science.gov (United States)

    Hyung, Yoo-Eup; Moon, Seong-In; Yum, Duk-Hyeng; Yun, Seong-Kyu

    A total of 100 Ah class lithium ion cells with C/LiCoO 2 cell system for electric vehicles (EVs) was developed. EV-size lithium ion battery was developed by Sony, KERI/STC, SAFT, VARTA, Sanyo and Matsushita. GS battery and Hitachi have developed also stationary type large scale (70-80 Ah) lithium ion batteries. Lithium ion battery module for EVs was demonstrated by Sony/Nissan and KERI/STC in 1996. At present, the performance of developed EV-cells was up to 115 Wh/kg and 286 W/kg of specific power at 80% DOD. We assume our EV cells to have 248 and 242 km driving distance per one charge with DST-120 mode and ECE-15 mode, respectively. Finally, we performed safety/abuse tests of developed lithium ion cell.

  16. TAFSIR ALQUR’AN PARADIGMA INTEGRATIF: STUDI ATAS QIRA’AH ALTHANIYAH MUHAMMAD SYAHRUR

    Directory of Open Access Journals (Sweden)

    Abdul Malik

    2017-06-01

    Full Text Available This article describes on the alternative reading (qira'ah altaniyah of Alqur’an proposed by Muhammad Shahrur, in his work “Alkitab wa Alqur’an: Qira'ah Almu'ashirah”. Through this work, Syahrur proposed an integrative-interpretation method which is built through combining analysis of natural science, social science, and tafsir. Based on the descriptive analysis approach to this works, this study found out two important things: (1 Syahrur using mathematical analysis to interpret the muhkamat’s verses and science analysis for mutasyabihat’s verses. (2 Hudud is a result of the integrative analysis interpretation based on the linguistic and mathematic analysis in understanding the Quranic verses about the law, while ta’wil ilmi is an understanding toward mutasyabihat verses, like the revelation, which is based on the analysis of natural science cognitive.

  17. ANALISIS POTENSI PENERIMAAN KUALITAS ALUMNI PROGRAM STUDI EKONOMI SYARI’AH STAIN KUDUS DITINJAU DARI PERSPEKTIF STAKEHOLDER

    Directory of Open Access Journals (Sweden)

    Ekawati Rahayu Ningsih

    2015-03-01

    Full Text Available GRADUATES RECEPTION QUALITYANALYSIS OF THE POTENTIAL ECONOMIC STUDIES SYARI’AH IN STAIN KUDUS VIEWED FROM THE PERSPECTIVE STAKEHOLDER. The first aim of  this study was to determine the potential reception of  graduates quality in Shariah Economic Studiesof  STAINKudus in the world of  work. Second, to determine the motivations and needs of  stakeholders on the acceptance of  the quality of  graduates in Economics   Shariah STAIN Kudus.And third, to determine what factors which are supporting and inhibiting the absorption of graduates of the Department of Shariah Economics STAIN Kudus in working world. The theory that was developed as a basis for the analysis is the pyramid theory of  motivation and needs of  Abraham Maslow. By using qualitative research approach, the analysis and discussion of this study are:First, the potential acceptance of  Shariah Economy graduates in the working world, especially in the banking and financial institutions Shari’ah is still very large and potentially growing along with the rapid growth in the number of  banking and financial institutions Shari’ah in Indonesia. Second, motivation and needs of  stakeholders for the graduates reception of Shariah Economic STAIN Kudus is because it is the only college in the state of  religion around the Pantura area having Shariah Economic Studies Program and easily accessible. In addition, in order to establish a more synergistic relationship with the STAIN kudus then either the shari’a banking and financial institutions are willing to accept graduates of  Shariah Economic Studies Program as employees, of course, with the various criteria established in the job requirements. Keywords:Potential,  Quality  Admissions,  Graduates, Economic Shariah, Stakeholder. Tujuan penelitian ini adalah: Pertama, untuk mengetahui potensi penerimaan kualitas alumni Program Studi Ekonomi Syari’ah STAIN Kudus di dunia kerja. Kedua, untuk mengetahui motivasi dan

  18. Lot 4 AH-64E Apache Attack Helicopter Follow-on Operational Test and Evaluation Report

    Science.gov (United States)

    2014-12-01

    engine is tested to determine its Engine Torque Factor ( ETF ) rating.6 To meet contract specifications, a new engine must have an ETF of 1.0. The...published AH-64E operator’s manual estimates performance based on engines with an ETF of 1.0, and pilots normally plan missions anticipating the 717...pound shortfall in hover performance at KPP conditions. The Apache Program Manager reports that new engines are delivered with an average ETF of

  19. PENERAPAN SYARI’AH DI NEGARA MODERN (Analisis Ijtihad Pemikiran Abdullahi Ahmed An-Na’im

    Directory of Open Access Journals (Sweden)

    Ahmad Bahrur Rozi

    2016-02-01

    Full Text Available Islam is a holistic religion. It means that Islam is a religion which does not only focus on the vertical relation between humans and God but also contains rules of horizontal relation between man and man. Laws with social characteristic lead to the existence of a power as the doer, such as the application of all the punishments and public rewards (al-hudûd wa al-'uqûbât. This article analyzes the thought of Abdullahi Ahmed An--Na’im about syari’ah reformation which is relevant to the constitutionalism standard, criminal law, international law and modern human right, a vision of “syariat modern” which is suitable with the nation state concept which beyond  the offering of the Nation of fundamentalist syariah and the offering of Modern Islamic Nation. The method used by Abdullahi Ahmed An--Na’im is the renewal method which is said as legalized evolution with hermeneutic as the main tool to reach the purpose and normative implication of the text as al-Qur’an. According to Abdullahi Ahmed An--Na’im, the failure of syari’ah application in modern country caused by the crisis on the traditional syari’ah methodology which became its base. Therefore, new syari’ah formulation is needed to be built on the new base. Naskh concept which is initiated by An-Na’im is for answering this crisis.Copyright (c 2016 by Al-Ihkam. All right reservedDOI: 10.19105/al-ihkam.v10i2.734

  20. LEO life tests on a 75 Ah bipolar nickel-hydrogen battery

    Science.gov (United States)

    Lenhart, S.; Koehler, C.; Applewhite, A.

    1988-01-01

    The design, building, and testing of an actively cooled 10-cell 75-Ah bipolar nickel/hydrogen battery are discussed. During the last 1000 cycles, the battery has shown some evidence of elecrical performance degradation. In particular, EOC and EOD voltages have increased and decreased by several millivolts, respectively, and deep discharge capacities to a 1.0 V/cell average cutoff voltage have decreased.

  1. Emergence of Islamic Sciences in Merv (First Two Centuries A.H.

    Directory of Open Access Journals (Sweden)

    Mesut CAN

    2016-12-01

    Full Text Available Merv, the first center and one of the four largest cities of Khorasan, had undergone some radical changes, which also influenced the history of the region it was located, in political, military, social, cultural and scientific aspects since its conquest. In this context, the emergence of Islamic sciences in Merv and its status in the first two centuries a.h. will be handled and some scientific personalities of the period will be mentioned within the scope of the article.

  2. Corporate Governance in Shareholding Companies: Comparing Legal Perspective and Position of Shari’ah

    OpenAIRE

    Aznan, H.; Harith Amir Hasan Al Timimi

    2015-01-01

    This study examines the concept of corporate governance in shareholding companies and the legal perspective in comparison with the position of Shari’ah. The purpose of governance is to instil confidence among the stakeholders that the Boards of Directors are applying a diligent legal and administrative framework, to avoid potential administrative and financial failures and corruption. The study has proceeded by defining the concept of governance from linguistics, accounting, administrat...

  3. Screening for Influenza A(H1N1)pdm09, Auckland International Airport, New Zealand

    Science.gov (United States)

    Hale, Michael J.; Baker, Michael G.

    2012-01-01

    Entry screening for influenza A(H1N1)pdm09 at Auckland International Airport, New Zealand, detected 4 cases, which were later confirmed, among 456,518 passengers arriving April 27–June 22, 2009. On the basis of national influenza surveillance data, which suggest that ≈69 infected travelers passed through the airport, sensitivity for screening was only 5.8%. PMID:22516105

  4. Influenza A(H6N1) Virus in Dogs, Taiwan

    Science.gov (United States)

    Lin, Hui-Ting; Wang, Ching-Ho; Chueh, Ling-Ling; Su, Bi-Ling

    2015-01-01

    We determined the prevalence of influenza A virus in dogs in Taiwan and isolated A/canine/Taiwan/E01/2014. Molecular analysis indicated that this isolate was closely related to influenza A(H6N1) viruses circulating in Taiwan and harbored the E627K substitution in the polymerase basic 2 protein, which indicated its ability to replicate in mammalian species. PMID:26583707

  5. PENGUNGKAPAN SYARI’AH COMPLIANCE DAN KEPATUHAN BANK SYARIAH TERHADAP PRINSIP SYARIAH

    Directory of Open Access Journals (Sweden)

    Asrori -

    2012-03-01

    Full Text Available Penelitian ini bertujuan mengukur niat para akuntan dan manager bank Islam untuk menerapkan praktek pengungkapan kepatuhan shariah sebagai tanggung jawab kepatuhan terhadap prinsip-prinsip bank Islam dilihat dari perspektif teori tindakan. Populasi untuk penelitian ini adalah para akuntan dan manager cabang bank Islam di kota Semarang dimana untuk respondennya berjumlah 36. Data dianalisis dengan menggunakan linear regression. Hasil dari penelitian ini untuk memberikan dukungan empiris terhadap teori tindakan dan juga untuk memprediksi niat para akuntan dan manager bank Islam untuk menerapkan praktek pengungkapan kepatuhan shariah. Praktek pengungkapan kepatuhan shariah disarankan untuk diterapkan pada pelaporan keuangan sebagai tanggung jawab kepatuhan bank Islam. This study aims to assess the intentions of accountants and managers of Islamic banks to apply the disclosure practices of syari’ah compliance as accountability for adherence to the principles of syari’ah Islamic banks in the perspective of the theory of reasoned action. The study population include accountants and managers of Islamic bank branches in the city of Semarang in which there are 36 respondents. Linear regression was implemented for analyzing the data to test the hypothesis used. The results of this study provide empirical support for the theory of reasoned action. Then, it can also be used to predict the intentions of accountants and managers of Islamic banks to apply the disclosure practices of syari’ah compliance. Syari’ah compliance disclosure practices is suggested to be applied in financial report as a compliance responsibility of Islamic banks.

  6. Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line.

    Science.gov (United States)

    Mohammadi, Saeed; Seyedhosseini, Fakhri Sadat; Behnampour, Nasser; Yazdani, Yaghoub

    2017-10-01

    The role of aryl hydrocarbon receptor (AhR) in carcinogenesis has been studied recently. Indole-3-carbinol (I3C) is an AhR agonist and a potential anticancer agent. Here, we investigated the effects of I3C on cell cycle progression and apoptosis through activation of AhR on THP-1 acute myeloid leukemia (AML) cell line. MTT viability assay was used to measure the cytotoxic effects of I3C on THP-1 cells. Apoptosis and cell cycle assays were investigated using flow cytometry. Real time RT-PCR was conducted to measure the alterations in the expression of AhR gene, key genes associated with AhR activation (IL1β and CYP1A1) and major genes involved in cell cycle regulation and apoptosis including P27, P21, CDK2, P53, BCL2 and FasR. Our findings revealed that I3C inhibits the proliferation of THP-1 cells in a dose- and time-dependent manner with minimal toxicity over normal monocytes. The AhR target genes (CYP1A1, IL1β) were overexpressed upon I3C treatment (p cycle arrest was also observed using flow cytometry. G1-acting cell cycle genes (P21, P27 and P53) were overexpressed (p cycle arrest in a dose- and time-dependent manner. Therefore, AhR could be targeted as a novel treatment possibility in AML.

  7. Impact of culture medium on maturation of bone marrow-derived murine dendritic cells via the aryl hydrocarbon receptor.

    Science.gov (United States)

    Ilchmann, Anne; Krause, Maren; Heilmann, Monika; Burgdorf, Sven; Vieths, Stefan; Toda, Masako

    2012-05-01

    The aryl hydrocarbon receptor (AhR) plays a role in modulating dendritic cell (DC) immunity. Iscove's modified Dulbecco's medium (IMDM) contains higher amounts of AhR ligands than RPMI1640 medium. Here, we examined the influence of AhR ligand-containing medium on the maturation and T-cell stimulatory capacity of bone marrow-derived murine dendritic cells (BMDCs). BMDCs generated in IMDM (BMDCs/IMDM) expressed higher levels of co-stimulatory and MHC class II molecules, and lower levels of pattern-recognition receptors, especially toll-like receptor (TLR) 2, TLR4, and scavenger receptor class A (SR-A), compared to BMDCs generated in RPMI1640 medium (BMDCs/RPMI). Cytokine responses against ligands of TLRs and antigen uptake mediated by SR-A were remarkably reduced in BMDCs/IMDM, whereas the T-cell stimulatory capacity of the cells was enhanced, compared to BMDCs/RPMI. The enhanced maturation of BMDCs/IMDM was attenuated in the presence of an AhR antagonist, indicating involvement of AhR in the maturation. Interestingly, BMDCs/IMDM induced Th2 and Th17 differentiation at low and high concentrations of antigen respectively, when co-cultured with CD4(+) T-cells from antigen-specific T-cell receptor transgenic mice. In contrast, BMDCs/RPMI induced Th1 differentiation predominantly in the co-culture. Taken together, optimal selection of medium seems necessary when studying BMDCs, depending on the target receptors on the cell surface of DCs and type of helper T-cells for the co-culture. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Telaah Fenomenologis Patrimonialisme Budaya Politik Terhadap Konflik Sunnî-Shî‘Ah Madura

    Directory of Open Access Journals (Sweden)

    Jatim Jatim

    2016-11-01

    Full Text Available The article attempts to discover the violence conflict between the Sunnî and the Shî‘ah Muslim communities in Karang Gayam and Blu’uran, Sampang, Madura. The conflict between the two communities has occurred since 2005 to 2013, and has escalated from one event to another. The conflict has caused the expulsion of Shî‘ah people out of Madura island to the refugee’s flats of Puspa Agro Sidoarjo on June 20, 2013. Based on the evidences found, the research is intended to study the phenomenon using phenomenological and patrimonial-political-cultural approa-ches. The study finds that the conflict itself has been caused by a set of hatred discourses and accusation of being heretic, which have been intensely propagated by the local religious elites, i.e. kiai against the Shî‘ah community led by Tajul Muluk. Moreover, the conflict escalation was, among other, due mainly to the strength of patronage relations of the kiais to infiltrate their hegemony and produce the mass to commit violent actions. Incongruously, the power of patronage has been also benefited by the government and many political elites to maintain their political electability and votes. As a result, the government seems to be reluctant to show a firm attitude by enforcing the existing rules to deal with the issue.

  9. BAGI HASIL DAN BANK SYARI’AH (Solusi terhadap Bunga Bank

    Directory of Open Access Journals (Sweden)

    Rudy Haryanto Rudy Haryanto

    2012-07-01

    Full Text Available Abstract: To save money in terms of investation is one of bank’s functions. Interest and production sharing are kinds of investation in banking system. Interest is a marketable entry in conventional banking, however production sharing is known in syari’ah banking system. Some people argue that interest cannot be seperated from the banking activity, in fact Islam recommends the followers to avoid it; hence it could be substituted with term of production sharing. It matches the priciple of musyarakah and mudharabah as being taught by Rasûlullâh SAW. Bank interest is considered ribâ (excessive interest and it is forbidden in Islam. Moreover, production sharing is more useful and beneficial for people. Unfortunately, the value of production sharing (syarî’ah banking product is lower than the value of banking interest (conventional banking product due to the fact that the ralationship established by syari’ah banking and its customer is based on the principle of gotong royong (mutual coorporation and production sharing partnership. Key Words: ribâ, musyarakah, mudharabah, dan bagi-hasil  

  10. Sedimentary evolution and ecosystem change in Ahémé lake, south-west Benin

    Science.gov (United States)

    Amoussou, Ernest; Totin Vodounon, Henri S.; Vissin, Expédit W.; Mahé, Gil; Oyédé, Marc Lucien

    2018-04-01

    Tropical moist ecosystems, such as Ahémé lake, south-west Benin, are increasingly marked by water degradation, linked with the activities of increasing riparian populations. The objective of this study is to analyze sedimentary dynamics and its influence on the changing ecosystem of Ahémé lake from 1961-2010. Data used to carry out the study are records of precipitation, flows, turbidity, suspended sediment, mineral elements and bathymetry. Grain size data from the sieving of sediment samples were used to interpret suspended solids distribution in the lake. Linear correlation coefficients were used to assess the degree of dependence between rainfall and runoff inputs to the lake. Lake depth measurements in some areas of the lake serve to determine the rate of infilling. The sorting index was used to highlight the distribution and origin of sediments in the lake. The results show a degradation of the lake Ahémé ecosystem characterized by infilling of its bed, a high correlation (r = 0.90) between rainfall and runoff, seasonal change in physicochemical parameters (total suspended sediment decrease by -91 %) and decrease in fish production by 135.8 t yr-1. The highest mean suspended sediment concentrations in lake inputs occur during high water periods (123 mg L-1) compared to low water periods (11.2 mg L-1).

  11. Corporate Governance in Shareholding Companies: Comparing Legal Perspective and Position of Shari’ah

    Directory of Open Access Journals (Sweden)

    Aznan, H.

    2015-12-01

    Full Text Available This study examines the concept of corporate governance in shareholding companies and the legal perspective in comparison with the position of Shari’ah. The purpose of governance is to instil confidence among the stakeholders that the Boards of Directors are applying a diligent legal and administrative framework, to avoid potential administrative and financial failures and corruption. The study has proceeded by defining the concept of governance from linguistics, accounting, administrative, and legal perspectives. The study also discusses the stands of international organisations on the issue of corporate governance. Then, it is proceeded by discussing the concept of corporate governance from Shari’ah point of view. The study found that even with the absence of the term “company governance” in Islamic Law, the concept of corporate governance is in line with the Shari’ah and that their scholars have clearly referred to it in their literature. The study has used the descriptive, analytical, inductive and comparative methodology in analyzing the subject matter.

  12. The influence of social-cognitive factors on personal hygiene practices to protect against influenzas: using modelling to compare avian A/H5N1 and 2009 pandemic A/H1N1 influenzas in Hong Kong.

    Science.gov (United States)

    Liao, Qiuyan; Cowling, Benjamin J; Lam, Wendy Wing Tak; Fielding, Richard

    2011-06-01

    Understanding population responses to influenza helps optimize public health interventions. Relevant theoretical frameworks remain nascent. To model associations between trust in information, perceived hygiene effectiveness, knowledge about the causes of influenza, perceived susceptibility and worry, and personal hygiene practices (PHPs) associated with influenza. Cross-sectional household telephone surveys on avian influenza A/H5N1 (2006) and pandemic influenza A/H1N1 (2009) gathered comparable data on trust in formal and informal sources of influenza information, influenza-related knowledge, perceived hygiene effectiveness, worry, perceived susceptibility, and PHPs. Exploratory factor analysis confirmed domain content while confirmatory factor analysis was used to evaluate the extracted factors. The hypothesized model, compiled from different theoretical frameworks, was optimized with structural equation modelling using the A/H5N1 data. The optimized model was then tested against the A/H1N1 dataset. The model was robust across datasets though corresponding path weights differed. Trust in formal information was positively associated with perceived hygiene effectiveness which was positively associated with PHPs in both datasets. Trust in formal information was positively associated with influenza worry in A/H5N1 data, and with knowledge of influenza cause in A/H1N1 data, both variables being positively associated with PHPs. Trust in informal information was positively associated with influenza worry in both datasets. Independent of information trust, perceived influenza susceptibility associated with influenza worry. Worry associated with PHPs in A/H5N1 data only. Knowledge of influenza cause and perceived PHP effectiveness were associated with PHPs. Improving trust in formal information should increase PHPs. Worry was significantly associated with PHPs in A/H5N1.

  13. The Airbag as a Supplement to Standard Restraint Systems in the AH-1 and AH-64 Attack Helicopters and Its Role in Reducing Head Strikes of the Copilot/ Gunner. Volume 1

    Science.gov (United States)

    1991-01-01

    shelf and locally available automotive airbag system was selected for the tests. The system was a driver’s side airbag designed by Honda Motor Company...allowance for hardware redesign or modifi- cation. Despite these limitations, the study succeeded in demonstrating a problem exists and a supplemental airbag ...JSAARL Repqrt No. 91-8 AD-A233 349 Volume’ I(3 The Airbag as a Supplement to Standard Restraint Systems in the AH-1 and AH-64 Attack Helicopters and

  14. Receptor assay

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K; Ibayashi, H [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1975-05-01

    This paper summarized present status and problems of analysis of hormone receptor and a few considerations on clinical significance of receptor abnormalities. It was pointed that in future clinical field quantitative and qualitative analysis of receptor did not remain only in the etiological discussion, but that it was an epoch-making field of investigation which contained the possiblity of artificial change of sensitivity of living body on drugs and the development connected directly with treatment of various diseases.

  15. From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation.

    Science.gov (United States)

    Frank, Annika; Abu-Lafi, Saleh; Adawi, Azmi; Schwed, Johannes S; Stark, Holger; Rayan, Anwar

    2017-10-01

    The aim was to evaluate the activity of seven medicinal, anti-inflammatory plants at the hH 4 R with focus on defined chemical compounds from Curcuma longa. Activities were analyzed with membrane preparations from Sf9 cells, transiently expressing the hH 4 R, G αi2 and G β1γ2 subunits. From the methanolic extract of C. longa curcumin (1), demethoxycurcumin (2) and bis(4-hydroxy-cinnamoyl)methane (3) were isolated, purified with HPLC (elution-time 10.20, 9.66, 9.20 min, respectively) and together with six additional extracts, were characterized via radioligand binding studies at the hH 4 R. Compounds from C. longa were the most potent ligands at the hH 4 R. They exhibited estimated K i values of 4.26-6.26 µM (1.57-2.31 µg/mL) (1); 6.66--8.97 µM (2.26-3.04 µg/mL) (2) and 10.24-14.57 µM (3.16-4.49 µg/mL) (3) (95% CI). The estimated K i value of the crude extract of curcuma was 0.50-0.81 µg/mL. Fractionated curcumin and the crude extract surpassed the effect of pure curcumin with a K i value of 5.54 µM or 2.04 µg/mL [95% CI (4.47-6.86 µM), (1.65-2.53 µg/mL)]. Within this study, defined compounds of C. longa were recognized as potential ligands and reasonable lead structures at the hH 4 R. The mode of anti-inflammatory action of curcumin was further elucidated and the role of extracts in traditional phytomedicine was strengthened.

  16. A Comparison of AH-64D and OH-58D Pilot Attitudes Toward Glass Cockpit Crewstation Designs

    National Research Council Canada - National Science Library

    Francis, Gregory

    2002-01-01

    .... This finding suggested that the details of crewstation design needed to be examined. To identify significant differences, this study assessed pilots' attitudes toward glass cockpit designs in the AH-64D Apache and OH-5SD Kiowa helicopters...

  17. Organizing Medical Care to Patients with Severe Pneumonias in the Presence of A/H1N1 Influenza

    Directory of Open Access Journals (Sweden)

    K. G. Shapovalov

    2010-01-01

    Full Text Available The paper describes the way medical and intensive cares are organized to patients with complicated forms of A/H1N1 and seasonal influenzas in the Trans-Baikal Territory in the fall of 2009.

  18. THE HISTORY OF JAMA‘AH TABLIGH IN SOUTHEAST ASIA: The Role of Islamic Sufism in Islamic Revival

    OpenAIRE

    Kamaruzzaman Bustamam-Ahmad

    2008-01-01

    The article examines the history of Jama‘ah Tabligh in Southeast Asia, especially in Kuala Lumpur and Aceh. The author traces the historical background of this religious movement with particular reference to the birth place of Jama‘ah Tabligh, India. The author investigates the major role of Indian in disseminating Islam in Southeast Asia, especially in Malaysia and Indonesia. Many scholars believe that Islam came to Southeast Asia from India (Gujarat), and this is the reason why many Islamic...

  19. The Peanut (Arachis hypogaea L. Gene AhLPAT2 Increases the Lipid Content of Transgenic Arabidopsis Seeds.

    Directory of Open Access Journals (Sweden)

    Silong Chen

    Full Text Available Lysophosphatidic acid acyltransferase (LPAT, which converts lysophosphatidic acid (LPA to phosphatidic acid (PA, catalyzes the addition of fatty acyl moieties to the sn-2 position of the LPA glycerol backbone in triacylglycerol (TAG biosynthesis. We recently reported the cloning and temporal-spatial expression of a peanut (Arachis hypogaea AhLPAT2gene, showing that an increase in AhLPAT2 transcript levels was closely correlated with an increase in seed oil levels. However, the function of the enzyme encoded by the AhLPAT2 gene remains unclear. Here, we report that AhLPAT2 transcript levels were consistently higher in the seeds of a high-oil cultivar than in those of a low-oil cultivar across different seed developmental stages. Seed-specific overexpression of AhLPAT2 in Arabidopsis results in a higher percentage of oil in the seeds and greater-than-average seed weight in the transgenic plants compared with the wild-type plants, leading to a significant increase in total oil yield per plant. The total fatty acid (FA content and the proportion of unsaturated FAs also increased. In the developing siliques of AhLPAT2-overexpressing plants, the expression levels of genes encoding crucial enzymes involved in de novo FA synthesis, acetyl-CoA subunit (AtBCCP2 and acyl carrier protein 1 (AtACP1 were elevated. AhLPAT2 overexpression also promoted the expression of several key genes related to TAG assembly, sucrose metabolism, and glycolysis. These results demonstrate that the expression of AhLPAT2 plays an important role in glycerolipid production in peanuts.

  20. EPOS Thematic Core Service ANTHROPOGENIC HAZARDS (TCS AH) - development of e-research platform

    Science.gov (United States)

    Orlecka-Sikora, Beata

    2017-04-01

    TCS AH is based on IS-EPOS Platform. The Platform facilitates research on anthropogenic hazards and is available online, free of charge https://tcs.ah-epos.eu/. The Platform is a final product of the IS-EPOS project, founded by the national programme - POIG - which was implemented in 2013-2015 (POIG.02.03.00-14-090/13-00). The platform is a result of a joint work of scientific community and industrial partners. Currently, the development of TCS AH is carried under EPOS IP project (H2020-INFRADEV-1-2015-1, INFRADEV-3-2015). Platform is an open virtual access point for researchers and Ph. D. students interested in anthropogenic seismicity and related hazards. This environment is designed to ensure a researcher the maximum possible liberty for experimentation by providing a virtual laboratory, in which the researcher can design own processing streams and process the data integrated on the platform. TCS AH integrates: data and specific high-level services. Data gathered in the so-called "episodes", comprehensively describing a geophysical process, induced or triggered by human technological activity, which, under certain circumstances can become hazardous for people, infrastructure and the environment. 7 sets of seismic, geological and technological data were made available on the Platform. The data come from Poland, Germany, UK and Vietnam, and refer to underground mining, reservoir impoundment, shale gas exploitation and geothermal energy production. The next at least 19 new episodes related to conventional hydrocarbon extraction, reservoir treatment, underground mining and geothermal energy production are being integrated within the framework of EPOS IP project. The heterogeneous multi-disciplinary data (seismic, displacement, geomechanical data, production data etc.) are transformed to unified structures to form integrated and validated datasets. To deal with this various data the problem-oriented services were designed and implemented. The particular attention

  1. Use of criteria pollutants, active and passive mercury sampling, and receptor modeling to understand the chemical forms of gaseous oxidized mercury in Florida

    Science.gov (United States)

    Huang, J.; Miller, M. B.; Edgerton, E.; Gustin, M. S.

    2015-04-01

    The highest mercury (Hg) wet deposition in the United States (US) occurs along the Gulf of Mexico, and in the southern and central Mississippi River Valley. Gaseous oxidized Hg (GOM) is thought to be a major contributor due to its high water solubility and reactivity. Therefore, it is critical to understand the concentrations, potential for wet and dry deposition, and GOM compounds present in the air. Concentrations and dry deposition fluxes of GOM were measured at Outlying Landing Field (OLF), Florida, using a Tekran® 2537/1130/1135, and active and passive samplers using cation-exchange and nylon membranes. Relationships with Tekran® derived data must be interpreted with caution, since GOM concentrations can be biased low depending on the chemical compounds in air, and interferences with water vapor and ozone. Only gaseous elemental Hg and GOM are discussed here since the PBM measurement uncertainties are higher. Criteria air pollutants were concurrently measured and Tekran® data were assessed along with these using Principal Component Analysis to identify associations among air pollutants. Based on the diel pattern, high GOM concentrations at this site were associated with fossil fuel combustion and gas phase oxidation during the day, and gas phase oxidation and transport in the free troposphere. The ratio of GEM/CO at OLF (0.008 ng m-3 ppbv-1) was much higher than the numbers reported for the Western United States and central New York for domestic emissions or biomass burning (0.001 ng m-3 ppbv-1), which we suggest is indicative of a marine boundary layer source. Results from nylon membranes with thermal desorption analyses suggest five potential GOM compounds exist in this area, including HgBr2, HgO, Hg(NO3)2, HgSO4, and an unknown compound. This indicates that the site is influenced by different gaseous phase reactions and sources. A~high GOM event related to high CO but average SO2 suggests the air parcels moved from the free troposphere and across

  2. γ-Tocotrienol upregulates aryl hydrocarbon receptor expression and enhances the anticancer effect of baicalein

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Shuya; Baba, Kiwako; Makio, Akiko; Kumazoe, Motofumi; Huang, Yuhui; Lin, I-Chian; Bae, Jaehoon; Murata, Motoki; Yamada, Shuhei; Tachibana, Hirofumi, E-mail: tatibana@agr.kyushu-u.ac.jp

    2016-05-13

    Previous studies have identified biomolecules that mediate the physiological actions of food factors, such as amino acids, vitamins, fatty acids, minerals, plant polyphenols, and lactobacilli, suggesting that our bodies are equipped with an innate system that senses which food factors are required to maintain our health. However, the effects of environmental factors on food factor sensing (FFS) remains largely unknown. Tocotorienols (T3s), which belongs to the vitamin E family, possess several physiological functions, including cholesterol lowering and neuroprotective effects. Here, we investigated the effects of naturally abundant γ-T3 on FFS-related gene expressions in melanoma using a DNA chip. Our results showed that γ-T3 increased the expression level of aryl hydrocarbon receptor (AhR), a sensing molecule to plant polyphenol baicalein. The co-treatment with γ-T3 and baicalein enhanced the anti-proliferative activity of baicalein, accompanied by the downstream events of AhR-activation induced by baicalein. These data suggest that γ-T3 upregulates AhR expression and enhances its sensitivity to baicalein. - Highlights: • γ-T3 upregulated the expression of AhR in mouse melanoma. • Promotion of the binding activity of Sp1 is associated with the increasing effect of γ-T3 on AhR expression. • γ-T3 enhanced the anti-proliferative activity of baicalein that has an AhR ligand activity. • γ-T3 enhanced the inducing activity of baicalein on the expression of AhR target genes.

  3. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism

    International Nuclear Information System (INIS)

    El Gendy, Mohamed A.M.; El-Kadi, Ayman O.S.

    2010-01-01

    Harman is a common compound in several foods, plants and beverages. Numerous studies have demonstrated its mutagenic, co-mutagenic and carcinogenic effects; however, the exact mechanism has not been fully identified. Aryl hydrocarbon receptor (AhR) is a transcription factor regulating the expression of the carcinogen-activating enzyme; cytochrome P450 1A1 (CYP1A1). In the present study, we examined the ability of harman to induce AhR-mediated signal transduction in human and rat hepatoma cells; HepG2 and H4IIE cells. Our results showed that harman significantly induced CYP1A1 mRNA in a time- and concentration-dependent manner. Similarly, harman significantly induced CYP1A1 at protein and activity levels in a concentration-dependent manner. Moreover, the AhR antagonist, resveratrol, inhibited the increase in CYP1A1 activity by harman. The RNA polymerase inhibitor, actinomycin D, completely abolished the CYP1A1 mRNA induction by harman, indicating a transcriptional activation. The role of AhR in CYP1A1 induction by harman was confirmed by using siRNA specific for human AhR. The ability of harman to induce CYP1A1 was strongly correlated with its ability to stimulate AhR-dependent luciferase activity and electrophoretic mobility shift assay. At post-transcriptional and post-translational levels, harman did not affect the stability of CYP1A1 at the mRNA and the protein levels, excluding other mechanisms participating in the obtained effects. We concluded that harman can directly induce CYP1A1 gene expression in an AhR-dependent manner and may represent a novel mechanism by which harman promotes mutagenicity, co-mutagenicity and carcinogenicity.

  4. ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.

    Science.gov (United States)

    Wu, Yanming; Chen, Xiao; Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  5. Chemical Peels

    Science.gov (United States)

    ... care Kids’ zone Video library Find a dermatologist Chemical peels Overview Chemical peels: Overview Also called chemexfoliation , derma peeling Do ... Overview Chemical peels: FAQs Chemical peels: Preparation FAQs Chemical peels: FAQs To help you decide whether this ...

  6. beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Udi Gluschnaider

    2010-02-01

    Full Text Available Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. beta-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis.Here we show that beta-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against beta-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that beta-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium.Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining beta-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.

  7. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9

    Directory of Open Access Journals (Sweden)

    Song Xin

    2009-04-01

    Full Text Available Abstract Background Abberant aryl hydrocarbon receptor (AhR expression and AhR pathway activation are involved in gastric carcinogenesis. However, the relationship between AhR pathway activation and gastric cancer progression is still unclear. In present study, we used 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD, a classic and most potent ligand of AhR, to activate AhR pathway and investigated the effect of AhR pathway activation on human gastric cancer AGS cell invasion and explored the corresponding mechanism. Results To determine whether AhR pathway can be activated in AGS cells, we examined the expression of CYP1A1, a classic target gene of AhR pathway, following TCDD exposure. RT-PCR and western blot analysis showed that both CYP1A1 mRNA and protein expression were increased in a dose-dependent manner following TCDD treatment and AhR antagonist resveratrol (RSV could reverse this TCDD-induced CYP1A1 expression. To determine whether TCDD treatment of AGS cells results in an induction of MMP-9 expression, we detected MMP-9 mRNA using RT-PCR and detected MMP-9 enzymatic activity using gelatin zymography. The results showed that both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. To examine whether AhR activation-induced MMP-9 expression and activity in AGS cells results in increased migration and invasion, we performed wound healing migration assay and transwell migration and invasion assay. After TCDD treatment, the migration distance and the migration and invasion abilities of AGS cells were increased with a dose-dependent manner. To demonstrate AhR activation-induced MMP-9 expression is mediated by c-Jun, siRNA transfection was performed to silence c-Jun mRNA in AGS cells. The results showed that MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD

  8. Infection of mice with a human influenza A/H3N2 virus induces protective immunity against lethal infection with influenza A/H5N1 virus.

    Science.gov (United States)

    Kreijtz, J H C M; Bodewes, R; van den Brand, J M A; de Mutsert, G; Baas, C; van Amerongen, G; Fouchier, R A M; Osterhaus, A D M E; Rimmelzwaan, G F

    2009-08-06

    The transmission of highly pathogenic avian influenza (HPAI) A viruses of the H5N1 subtype from poultry to man and the high case fatality rate fuels the fear for a pandemic outbreak caused by these viruses. However, prior infections with seasonal influenza A/H1N1 and A/H3N2 viruses induce heterosubtypic immunity that could afford a certain degree of protection against infection with the HPAI A/H5N1 viruses, which are distantly related to the human influenza A viruses. To assess the protective efficacy of such heterosubtypic immunity mice were infected with human influenza virus A/Hong Kong/2/68 (H3N2) 4 weeks prior to a lethal infection with HPAI virus A/Indonesia/5/05 (H5N1). Prior infection with influenza virus A/Hong Kong/2/68 reduced clinical signs, body weight loss, mortality and virus replication in the lungs as compared to naive mice infected with HPAI virus A/Indonesia/5/05. Priming by infection with respiratory syncytial virus, a non-related virus did not have a beneficial effect on the outcome of A/H5N1 infections, indicating that adaptive immune responses were responsible for the protective effect. In mice primed by infection with influenza A/H3N2 virus cytotoxic T lymphocytes (CTL) specific for NP(366-374) epitope ASNENMDAM and PA(224-232) SCLENFRAYV were observed. A small proportion of these CTL was cross-reactive with the peptide variant derived from the influenza A/H5N1 virus (ASNENMEVM and SSLENFRAYV respectively) and upon challenge infection with the influenza A/H5N1 virus cross-reactive CTL were selectively expanded. These CTL, in addition to those directed to conserved epitopes, shared by the influenza A/H3N2 and A/H5N1 viruses, most likely contributed to accelerated clearance of the influenza A/H5N1 virus infection. Although also other arms of the adaptive immune response may contribute to heterosubtypic immunity, the induction of virus-specific CTL may be an attractive target for development of broad protective vaccines. Furthermore the

  9. The aryl hydrocarbon receptor ligand ITE inhibits TGFβ1-induced human myofibroblast differentiation.

    Science.gov (United States)

    Lehmann, Geniece M; Xi, Xia; Kulkarni, Ajit A; Olsen, Keith C; Pollock, Stephen J; Baglole, Carolyn J; Gupta, Shikha; Casey, Ann E; Huxlin, Krystel R; Sime, Patricia J; Feldon, Steven E; Phipps, Richard P

    2011-04-01

    Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-β1 (TGFβ1). In this study, we demonstrate that TGFβ1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGFβ1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGFβ1-driven myofibroblast differentiation in AhR(-/-) fibroblasts: Its ability to inhibit TGFβ1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  10. Predominance of HA-222D/G polymorphism in influenza A(H1N1pdm09 viruses associated with fatal and severe outcomes recently circulating in Germany.

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    Marianne Wedde

    Full Text Available Influenza A(H1N1pdm09 viruses cause sporadically very severe disease including fatal clinical outcomes associated with pneumonia, viremia and myocarditis. A mutation characterized by the substitution of aspartic acid (wild-type to glycine at position 222 within the haemagglutinin gene (HA-D222G was recorded during the 2009 H1N1 pandemic in Germany and other countries with significant frequency in fatal and severe cases. Additionally, A(H1N1pdm09 viruses exhibiting the polymorphism HA-222D/G/N were detected both in the respiratory tract and in blood. Specimens from mild, fatal and severe cases were collected to study the heterogeneity of HA-222 in A(H1N1pdm09 viruses circulating in Germany between 2009 and 2011. In order to enable rapid and large scale analysis we designed a pyrosequencing (PSQ assay. In 2009/2010, the 222D wild-type of A(H1N1pdm09 viruses predominated in fatal and severe outcomes. Moreover, co-circulating virus mutants exhibiting a D222G or D222E substitution (8/6% as well as HA-222 quasispecies were identified (10%. Both the 222D/G and the 222D/G/N/V/Y polymorphisms were confirmed by TA cloning. PSQ analyses of viruses associated with mild outcomes revealed mainly the wild-type 222D and no D222G change in both seasons. However, an increase of variants with 222D/G polymorphism (60% was characteristic for A(H1N1pdm09 viruses causing fatal and severe cases in the season 2010/2011. Pure 222G viruses were not observed. Our results support the hypothesis that the D222G change may result from adaptation of viral receptor specificity to the lower respiratory tract. This could explain why transmission of the 222G variant is less frequent among humans. Thus, amino acid changes at HA position 222 may be the result of viral intra-host evolution leading to the generation of variants with an altered viral tropism.

  11. Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

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    Chawon Yun

    2018-01-01

    Full Text Available The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other

  12. Insights into the Indian peanut genotypes for ahFAD2 gene polymorphism regulating its oleic and linoleic acid fluxes

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    Bhagwat Nawade

    2016-08-01

    Full Text Available In peanut (Arachis hypogaea L., the customization of fatty acid profile is an evolving area to fulfil the nutritional needs in the modern market. A total of 174 peanut genotypes, including 167 Indian cultivars, 6 advanced breeding lines and ‘SunOleic’‒ a double mutant line, were investigated using AS-PCRs, CAPS and gene sequencing for the ahFAD2 allele polymorphism, along with its fatty acid compositions. Of these, 80 genotypes were found having substitution (448G>A mutation only in ahFAD2A gene, while none recorded 1-bp insertion (441_442insA mutation in ahFAD2B gene. Moreover, 22 wild peanut accessions found lacking both the mutations. Among botanical types, the ahFAD2A mutation was more frequent in ssp. hypogaea (89% than in ssp. fastigiata (17%. This single allele mutation, found affecting not only oleic to linoleic acid fluxes, but also the composition of other fatty acids in the genotypes studied. Repeated use of a few selected genotypes in the Indian varietal development programs were also eminently reflected in its ahFAD2 allele polymorphism. Absence of known mutations in the wild-relatives indicated the possible origin of these mutations, after the allotetraploidization of cultivated peanut. The SNP analysis of both ahFAD2A and ahFAD2B genes, revealed haplotype diversity of 1.05% and 0.95%, while Ka/Ks ratio of 0.36 and 0.39 respectively, indicating strong purifying selection pressure on these genes. Cluster analysis, using ahFAD2 gene SNPs, showed presence of both mutant and non-mutant genotypes in the same cluster, which might be due the presence of ahFAD2 gene families. This investigation provided insights into the large number of Indian peanut genotypes, covering various aspects related to O/L flux regulation and ahFAD2 gene polymorphism.

  13. Assessing evidence for avian-to-human transmission of influenza A/H9N2 virus in rural farming communities in northern Vietnam.

    Science.gov (United States)

    Hoa, Le Nguyen Minh; Tuan, Nguyen Anh; My, Pham Ha; Huong, Tran Thi Kieu; Chi, Nguyen Thi Yen; Hau Thu, Trang Thi; Carrique-Mas, Juan; Duong, Mai Thuy; Tho, Nguyen Dang; Hoang, Nguyen Dang; Thanh, To Long; Diep, Nguyen Thi; Duong, Nguyen van; Toan, Tran Khanh; Tung, Trinh Son; Mai, Le Quynh; Iqbal, Munir; Wertheim, Heiman; van Doorn, H Rogier; Bryant, Juliet E; The Vizions Consortium

    2017-08-01

    Rural farming communities in northern Vietnam do not routinely practice vaccination for influenza A viruses (IAV) for either humans or poultry, which enables us to study transmission intensity via seroepidemiology. Using samples from a longitudinal cohort of farming households, we determined the number of symptomatic and asymptomatic human infections for seasonal IAV and avian A/H9 over 2 years. As expected, we detected virologically confirmed acute cases of seasonal IAV in humans, as well as large numbers of subclinical seroconversions to A/H1pdm [55/265 (21 %)], A/H3 [95/265 (36 %)] and A/H9 [24/265 (9 %)]. Five of the A/H9 human seroconverters likely represented true infections rather than heterosubtypic immunity, because the individuals seroconverted solely to A/H9. Among co-located poultry, we found significantly higher seroprevalance for A/H5 compared to A/H9 in both chickens and ducks [for northern study sites overall, 337/1105 (30.5 %) seropositive for A/H5 and 123/1105 (11.1 %) seropositive for A/H9].

  14. Konversi Agama dan Pemahaman Nilai Islam Santri Pondok Itikaf Jama’ah Ngaji Lelaku Lawang

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    Ahmad Redhani

    2017-05-01

    Full Text Available Pondok Itikaf Jama'ah Ngaji Lelaku, Lawang is one of the containers to learn and understand Islam, the background of santri like people who have a black background, such as ex-thugs, gamblers, drunkards, people who have problems of life and people who want to learn religion But have limitations in Arabic. The way santri learn religion, that is by trying to understand the holy verses of the Qur'an and hadith, one of his understanding that is belief in performing the congregational prayer accompanied by the language translation of his people, this is contrary to the prevailing Islamic law. The purpose of the research is to find out 1 why the subject is interested to join the Pondok Itikaf Jama'ah Ngaji Lelaku, Lawang, 2 the psychological factors that cause the students of Pondok Itikaf Jama'ah Ngaji Lelaku, Lawang change beliefs bergama, 3 how the process of belief change students santri Itikaf Jama'ah Ngaji Lelaku, Lawang, and 4 how the understanding of Islamic values of Santri Pondok Itikaf Jam'ah Ngaji Lelaku, Lawang. The research method used is single case study method. Data collection is done through interview, observation, and documentation. Data analysis is done by using descriptive analysis, that is using words to describe what the purpose of this research. The results showed that 1 subjects interested in joining and believing to implement the teachings received in the cottage because the subject is acceptable as it is by the manager of the cottage, the manager also patient and painstaking provide guidance on the subject, the subjects at least get the peace of mind and can change the attitude of the subject, At least get the peace of mind and can change the attitude of the subject to a better direction, there is a common background between students who are with each other. 2 psychological factors causing the subject to change beliefs, subjects experiencing symptoms of inner pressure caused by the emotional attitudes of the subject, it

  15. TRANSFORMATION OF MAQÂSHID Al-SYARÎ’AH (An Overview of the Development of Islamic Law in Indonesia

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    Absori .

    2016-07-01

    Full Text Available Abstract:This study is part of an effort to systematize the basic conception of the values of the sharia as the foundation in the life of nation and state life, where the orientation is to embody the essence of the religious life through the maqâshid al-syarî`ah. Islam as al-dîn has been providing the basics of life of Muslims through the al-Qur’an and as-Sunnah. Both of these contain guidance values of human life, including in running the sharia for Muslims. Sharia (syarî`ah in perspective of terminology is "street". In an isthilâhî perspective, it is a way to get to God. The basic meaning of sharia itself should be realized in the basic understanding maqâshid al-syarî`ah, which can be interpreted within the scope of statehood, because the meaning contained are the values of universality of maqâshid al-syarî`ah. In the context of Indonesian, then maqâshid al-syarî`ah is part of the basic conception air Almighty God with the aim of creating prosperity for the people of Indonesia. In this study, the approach used is the doctrinal bases to study literature. This study is the strengthening of the maqâshid al-syarî`ah as the basis for the development of Islamic law.Abstrak:Kajian ini merupakan bagian dari upaya untuk sistematisasi konsep dasar dari nilai-nilai syari’ah sebagai pondasi dalam kehidupan berbangsa dan kehidupan bernegara, dimana orientasi tersebut adalah untuk mewujudkan hakikat kehidupan dalam beragama melalui maqâshid al-syarî`ah. Islam sebagai al-dîn telah memberikan dasar-dasar kehidupan umat Muslim melalui al-Qur’an dan al-Sunnah. Kedua hal tersebut mengandung nilai-nilai tuntunan kehidupan umat manusia termasuk dalam menjalankan syariah bagi umat Muslim. Syari’ah dalam perspektif terminologi merupakan “jalan”. Sedangkan secara isthilâhî, ia dimaknai sebagai jalan untuk sampai kepada Allah SWT. Makna dasar dari syari’ah itu sendiri harus diwujudkan dalam pemahaman dasar maqâshid al-syarî’ah, di

  16. Maqasid al-Shari’ah as a Framework for Economic Development Theorization

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    Abdullahi Abubakar LAMIDO

    2016-04-01

    Full Text Available Development studies has so far created a huge intellectual resource, including theories, models and policy prescriptions that have been implemented in most developing economies. However, development theorization has been generally dominated by the western materialist paradigm which is antithetical to the very philosophical foundations of Islam. Muslims, constituting at least a quarter of the world population, mostly live in the less developed economies and are therefore among the largest consumers of these materialist theories.  Based on the premises that the Muslim world cannot address its multifarious development challenges by relying only on imported theories and models, and that as important stakeholders in the world, Muslims need to contribute to the global development discourse; this paper presents an Islamic alternative approach to the analysis of development based on the theory of maqasid al-Shari’ah. The paper proposes a maqasid-based development approach which sees development from the perspective of drawing benefit and removing harm, which require promoting things that make life easy, meaningful and prosperous and blocking all means to harm, socio-economic difficulty and underdevelopment. The three-stages development approach focuses on promoting wellbeing through the preservation and enhancement of five essential components; faith, life, intellect, offspring and wealth. The paper submits that maqasid al-Shari’ah is a veritable framework for, inter alia, formulating development policies and prioritizing development projects. The strength of the approach lies in the proper place it accords to faith, spirituality, and moral ethics as trigger mechanisms for sustained moderate development in addition to its emphasis on all-encompassing but moderate material progress. The paper calls for an extensive study of the science of maqasid al-Shari’ah as it pertains to economic development discourse.  

  17. On Dimension Theory for a Certain Class of Simple AH Algebras

    International Nuclear Information System (INIS)

    Ho, Toan M.

    2010-06-01

    A class of unital diagonal AH algebras will be studied in this paper. The density property of the set of all elements which are nilpotent up to (left and right multiple) unitaries is presented. As a consequence, these algebras have stable rank one. Section 3 also shows that an algebra in this class has the property LP (i.e., the linear span of projections is dense) provided a certain condition. Finally, restricting our attention to a special subclass which includes Villadsen algebras of the first type, we give the necessary and sufficient condition of real rank zero. (author)

  18. Architectuur als beschavingsideaal: Het bezield modernisme van A.H. Wegerif

    OpenAIRE

    Thomas, H.

    2014-01-01

    Architecture as civilizing ideal - The inspired modernism of A.H. Wegerif Ahazuerus Hendrikus (Henk) Wegerif was born in Apeldoorn on 13th of April 1888, the son of Gerrit Wegerif and Elsje Breman. Both his father and grandfather were building contractors, as was his paternal uncle, Chris Wegerif. This versatile man in particular had a great influence on Henk Wegerif’s spiritual development. Around 1900, Chris Wegerif, co-founder of the Hague art shop ‘Arts and Crafts’, and his wife Agathe Gr...

  19. Performance features of 22-cell, 19Ah single pressure vessel nickel hydrogen battery

    Energy Technology Data Exchange (ETDEWEB)

    Rao, G.M.; Vaidyanathan, H.

    1996-02-01

    Two 22-cells 19Ah Nickel-Hydrogen (Ni-H2) Single Pressure Vessel (SPV) Qual batteries, one each from EPI/Joplin and EPI/Butler, were designed and procured. The two batteries differ in the cell encapsulation technology, stack preload, and activation procedure. Both the Butler and Joplin batteries met the specified requirements when subjected to qualification testing and completed 2100 and 1300 LEO cycles respectively, with nominal performance. This paper discusses advantages, design features, testing procedures, and results of the two single pressure vessel Ni-H2 batteries.

  20. Performance features of 22-cell, 19Ah single pressure vessel nickel hydrogen battery

    Science.gov (United States)

    Rao, Gopalakrishna M.; Vaidyanathan, Hari

    1996-01-01

    Two 22-cells 19Ah Nickel-Hydrogen (Ni-H2) Single Pressure Vessel (SPV) Qual batteries, one each from EPI/Joplin and EPI/Butler, were designed and procured. The two batteries differ in the cell encapsulation technology, stack preload, and activation procedure. Both the Butler and Joplin batteries met the specified requirements when subjected to qualification testing and completed 2100 and 1300 LEO cycles respectively, with nominal performance. This paper discusses advantages, design features, testing procedures, and results of the two single pressure vessel Ni-H2 batteries.

  1. Pandemic influenza A/H1N1pdm in Italy: age, risk and population susceptibility.

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    Stefano Merler

    Full Text Available BACKGROUND: A common pattern emerging from several studies evaluating the impact of the 2009 A/H1N1 pandemic influenza (A/H1N1pdm conducted in countries worldwide is the low attack rate observed in elderly compared to that observed in children and young adults. The biological or social mechanisms responsible for the observed age-specific risk of infection are still to be deeply investigated. METHODS: The level of immunity against the A/H1N1pdm in pre and post pandemic sera was determined using left over sera taken for diagnostic purposes or routine ascertainment obtained from clinical laboratories. The antibody titres were measured by the haemagglutination inhibition (HI assay. To investigate whether certain age groups had higher risk of infection the presence of protective antibody (≥1∶40, was calculated using exact binomial 95% CI on both pre- and post- pandemic serological data in the age groups considered. To estimate age-specific susceptibility to infection we used an age-structured SEIR model. RESULTS: By comparing pre- and post-pandemic serological data in Italy we found age- specific attack rates similar to those observed in other countries. Cumulative attack rate at the end of the first A/H1N1pdm season in Italy was estimated to be 16.3% (95% CI 9.4%-23.1%. Modeling results allow ruling out the hypothesis that only age-specific characteristics of the contact network and levels of pre-pandemic immunity are responsible for the observed age-specific risk of infection. This means that age-specific susceptibility to infection, suspected to play an important role in the pandemic, was not only determined by pre-pandemic levels of H1N1pdm antibody measured by HI. CONCLUSIONS: Our results claim for new studies to better identify the biological mechanisms, which might have determined the observed pattern of susceptibility with age. Moreover, our results highlight the need to obtain early estimates of differential susceptibility with age in

  2. Genetic structure of human A/H1N1 and A/H3N2 influenza virus on Corsica Island: phylogenetic analysis and vaccine strain match, 2006-2010.

    Directory of Open Access Journals (Sweden)

    Alessandra Falchi

    Full Text Available BACKGROUND: The aim of this study was to analyse the genetic patterns of Hemagglutinin (HA genes of influenza A strains circulating on Corsica Island during the 2006-2009 epidemic seasons and the 2009-2010 pandemic season. METHODS: Nasopharyngeal samples from 371 patients with influenza-like illness (ILI were collected by General Practitioners (GPs of the Sentinelles Network through a randomised selection routine. RESULTS: Phylogenetic analysis of HA revealed that A/H3N2 strains circulating on Corsica were closely related to the WHO recommended vaccine strains in each analyzed season (2006-2007 to 2008-2009. Seasonal Corsican influenza A/H1N1 isolated during the 2007-2008 season had drifted towards the A/Brisbane/59/2007 lineage, the A/H1N1 vaccine strain for the 2008-2009 season. The A/H1N1 2009 (A/H1N1pdm strains isolated on Corsica Island were characterized by the S220T mutation specific to clade 7 isolates. It should be noted that Corsican isolates formed a separate sub-clade of clade 7 as a consequence of the presence of the fixed substitution D222E. The percentages of the perfect match vaccine efficacy, estimated by using the p(epitope model, against influenza viruses circulating on Corsica Island varied substantially across the four seasons analyzed, and tend to be highest for A/H1N1 compared with A/H3N2 vaccines, suggesting that cross-immunity seems to be stronger for the H1 HA gene. CONCLUSION: The molecular analysis of the HA gene of influenza viruses that circulated on Corsica Island between 2006-2010 showed for each season the presence of a dominant lineage characterized by at least one fixed mutation. The A/H3N2 and A/H1N1pdm isolates were characterized by multiples fixation at antigenic sites. The fixation of specific mutations at each outbreak could be explained by the combination of a neutral phenomenon and a founder effect, favoring the presence of a dominant lineage in a closed environment such as Corsica Island.

  3. Activation of the aryl hydrocarbon receptor is the major toxic mode of action of an organic extract of a reference urban dust particulate matter mixture: The role of polycyclic aromatic hydrocarbons

    International Nuclear Information System (INIS)

    Andrysik, Zdenek; Vondracek, Jan; Marvanova, Sona; Ciganek, Miroslav; Neca, Jiri; Pencikova, Katerina; Mahadevan, Brinda; Topinka, Jan; Baird, William M.; Kozubik, Alois; Machala, Miroslav

    2011-01-01

    Highlights: → SRM1649a extract and its fractions are potent activators of AhR in a model of epithelial cells. → AhR-dependent effects include both induction of CYP1 enzymes and disruption of cell proliferation control. → Polycyclic aromatic hydrocarbons present in the neutral SRM1649a fraction are major contributors to the AhR-mediated toxic effects. → Activation of AhR and related nongenotoxic effects occur at significantly lower doses than the formation of DNA adducts and activation of DNA damage response. → More attention should be paid to the AhR-dependent nongenotoxic events elicited by urban particulate matter constituents. - Abstract: Many of the toxic and carcinogenic effects of urban air pollution have been linked to polycyclic aromatic hydrocarbons (PAHs) adsorbed to airborne particulate matter (PM). The carcinogenic properties of PAHs in complex organic mixtures derived from PM have been chiefly attributed to their mutagenicity. Nevertheless, PAHs are also potent activators of the aryl hydrocarbon receptor (AhR), which may contribute to their nongenotoxic effects, including tumor promotion. As the genotoxicity of carcinogenic PAHs in complex mixtures derived from urban PM is often inhibited by other mixture constituents, the AhR-mediated activity of urban PM extracts might significantly contribute to the carcinogenic activity of such mixtures. In the present study, we used an organic extract of the urban dust standard reference material, SRM1649a, as a model mixture to study a range of toxic effects related to DNA damage and AhR activation. Both the organic extract and its neutral aromatic fraction formed a low number of DNA adducts per nucleotide in the liver epithelial WB-F344 cells model, without inducing DNA damage response, such as tumor suppressor p53 activation and apoptosis. In contrast, we found that this extract, as well as its neutral and polar fractions, were potent inducers of a range of AhR-mediated responses, including induction

  4. Chemical Emergencies

    Science.gov (United States)

    When a hazardous chemical has been released, it may harm people's health. Chemical releases can be unintentional, as in the case of an ... the case of a terrorist attack with a chemical weapon. Some hazardous chemicals have been developed by ...

  5. Novel pandemic influenza A(H1N1 viruses are potently inhibited by DAS181, a sialidase fusion protein.

    Directory of Open Access Journals (Sweden)

    Gallen B Triana-Baltzer

    2009-11-01

    Full Text Available The recent emergence of a novel pandemic influenza A(H1N1 strain in humans exemplifies the rapid and unpredictable nature of influenza virus evolution and the need for effective therapeutics and vaccines to control such outbreaks. However, resistance to antivirals can be a formidable problem as evidenced by the currently widespread oseltamivir- and adamantane-resistant seasonal influenza A viruses (IFV. Additional antiviral approaches with novel mechanisms of action are needed to combat novel and resistant influenza strains. DAS181 (Fludase is a sialidase fusion protein in early clinical development with in vitro and in vivo preclinical activity against a variety of seasonal influenza strains and highly pathogenic avian influenza strains (A/H5N1. Here, we use in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181 against several pandemic influenza A(H1N1 viruses.The activity of DAS181 against several pandemic influenza A(H1N1 virus isolates was examined in MDCK cells, differentiated primary human respiratory tract culture, ex-vivo human bronchi tissue and mice. DAS181 efficiently inhibited viral replication in each of these models and against all tested pandemic influenza A(H1N1 strains. DAS181 treatment also protected mice from pandemic influenza A(H1N1-induced pathogenesis. Furthermore, DAS181 antiviral activity against pandemic influenza A(H1N1 strains was comparable to that observed against seasonal influenza virus including the H274Y oseltamivir-resistant influenza virus.The sialidase fusion protein DAS181 exhibits potent inhibitory activity against pandemic influenza A(H1N1 viruses. As inhibition was also observed with oseltamivir-resistant IFV (H274Y, DAS181 may be active against the antigenically novel pandemic influenza A(H1N1 virus should it acquire the H274Y mutation. Based on these and previous results demonstrating DAS181 broad-spectrum anti-IFV activity, DAS181 represents a potential therapeutic agent for

  6. Quantitative autoradiography of brain binding sites for the vesicular acetylcholine transport blocker 2-(4-phenylpiperidino)cyclohexanol (AH5183)

    International Nuclear Information System (INIS)

    Marien, M.R.; Parsons, S.M.; Altar, C.A.

    1987-01-01

    2-(4-Phenylpiperidino)cyclohexanol (AH5183) is a noncompetitive and potent inhibitor of high-affinity acetylcholine transport into cholinergic vesicles. It is reported here that [ 3 H]AH5183 binds specifically and saturably to slide-mounted sections of the rat forebrain (Kd = 1.1 to 2.2 X 10(-8) M; Bmax = 286 to 399 fmol/mg of protein). The association and dissociation rate constants for [ 3 H]AH5183 binding are 8.6 X 10(6) M-1 X min-1 and 0.18 min-1, respectively. Bound [ 3 H]AH5183 can be displaced by nonradioactive AH5183 and by the structural analog (2 alpha,3 beta,4A beta,8A alpha)-decahydro-3-(4-phenyl-1-piperidinyl)-2- naphthalenol but not by 10 microM concentrations of the cholinergic drugs acetylcholine, choline, atropine, hexamethonium, eserine, or hemicholinium-3 or by the structurally related compounds 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridine, (+/-)-N-allylnormetazocine (SKF 10,047), levoxadrol, or dexoxadrol. Quantitative autoradiography reveals that [ 3 H]AH5183 binding sites are distributed heterogenously throughout the rat forebrain and are highly localized to cholinergic nerve terminal regions. At the level of the caudate nucleus-putamen, the highest concentrations of saturable [ 3 H]AH5183 binding (713-751 fmol/mg of protein) are found in the vertical limb of the diagonal band and the olfactory tubercle, with lesser amounts (334-516 fmol/mg of protein) in the caudate-putamen, nucleus accumbens, superficial layers of the cerebral cortex, and the primary olfactory cortex. At day 7 after transsection of the left fimbria, [ 3 H]AH5183 binding and choline acetyltransferase activity in the left hippocampus were reduced by 33 +/- 6% and 61 +/- 7%, respectively. These findings indicate that [ 3 H]AH5183 binds to a unique recognition site in rat brain that is topographically associated with cholinergic nerve terminals

  7. Biocompatibility of RealSeal, its primer and AH Plus implanted in subcutaneous connective tissue of rats

    Directory of Open Access Journals (Sweden)

    Fabiana Soares Grecca

    2011-02-01

    Full Text Available OBJECTIVE: This study tested rat connective tissue response to RealSeal, RealSeal primer or AH Plus after 7, 15, 30, 60 and 90 days of implantation. MATERIAL AND METHODS: Thirty Wistar rats had subcutaneous sockets created on their back and received four implants each of polyethylene tubes containing one of the materials tested according to the groups: AH (AH Plus Sealer; RS (RealSeal Sealer; RP (RealSeal Primer; CG (control group - empty tube. After histological processing, sections were analyzed to identify the presence of neutrophils, lymphocytes and plasma cells, eosinophils, macrophages and giant cells, as well as fibrous capsule and abscesses, by an examiner using light microscope. Kruskal-Wallis and multiple-comparisons test were used for statistical analysis. Significance level was set at 5%. RESULTS: Lymphoplasmacytic infiltrate scores significantly higher than those of the control group were observed at 14 and 60 days in AH group, and at 90 days in RS group (p<0.05. There were no differences in terms of presence of macrophages, giant cells, eosinophils, neutrophils or fibrosis. AH Plus group scored higher for abscesses at 7 days than after any other period (p=0.031. RP group scored higher for lymphoplasmacytic infiltrate at 14 days than at 90 days (p=0.04. CONCLUSION: The main contribution of this study was to demonstrate that issues involved with tissue tolerance of a Resilon-containing sealer, RealSeal Sealer, cannot be attributed to its primer content.

  8. The Linear Span of Projections in AH Algebras and for Inclusions of C*-Algebras

    Directory of Open Access Journals (Sweden)

    Dinh Trung Hoa

    2013-01-01

    Full Text Available In the first part of this paper, we show that an AH algebra A=lim→(Ai,ϕi has the LP property if and only if every element of the centre of Ai belongs to the closure of the linear span of projections in A. As a consequence, a diagonal AH-algebra has the LP property if it has small eigenvalue variation in the sense of Bratteli and Elliott. The second contribution of this paper is that for an inclusion of unital C*-algebras P⊂A with a finite Watatani index, if a faithful conditional expectation E:A→P has the Rokhlin property in the sense of Kodaka et al., then P has the LP property under the condition thatA has the LP property. As an application, let A be a simple unital C*-algebra with the LP property, α an action of a finite group G onto Aut(A. If α has the Rokhlin property in the sense of Izumi, then the fixed point algebra AG and the crossed product algebra A ⋊α G have the LP property. We also point out that there is a symmetry on the CAR algebra such that its fixed point algebra does not have the LP property.

  9. Effect of LEO cycling on 125 Ah advanced design IPV nickel-hydrogen battery cells

    Science.gov (United States)

    Smithrick, John J.; Hall, Stephen W.

    1990-01-01

    An advanced 125 Ah individual pressure vessel (IPV) nickel-hydrogen cell was designed. The primary function of the advanced cell is to store and deliver energy for long-term, low earth-orbit (LEO) spacecraft missions. The new features of this design are: (1) use of 26 percent rather than 31 percent potassium hydroxide (KOH) electrolyte, (2) use of a patented catalyzed wall wick, (3) use of serrated-edge separators to facilitate gaseous oxygen and hydrogen flow within the cell, while still maintaining physical contact with the wall wick for electrolyte management, and (4) use of a floating rather than a fixed stack (state-of-the-art) to accommodate nickel electrode expansion. Six 125-Ah flight cells based on this design were fabricated by Eagle-Picher. Three of the cells contain all of the advanced features (test cells) and three are the same as the test cells except they don't have catalyst on the wall wick (control cells). All six cells are in the process of being evaluated in a LEO cycle life test. The cells have accumulated about 4700 LEO cycles (60 percent DOD 10 C). There have been no cell failures; the catalyzed wall wick cells, however, are performing better.

  10. Dehydration of a layered double hydroxide-C2AH8

    International Nuclear Information System (INIS)

    Ukrainczyk, N.; Matusinovic, T.; Kurajica, S.; Zimmermann, B.; Sipusic, J.

    2007-01-01

    Thermal dehydration of dicalcium aluminate hydrate, C 2 AH 8 , has been investigated by simultaneous differential thermal and thermo gravimetric analysis (DTA/TGA), powder X-ray diffraction (XRD), temperature-dependent infrared spectroscopy (FT-IR), and BET method of surface area measurement. The temperature-dependent infrared measurements were studied by two-dimensional infrared (2D-IR) correlation spectroscopy. The structure of aluminum-oxide polyhedron, characterized by 27 Al solid state NMR spectrum method and FT-IR, shows tetrahedron and octahedron as the main forms of aluminum-oxide polyhedrons in C 2 AH 8 sample. From the results obtained a variety of structural transformations observed are explained as a consequence of the removal of loosely held interlayer water molecules at lower temperatures, followed by grafting process of the interlayer [Al(OH) 4 ] - anion. Structural model of a grafting process of the interlayer [Al(OH) 4 ] - tetrahedron onto hydroxylated octahedrons of [Ca 2 Al(OH) 6 ] + layers has been proposed in order to explain observed loss of one water molecule, shrinkage of interlayer spacing and qualitative changes of FT-IR spectra. At higher temperatures the dehydroxylation of the lattice and decomposition of the interlayer species occurs, yielding amorphous material that crystallizes into C 3 A and C 12 A 7 at 885 deg. C. Those findings provide improvement in the interpretation of thermo-analytical results of calcium aluminate cements (CAC) hydration products, and better understanding of CAC conversion process

  11. The pandemic potential of avian influenza A(H7N9) virus: a review.

    Science.gov (United States)

    Tanner, W D; Toth, D J A; Gundlapalli, A V

    2015-12-01

    In March 2013 the first cases of human avian influenza A(H7N9) were reported to the World Health Organization. Since that time, over 650 cases have been reported. Infections are associated with considerable morbidity and mortality, particularly within certain demographic groups. This rapid increase in cases over a brief time period is alarming and has raised concerns about the pandemic potential of the H7N9 virus. Three major factors influence the pandemic potential of an influenza virus: (1) its ability to cause human disease, (2) the immunity of the population to the virus, and (3) the transmission potential of the virus. This paper reviews what is currently known about each of these factors with respect to avian influenza A(H7N9). Currently, sustained human-to-human transmission of H7N9 has not been reported; however, population immunity to the virus is considered very low, and the virus has significant ability to cause human disease. Several statistical and geographical modelling studies have estimated and predicted the spread of the H7N9 virus in humans and avian species, and some have identified potential risk factors associated with disease transmission. Additionally, assessment tools have been developed to evaluate the pandemic potential of H7N9 and other influenza viruses. These tools could also hypothetically be used to monitor changes in the pandemic potential of a particular virus over time.

  12. Phylogeography of Influenza A(H3N2) Virus in Peru, 2010-2012.

    Science.gov (United States)

    Pollett, Simon; Nelson, Martha I; Kasper, Matthew; Tinoco, Yeny; Simons, Mark; Romero, Candice; Silva, Marita; Lin, Xudong; Halpin, Rebecca A; Fedorova, Nadia; Stockwell, Timothy B; Wentworth, David; Holmes, Edward C; Bausch, Daniel G

    2015-08-01

    It remains unclear whether lineages of influenza A(H3N2) virus can persist in the tropics and seed temperate areas. We used viral gene sequence data sampled from Peru to test this source-sink model for a Latin American country. Viruses were obtained during 2010-2012 from influenza surveillance cohorts in Cusco, Tumbes, Puerto Maldonado, and Lima. Specimens positive for influenza A(H3N2) virus were randomly selected and underwent hemagglutinin sequencing and phylogeographic analyses. Analysis of 389 hemagglutinin sequences from Peru and 2,192 global sequences demonstrated interseasonal extinction of Peruvian lineages. Extensive mixing occurred with global clades, but some spatial structure was observed at all sites; this structure was weakest in Lima and Puerto Maldonado, indicating that these locations may experience greater viral traffic. The broad diversity and co-circulation of many simultaneous lineages of H3N2 virus in Peru suggests that this country should not be overlooked as a potential source for novel pandemic strains.

  13. Phylogeography of Influenza A(H3N2) Virus in Peru, 2010–2012

    Science.gov (United States)

    Nelson, Martha I.; Kasper, Matthew; Tinoco, Yeny; Simons, Mark; Romero, Candice; Silva, Marita; Lin, Xudong; Halpin, Rebecca A.; Fedorova, Nadia; Stockwell, Timothy B.; Wentworth, David; Holmes, Edward C.; Bausch, Daniel G.

    2015-01-01

    It remains unclear whether lineages of influenza A(H3N2) virus can persist in the tropics and seed temperate areas. We used viral gene sequence data sampled from Peru to test this source–sink model for a Latin American country. Viruses were obtained during 2010–2012 from influenza surveillance cohorts in Cusco, Tumbes, Puerto Maldonado, and Lima. Specimens positive for influenza A(H3N2) virus were randomly selected and underwent hemagglutinin sequencing and phylogeographic analyses. Analysis of 389 hemagglutinin sequences from Peru and 2,192 global sequences demonstrated interseasonal extinction of Peruvian lineages. Extensive mixing occurred with global clades, but some spatial structure was observed at all sites; this structure was weakest in Lima and Puerto Maldonado, indicating that these locations may experience greater viral traffic. The broad diversity and co-circulation of many simultaneous lineages of H3N2 virus in Peru suggests that this country should not be overlooked as a potential source for novel pandemic strains. PMID:26196599

  14. Advanced driver assistance system for AHS over communication links with random packet dropouts

    Science.gov (United States)

    Srinivasan, Seshadhri; Ayyagari, Ramakalyan

    2014-12-01

    In this paper, we propose an advanced driver assist system (ADAS) for platoon based automated highway system (AHS) with packet loss in inter-vehicle communication. Using the concept of rigidity, we first show that vehicles in a platoon tend to fall apart in the event of a packet loss among vehicles. To overcome this, we propose an estimation based dynamic platooning algorithm which employs the state estimate to maintain the platoon. Communication among the vehicle is reduced by using minimum spanning tree (MST) in state estimation algorithm. Effectiveness of the proposed ADAS scheme is illustrated by simulation wherein, dynamic platoons of holonomic vehicles with integrator dynamics are considered. Simulation studies indicate that the proposed algorithm maintains the platoon up to a packet loss rate of 48%. State transmission scheme proposed in our algorithm has three significant advantages, they are: (1) it handles packet loss in inter-vehicle communication, (2) reduces the effect of error in measured output, and (3) reduces the inter-vehicle communication. These advantages significantly increase the reliability and safety of the AHS.

  15. Global patterns in seasonal activity of influenza A/H3N2, A/H1N1, and B from 1997 to 2005: viral coexistence and latitudinal gradients.

    Directory of Open Access Journals (Sweden)

    Brian S Finkelman

    Full Text Available Despite a mass of research on the epidemiology of seasonal influenza, overall patterns of infection have not been fully described on broad geographic scales and for specific types and subtypes of the influenza virus. Here we provide a descriptive analysis of laboratory-confirmed influenza surveillance data by type and subtype (A/H3N2, A/H1N1, and B for 19 temperate countries in the Northern and Southern hemispheres from 1997 to 2005, compiled from a public database maintained by WHO (FluNet. Key findings include patterns of large scale co-occurrence of influenza type A and B, interhemispheric synchrony for subtype A/H3N2, and latitudinal gradients in epidemic timing for type A. These findings highlight the need for more countries to conduct year-round viral surveillance and report reliable incidence data at the type and subtype level, especially in the Tropics.

  16. TLX: An elusive receptor.

    Science.gov (United States)

    Benod, Cindy; Villagomez, Rosa; Webb, Paul

    2016-03-01

    TLX (tailless receptor) is a member of the nuclear receptor superfamily and belongs to a class of nuclear receptors for which no endogenous or synthetic ligands have yet been identified. TLX is a promising therapeutic target in neurological disorders and brain tumors. Thus, regulatory ligands for TLX need to be identified to complete the validation of TLX as a useful target and would serve as chemical probes to pursue the study of this receptor in disease models. It has recently been proved that TLX is druggable. However, to identify potent and specific TLX ligands with desirable biological activity, a deeper understanding of where ligands bind, how they alter TLX conformation and of the mechanism by which TLX mediates the transcription of its target genes is needed. While TLX is in the process of escaping from orphanhood, future ligand design needs to progress in parallel with improved understanding of (i) the binding cavity or surfaces to target with small molecules on the TLX ligand binding domain and (ii) the nature of the TLX coregulators in particular cell and disease contexts. Both of these topics are discussed in this review. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Determination of preventive behaviors for pandemic influenza A/H1N1 based on protection motivation theory among female high school students in Isfahan, Iran

    OpenAIRE

    Sharifirad, Gholamreza; Yarmohammadi, Parastoo; Sharifabad, Mohammad Ali Morowati; Rahaei, Zohreh

    2014-01-01

    Introduction: Influenza A/H1N1 pandemic has recently threatened the health of world's population more than ever. Non-pharmaceutical measures are important to prevent the spread of influenza A/H1N1 and to prevent a pandemic. Effective influenza pandemic management requires understanding of the factors influencing preventive behavioral. This study reports on predictors of students’ preventive behaviors for pandemic influenza A/H1N1 using variables based on the protection motivation theory (PMT)...

  18. The European I-MOVE Multicentre 2013-2014 Case-Control Study. Homogeneous moderate influenza vaccine effectiveness against A(H1N1)pdm09 and heterogenous results by country against A(H3N2).

    LENUS (Irish Health Repository)

    Valenciano, Marta

    2015-06-04

    In the first five I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe) influenza seasons vaccine effectiveness (VE) results were relatively homogenous among participating study sites. In 2013-2014, we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in six European Union (EU) countries to measure 2013-2014 influenza VE against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. Influenza A(H3N2) and A(H1N1)pdm09 viruses co-circulated during the season.

  19. The antisense expression of AhPEPC1 increases seed oil production in peanuts (Arachis hypogaea L.)

    Energy Technology Data Exchange (ETDEWEB)

    Pan, L.; Zhang, J.; Chi, X.; Chen, N.; Chen, M.; Wang, M.; Wang, T.; Yang, Z.; Zhang, Z.; Wan, Y.; Yu, S.; Liu, F.

    2016-07-01

    Although phosphoenolpyruvate carboxylases (PEPCs) are reported to be involved in fatty acid accumulation, nitrogen assimilation, and salt and drought stresses, knowledge regarding PEPC gene functions is still limited, particularly in peanuts (Arachis hypogaea L.). In this study, the antisense expression of the peanut PEPC isoform 1 (AhPEPC1) gene increased the lipid content by 5.7%–10.3%. This indicated that AhPEPC1 might be related to plant lipid accumulation. The transgenic plants underwent more root elongation than the wild-type under salinity stress. Additionally, the specific down regulation of the AhPEPC1 gene improved the salt tolerance in peanuts. This is the first report on the role of PEPC in lipid accumulation and salt tolerance in peanuts.

  20. Stable Engraftment of Bifidobacterium longum AH1206 in the Human Gut Depends on Individualized Features of the Resident Microbiome.

    Science.gov (United States)

    Maldonado-Gómez, María X; Martínez, Inés; Bottacini, Francesca; O'Callaghan, Amy; Ventura, Marco; van Sinderen, Douwe; Hillmann, Benjamin; Vangay, Pajau; Knights, Dan; Hutkins, Robert W; Walter, Jens

    2016-10-12

    Live bacteria (such as probiotics) have long been used to modulate gut microbiota and human physiology, but their colonization is mostly transient. Conceptual understanding of the ecological principles as they apply to exogenously introduced microbes in gut ecosystems is lacking. We find that, when orally administered to humans, Bifidobacterium longum AH1206 stably persists in the gut of 30% of individuals for at least 6 months without causing gastrointestinal symptoms or impacting the composition of the resident gut microbiota. AH1206 engraftment was associated with low abundance of resident B. longum and underrepresentation of specific carbohydrate utilization genes in the pre-treatment microbiome. Thus, phylogenetic limiting and resource availability are two factors that control the niche opportunity for AH1206 colonization. These findings suggest that bacterial species and functional genes absent in the gut microbiome of individual humans can be reestablished, providing opportunities for precise and personalized microbiome reconstitution. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Unusually High Mortality in Waterfowl Caused by Highly Pathogenic Avian Influenza A(H5N1) in Bangladesh

    DEFF Research Database (Denmark)

    Haider, Najmul; Sturm-Ramirez, K.; Khan, S. U.

    2017-01-01

    a survey in three of these villages to identify suspected human influenza-like illness cases and collected nasopharyngeal and throat swabs. We tested all swabs by real-time RT-PCR, sequenced cultured viruses, and examined tissue samples by histopathology and immunohistochemistry to detect and characterize...... and immunohistochemistry staining of avian influenza viral antigens were recognized in the brain, pancreas and intestines of ducks and chickens. We identified ten human cases showing signs compatible with influenza-like illness; four were positive for influenza A/H3; however, none were positive for influenza A/H5......Mortality in ducks and geese caused by highly pathogenic avian influenza A(H5N1) infection had not been previously identified in Bangladesh. In June-July 2011, we investigated mortality in ducks, geese and chickens with suspected H5N1 infection in a north-eastern district of the country to identify...

  2. Spatiotemporal Analysis of the Genetic Diversity of Seal Influenza A(H10N7) Virus, Northwestern Europe

    DEFF Research Database (Denmark)

    Bodewes, Rogier; Zohari, Siamak; Krog, Jesper Schak

    2016-01-01

    and Denmark. Within a few months, this virus spread to seals of the coastal waters of Germany and the Netherlands, causing the death of thousands of animals. Genetic analysis of the hemagglutinin (HA) and neuraminidase (NA) genes of this seal influenza A(H10N7) virus revealed that it was most closely related...... to various avian influenza A(H10N7) viruses. The collection of samples from infected seals during the course of the outbreak provided a unique opportunity to follow the adaptation of the avian virus to its new seal host. Sequence data for samples collected from 41 different seals from four different......, various sequencing methods were used to elucidate the genetic changes that occurred after the introduction and subsequent spread of an avian influenza A(H10N7) virus among harbor seals of northwestern Europe by use of various samples collected during the outbreak. Such detailed knowledge of genetic...

  3. Developing Maqasid al-Shari’ah Index to Evaluate Social Performance of Islamic Banks: A Conceptual and Empirical Attempt

    Directory of Open Access Journals (Sweden)

    Mehmet Asutay

    2015-07-01

    Full Text Available The rise of Islamic banking and finance is now a reality with Shari 'ah compliant financial operations existing in many different parts of the world. However, its development has recently been subjected to criticism in relation to the aspirational objectives of Islamic moral economy, which constitutes the moral foundations of Islamic finance. The aspirational objectives are general expressed with maqasid al-Shari'ah, which is defined as 'human well-being'.The aim of this research, hence, is to evaluate the social performance of Islamic banks according to maqasid al-Shari'ah upon the realization of Islamic Moral Economy aspirations. AbdelMajid Najjar's concept of maqasid al-Shari 'ah with eight orientations or articulations is adopted to construct an evaluation framework aligned with the objective of rendering a critical improvement of current empirical studies.In operationalizing the developed framework, this study conducts empirical investigations by taking 13 banks from 6 countries for 5-year period (2008-2012 as a sample. In doing so, the annual reports of the sampled banks for the period are subjected to content analysis to generate the necessary data in applying to the formulated framework.Empirical evidence indicates that there is lack of achievement in maqasid al-Shari 'ah performance of Islamic bank and finance. Nevertheless, the overall industry concentrates mainly on self, faith and rights and stakeholding rather than wealth orientation, despite the fewer contributions in social entity, intellect, posterity and ecology. Additionally, the empirical results find that there are different orientations across the banks and countries. Finally, the industry orientation is estimated in this research, which is located to be somewhere betweenfaith and rights and stakeholding.Keywords: Maqasid al-Shari 'ah, Islamic Banking and Finance, Evaluation, Performance

  4. Clinical characteristics and outcomes among pediatric patients hospitalized with pandemic influenza A/H1N1 2009 infection

    Directory of Open Access Journals (Sweden)

    Eun Lee

    2011-08-01

    Full Text Available Purpose : The purpose of this article is to describe the clinical and epidemiologic features and outcomes among children hospitalized with pandemic influenza A/H1N1 2009 infection. Methods : We retrospectively reviewed the charts of hospitalized pediatric patients (&lt;18 years diagnosed with pandemic influenza A/H1N1 2009 infection by reverse-transcriptase polymerase chain reaction at a tertiary hospital in Seoul, Korea, between September 2009 and February 2010. Results : A total of 72 children were hospitalized with pandemic influenza A/H1N1 2009 infection (median age, 6.0 years; range, 2 months to 18 years. A total of 40% had at least 1 underlying medical condition, including asthma (17%, malignancies (19%, and heart diseases (17%. Of the 72 patients, 54 (76% children admitted with H1N1 infection showed radiographic alterations compatible with pneumonia. There was no significant difference in pre-existing conditions between pandemic influenza A/H1N1 infected patients with or without pneumonia. Children with pandemic influenza A/ H1N1 pneumonia were more likely to have a lower lymphocyte ratio (P=0.02, higher platelet count (P=0.02, and higher level of serum glucose (P=0.003, and more commonly presented with dyspnea than did those without pneumonia (P=0.04. Conclusion : No significant differences in age, sex, or presence of preexisting conditions were found between children hospitalized with pandemic influenza A/H1N1 H1N1 influenza infection with pneumonia and those without pneumonia. Higher leukocyte count, higher glucose level, and a lower lymphocyte ratio were associated with the development of pandemic A/H1N1 2009 influenza pneumonia.

  5. Entry and exit screening of airline travellers during the A(H1N1) 2009 pandemic: a retrospective evaluation.

    Science.gov (United States)

    Khan, Kamran; Eckhardt, Rose; Brownstein, John S; Naqvi, Raza; Hu, Wei; Kossowsky, David; Scales, David; Arino, Julien; MacDonald, Michael; Wang, Jun; Sears, Jennifer; Cetron, Martin S

    2013-05-01

    To evaluate the screening measures that would have been required to assess all travellers at risk of transporting A(H1N1)pdm09 out of Mexico by air at the start of the 2009 pandemic. Data from flight itineraries for travellers who flew from Mexico were used to estimate the number of international airports where health screening measures would have been needed, and the number of travellers who would have had to be screened, to assess all air travellers who could have transported the H1N1 influenza virus out of Mexico during the initial stages of the 2009 A(H1N1) pandemic. Exit screening at 36 airports in Mexico, or entry screening of travellers arriving on direct flights from Mexico at 82 airports in 26 other countries, would have resulted in the assessment of all air travellers at risk of transporting A(H1N1)pdm09 out of Mexico at the start of the pandemic. Entry screening of 116 travellers arriving from Mexico by direct or connecting flights would have been necessary for every one traveller at risk of transporting A(H1N1)pdm09. Screening at just eight airports would have resulted in the assessment of 90% of all air travellers at risk of transporting A(H1N1)pdm09 out of Mexico in the early stages of the pandemic. During the earliest stages of the A(H1N1) pandemic, most public health benefits potentially attainable through the screening of air travellers could have been achieved by screening travellers at only eight airports.

  6. Avaliação comparativa da citotoxicidade dos cimentos MTA Fillapex e AH Plus: revisão integrativa

    OpenAIRE

    Marinho, Jéssica Cristina Soares; Cunha, Ludmila de Almeida; Lacerda, Mariane Floriano Lopes Santos; Lacerda, Gabriel Pinheiro; Coelho, Renato Girelli; Girelli, Caroline Felipe Magalhães

    2017-01-01

    Objetivo: O objetivo deste estudo foi realizar uma revisão integrativa comparando a citotoxicidade dos cimentos MTA Fillapex e AH Plus aos tecidos periapicais. Métodos: Foram utilizados artigos na íntegra, nos idiomas português e inglês, publicados durante os períodos de 2010 a 2017, selecionados na base de dados Scielo e Pubmed, utilizando os seguintes descritores: AH Plus, MTA Fillapex e citotoxicidade. Foram excluídos, os trabalhos no idioma não inglês, artigos sem resumo, trabalhos realiz...

  7. Immune protection induced on day 10 following administration of the 2009 A/H1N1 pandemic influenza vaccine.

    Directory of Open Access Journals (Sweden)

    Yizhuo Sun

    Full Text Available BACKGROUND: The 2009 swine-origin influenza virus (S-OIV H1N1 pandemic has caused more than 18,000 deaths worldwide. Vaccines against the 2009 A/H1N1 influenza virus are useful for preventing infection and controlling the pandemic. The kinetics of the immune response following vaccination with the 2009 A/H1N1 influenza vaccine need further investigation. METHODOLOGY/PRINCIPAL FINDINGS: 58 volunteers were vaccinated with a 2009 A/H1N1 pandemic influenza monovalent split-virus vaccine (15 µg, single-dose. The sera were collected before Day 0 (pre-vaccination and on Days 3, 5, 10, 14, 21, 30, 45 and 60 post vaccination. Specific antibody responses induced by the vaccination were analyzed using hemagglutination inhibition (HI assay and enzyme-linked immunosorbent assay (ELISA. After administration of the 2009 A/H1N1 influenza vaccine, specific and protective antibody response with a major subtype of IgG was sufficiently developed as early as Day 10 (seroprotection rate: 93%. This specific antibody response could maintain for at least 60 days without significant reduction. Antibody response induced by the 2009 A/H1N1 influenza vaccine could not render protection against seasonal H1N1 influenza (seroconversion rate: 3% on Day 21. However, volunteers with higher pre-existing seasonal influenza antibody levels (pre-vaccination HI titer ≥1∶40, Group 1 more easily developed a strong antibody protection effect against the 2009 A/H1N1 influenza vaccine as compared with those showing lower pre-existing seasonal influenza antibody levels (pre-vaccination HI titer <1∶40, Group 2. The titer of the specific antibody against the 2009 A/H1N1 influenza was much higher in Group 1 (geometric mean titer: 146 on Day 21 than that in Group 2 (geometric mean titer: 70 on Day 21. CONCLUSIONS/SIGNIFICANCE: Recipients could gain sufficient protection as early as 10 days after vaccine administration. The protection could last at least 60 days. Individuals with a

  8. MASA PEMBAYARAN BEBAN NAFKAH IDDAH DAN MUT’AH DALAM PERKARA CERAI TALAK (Sebuah Implementasi Hukum Acara di Pengadilan Agama

    Directory of Open Access Journals (Sweden)

    syaiful annas

    2017-12-01

    Full Text Available This paper will discuss the implementation of payment of  iddah and mut'ah in the divorce (raj’i. Judges often faced  a problem between text and context. Their decision imposes on men pays iddah and mut'ah life as a right for his ex-wife, but it was not implemented as the judge's decision, so that women tend to be disadvantaged ones, although the formal law can be prosecuted fiat execution, but it is not easy for a woman, sometimes the cost of iddah and mut'ah charge is not comparable with the cost of carrying out the execution, not to mention ex-husband who went (fuzzy away unnoticed after divorce statement. Therefore the necessary of a legal breakthrough to provide legal certainty for the rights of womens through the judge's decision, with consideration argumentative primarily to determine a living payout time of iddah And mut'ah. In this paper will be described legal reasons in court as legal considerations which contains elements of juridical, sociological, philosophical in decision   [Tulisan ini hendak mendiskusikan bagaimana pelaksanaan pembebanan pembayaran nafkah iddah dan mut’ah dalam perkara talak (raj'i. Seringkali hakim dihadapkan pada problematika antara teks dan konteks. Adanya putusan yang membebankan terhadap laki-laki membayar sejumlah nafkah iddah dan mut’ah sebagai hak bagi mantan istri, akan tetapi tidak dilaksanakan sebagaimana putusan hakim, sehingga perempuan cenderung dirugikan, meskipun secara yuridis-formil dapat dituntut fiat eksekusi, tetapi tidak mudah bagi pihak perempuan, karena kadang biaya pembebanan nafkah iddah dan mut’ah tidak sebanding dengan biaya melaksanakan eksekusi, belum lagi problem mantan suami yang pergi tanpa diketahui lagi keberadaannya setelah pengucapan ikrar talaknya. Oleh karena itu perlu terobosan hukum guna menjamin hak perempuan tersebut melalui putusan hakim dengan pertimbangan yang argumentatif terutama untuk menentukan masa pembayaran nafkah iddah dan mut’ah tersebut. Dalam

  9. Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines.

    Science.gov (United States)

    Novotna, Aneta; Srovnalova, Alzbeta; Svecarova, Michaela; Korhonova, Martina; Bartonkova, Iveta; Dvorak, Zdenek

    2014-01-01

    Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and induce