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Sample records for a3 a4 a5

  1. Cytochrome P450 3A4 and CYP3A5-Catalyzed Bioactivation of Lapatinib.

    PubMed

    Towles, Joanna K; Clark, Rebecca N; Wahlin, Michelle D; Uttamsingh, Vinita; Rettie, Allan E; Jackson, Klarissa D

    2016-10-01

    Metabolic activation of the dual-tyrosine kinase inhibitor lapatinib by cytochromes CYP3A4 and CYP3A5 has been implicated in lapatinib-induced idiosyncratic hepatotoxicity; however, the relative enzyme contributions have not been established. The objective of this study was to examine the roles of CYP3A4 and CYP3A5 in lapatinib bioactivation leading to a reactive, potentially toxic quinoneimine. Reaction phenotyping experiments were performed using individual human recombinant P450 enzymes and P450-selective chemical inhibitors. Lapatinib metabolites and quinoneimine-glutathione (GSH) adducts were analyzed using liquid chromatography-tandem mass spectrometry. A screen of cDNA-expressed P450s confirmed that CYP3A4 and CYP3A5 are the primary enzymes responsible for quinoneimine-GSH adduct formation using lapatinib or O-dealkylated lapatinib as the substrate. The mean kinetic parameters (Km and kcat) of lapatinib O-dealkylation revealed that CYP3A4 was 5.2-fold more efficient than CYP3A5 at lapatinib O-dealkylation (CYP3A4 kcat/Km = 6.8 μM(-1) min(-1) versus CYP3A5 kcat/Km = 1.3 μM(-1) min(-1)). Kinetic analysis of GSH adduct formation indicated that CYP3A4 was also 4-fold more efficient at quinoneimine-GSH adduct formation as measured by kcat (maximum relative GSH adduct levels)/Km (CYP3A4 = 0.0082 vs. CYP3A5 = 0.0021). In human liver microsomal (HLM) incubations, CYP3A4-selective inhibitors SR-9186 and CYP3cide reduced formation of GSH adducts by 78% and 72%, respectively, compared with >90% inhibition by the pan-CYP3A inhibitor ketoconazole. The 16%-22% difference between CYP3A- and CYP3A4-selective inhibition indicates the involvement of remaining CYP3A5 activity in generating reactive metabolites from lapatinib in pooled HLMs. Collectively, these findings support the conclusion that both CYP3A4 and CYP3A5 are quantitatively important contributors to lapatinib bioactivation. PMID:27450182

  2. Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

    PubMed Central

    Forse, Garry Jason; Uson, Maria Loressa; Nasertorabi, Fariborz; Kolatkar, Anand; Lamberto, Ilaria; Pasquale, Elena Bianca; Kuhn, Peter

    2015-01-01

    The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins. PMID:25993310

  3. Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone.

    PubMed

    Hong, Yanjun; Chia, Yvonne Mei Fen; Yeo, Ray Hng; Venkatesan, Gopalakrishnan; Koh, Siew Kwan; Chai, Christina Li Lin; Zhou, Lei; Kojodjojo, Pipin; Chan, Eric Chun Yong

    2016-01-01

    Dronedarone is an antiarrhythmic agent approved in 2009 for the treatment of atrial fibrillation. An in-house preliminary study demonstrated that dronedarone inhibits cytochrome P450 (CYP) 3A4 and 3A5 in a time-dependent manner. This study aimed to investigate the inactivation of CYP450 by dronedarone. We demonstrated for the first time that both dronedarone and its main metabolite N-desbutyl dronedarone (NDBD) inactivate CYP3A4 and CYP3A5 in a time-, concentration-, and NADPH-dependent manner. For the inactivation of CYP3A4, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 0.87 µM and 0.039 minute(-1), respectively, for dronedarone, and 6.24 µM and 0.099 minute(-1), respectively, for NDBD. For CYP3A5 inactivation, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 2.19 µM and 0.0056 minute(-1) for dronedarone and 5.45 µM and 0.056 minute(-1) for NDBD. The partition ratios for the inactivation of CYP3A4 and CYP3A5 by dronedarone are 51.1 and 32.2, and the partition ratios for the inactivation of CYP3A4 and CYP3A5 by NDBD are 35.3 and 36.6. Testosterone protected both CYP3A4 and CYP3A5 from inactivation by dronedarone and NDBD. Although the presence of Soret peak confirmed the formation of a quasi-irreversible metabolite-intermediate complex between dronedarone/NDBD and CYP3A4/CYP3A5, partial recovery of enzyme activity by potassium ferricyanide illuminated an alternative irreversible mechanism-based inactivation (MBI). MBI of CYP3A4 and CYP3A5 was further supported by the discovery of glutathione adducts derived from the quinone oxime intermediates of dronedarone and NDBD. In conclusion, dronedarone and NDBD inactivate CYP3A4 and CYP3A5 via unique dual mechanisms of MBI and formation of the metabolite-intermediate complex. Our novel findings contribute new knowledge for

  4. 40 CFR Table A-5 to Subpart A of... - Supplier Category List for § 98.2(a)(4)

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 21 2011-07-01 2011-07-01 false Supplier Category List for § 98.2(a)(4) A Table A-5 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt....

  5. Linkage and association of haplotypes at the APOA1/C3/A4/A5 genecluster to familial combined hyperlipidemia

    SciTech Connect

    Eichenbaum-Voline, Sophie; Olivier, Michael; Jones, Emma L.; Naoumova, Rossitza P.; Jones, Bethan; Gau, Brian; Seed, Mary; Betteridge,D. John; Galton, David J.; Rubin, Edward M.; Scott, James; Shoulders,Carol C.; Pennacchio, Len A.

    2002-09-15

    Combined hyperlipidemia (CHL) is a common disorder of lipidmetabolism that leads to an increased risk of cardiovascular disease. Thelipid profile of CHL is characterised by high levels of atherogeniclipoproteins and low levels of high-density-lipoprotein-cholesterol.Apolipoprotein (APO) A5 is a newly discovered gene involved in lipidmetabolism located within 30kbp of the APOA1/C3/A4 gene cluster. Previousstudies have indicated that sequence variants in this cluster areassociated with increased plasma lipid levels. To establish whethervariation at the APOA5 gene contributes to the transmission of CHL, weperformed linkage and linkage disequilibrium (LD) tests on a large cohortof families (n=128) with familial CHL (FCHL). The linkage data producedevidence for linkage of the APOA1/C3/A4/A5 genomic interval to FCHL (NPL= 1.7, P = 0.042). The LD studies substantiated these data. Twoindependent rare alleles, APOA5c.56G and APOC3c.386G of this gene clusterwere over-transmitted in FCHL (P = 0.004 and 0.007, respectively), andthis was associated with a reduced transmission of the most commonAPOA1/C3/A4/A5 haplotype (frequency 0.4425) to affected subjects (P =0.013). The APOA5c.56G allele was associated with increased plasmatriglyceride levels in FCHL probands, whereas the second, andindependent, APOC3c.386G allele was associated with increased plasmatriglyceride levels in FCHL pedigree founders. Thus, this allele (or anallele in LD) may mark a quantitative trait associated with FCHL, as wellas representing a disease susceptibility locus for the condition. Thisstudy establishes that sequence variation in the APOA1/C3/A4/A5 genecluster contributes to the transmission of FCHL in a substantialproportion of affected families, and that these sequence variants mayalso contribute to the lipid abnormalities of the metabolic syndrome,which is present in up to 40 percent of persons with cardiovasculardisease.

  6. X-ray structure analysis of a solid solution of milbemycins A3 and A4.

    PubMed

    Bizdena, E; Belyakov, S; Jure, M; Grinsteine, I; Kumpiņš, V; Turks, M

    2013-10-01

    Milbemycins A3 and A4 are pharmaceutically and agriculturally useful macrolides isolated from Streptomyces species. The molecular structures of the title compounds were unambiguously established by a single crystal X-ray analysis of the solid solution of both compounds. The crystals present trigonal system, space group P32 with Z = 3, unit cell dimensions: a = 12.2211(4), c = 17.5372(7) Å; V = 2268.4(1) Å(3), μ = 0.082 mm(- 1); d = 1.183 g cm(- 3). An interesting system of intramolecular hydrogen bonds and weak intermolecular CH…O type hydrogen bond was observed in the solid state.

  7. Primary identification of Microbacterium spp. encountered in clinical specimens as CDC coryneform group A-4 and A-5 bacteria.

    PubMed Central

    Funke, G; Falsen, E; Barreau, C

    1995-01-01

    Over nearly two decades, 13 yellow- or orange-pigmented, fermentative gram-positive rods belonging to the genus Microbacterium were encountered in clinical specimens. All 13 strains, 10 of which came from blood cultures, were initially identified as CDC coryneform group A-4 and A-5 bacteria according to the scheme of Hollis and Weaver for the identification of gram-positive rods. The clinical isolates were compared with the type strains of the six species constituting the genus Microbacterium as well as with three Microbacterium strains isolated from hospital environments. By biochemical methods only 5 of 13 clinical isolates could be identified to species level. Peptidoglycan analysis proved to be a valuable tool for differentiation between Microbacterium spp. and related genera, whereas cellular fatty acid analysis did not allow species identification within the genus Microbacterium. The 22 Microbacterium strains studied were, in general, susceptible to antimicrobial agents used in the treatment of infections caused by gram-positive rods. This report is the first one concerning the isolation of Microbacterium strains from clinical specimens. The sources as well as the mode of transmission remain to be established. PMID:7699039

  8. Desipramine targets astrocytes to attenuate synaptic plasticity via modulation of the ephrinA3/EphA4 signalling.

    PubMed

    Tanasic, Sascha; Mattusch, Corinna; Wagner, Eva Maria; Eder, Matthias; Rupprecht, Rainer; Rammes, Gerhard; Di Benedetto, Barbara

    2016-06-01

    Long-term potentiation (LTP), a major cellular correlate of memory storage, depends on activation of the ERK/MAPK signalling pathway, but the cell type-specific localization of activated MAPKs remains unknown. We found that in the CA1 field of the hippocampus, shortly after LTP induction, an increase in the number of MAPK-positive cells occurred specifically among astrocytes of the stratum radiatum, suggesting a putative role of astrocytes for LTP. Desipramine (DMI) is an antidepressant which is used to treat major depressive disorder, but also other pathologies such as neuropathic pain or attention-deficit/hyperactivity disorder. Tricyclic antidepressants such as DMI may cause memory impairment as a side effect. However, biological underpinnings of this effect still remain unclear. Here, we show that DMI inhibited the astrocytic MAPK activation and thereby hindered synaptic potentiation. These effects correlated with a reduced neuronal activation in the stratum pyramidale, thereby prompting us to analyse a regulator of LTP located at the astrocyte-neuron interface in the stratum radiatum, namely the ephrinA3/EphA4 signalling pathway. DMI enhanced EphA4 clustering, which favoured an increased ephrinA3-mediated EphA4 phosphorylation and elevated EphA4 forward signalling. The co-administration of DMI with the Src inhibitor SU6656, which blocks EphA4 forward signalling, could partially reverse the LTP attenuation, further supporting the targeting of the ephrinA3/EphA4 pathway by DMI. Thus, our findings suggest a putative novel mechanism for DMI to modulate LTP through the regulation of the ephrinA3/EphA4 signalling pathway. A further exploration of the molecular and behavioral consequences of targeting ephrinA3/EphA4 might help to improve the clinical use of DMI.

  9. Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism

    PubMed Central

    Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

    2015-01-01

    The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

  10. Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

    PubMed

    Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

    2015-11-09

    The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.

  11. Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

    PubMed

    Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

    2015-01-01

    The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

  12. Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism

    PubMed Central

    Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

    2015-01-01

    The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

  13. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis

    PubMed Central

    Malone, Andrew F; Phelan, Paul J; Hall, Gentzon; Cetincelik, Umran; Homstad, Alison; Alonso, Andrea; Jiang, Ruiji; Lindsey, Thomas; Wu, Guanghong; Sparks, Matthew A; Smith, Stephen R; Webb, Nicholas J A; Kalra, Philip; Adeyemo, Adebowale; Shaw, Andrey S; Conlon, Peter J; Jennette, J Charles; Howell, David N; Winn, Michelle P; Gbadegesin, Rasheed A

    2014-01-01

    Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes. PMID:25229338

  14. [Protein-protein interactions of cytochromes P450 3A4 and 3A5 with their intermediate redox partners cytochromes b5].

    PubMed

    Gnedenko, O V; Ivanov, A S; Iablokov, E O; Usanov, S A; Mukha, D V; Sergeev, G V; Kuzikov, A V; Moskaleva, N E; Bulko, T V; Shumiantseva, V V; Archakov, A I

    2014-01-01

    Molecular interactions between proteins redox partners (cytochromes P450 3A4, 3A5 and cytochrome b5) within the monooxygenase system, which is known to be involved in drug biotransformation, were investigated. Human cytochromes P450 3A4 and 3A5 (CYP3A4 and CYP3A5) form complexes with various cytochromes b5: the microsomal (b5mc) and mitochondrial (b5om) forms of this protein, as well as with 2 "chimeric" proteins, b5(om-mc), b5(mc-om). Kinetic constants and equilibrium dissociation constants were determined by the SPR biosensor. Essential distinction between CYP3A4 and CYP3A5 was only observed upon their interactions with cytochrome b5om. Electroanalytical characteristics of electrodes with immobilized hemoproteins were obtained. The electrochemical analysis of CYP3A4, CYP3A5, b5mc, b5om, b5(om-mc), and b5(mc-om) immobilized on screen printed graphite electrodes modified with membranous matrix revealed that these proteins have very close reduction potentials -0.435 - -0.350 V (vs. Ag/AgCl). Cytochrome b5mc was shown to be capable of stimulating the electrocatalytic activity of CYP3A4 to testosterone.

  15. Differential Interactions of Cytochrome P450 3A5 and 3A4 with Chemotherapeutic Agent-Vincristine: A Comparative Molecular Dynamics Study.

    PubMed

    Saba, Nikhat; Bhuyan, Rajabrata; Nandy, Suman Kumar; Seal, Alpana

    2015-01-01

    The chemotherapeutic agent vincristine, used for treatment of acute lymphoblastic leukemia is metabolized preferentially by polymorphic cytochrome P450 3A5 (CYP3A5) with higher clearance rate than cytochrome P450 3A4 (CYP3A4). As a result, CYP3A5 expressers have a reduced amount of vincristine-induced peripheral neuropathy than non-expressers. We modeled the structure of CYP3A5 and its interaction with vincristine, compared with CYP3A4-vincristine complex using molecular docking and simulation studies. This relative study helped us to understand the molecular mechanisms behind the interaction at the atomic level through interaction energy, binding free energy, hydrogen bond and solvent accessible surface area analysis - giving an insight into the binding mode and the main residues involved in this particular interaction. Our results show that the interacting groups get closer in CYP3A5-vincristine complex due to different orientation of vincristine. This leads to higher binding affinity of vincristine towards CYP3A5 compared to CYP3A4 and explains the preferential metabolism of vincristine by CYP3A5. We believe that, the results of the current study will be helpful for future studies on structure-based drug design in this area.

  16. The APOA1/C3/A4/A5 cluster and markers of allostatic load in the Boston Puerto Rican Health Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The APOA1/C3/A4/A5 cluster encodes key regulators of plasma lipids. Interactions between dietary factors and single nucleotide polymorphisms (SNPs) in the cluster have been reported. Allostatic load, or physiological dysregulation in response to stress, has been implicated in shaping health disparit...

  17. Functional studies and polymerization of recombinant hemoglobin Glu-alpha2beta26(A3) --> Val/Glu-7(A4) --> Ala.

    PubMed

    Lesecq, S; Baudin, V; Kister, J; Marden, M C; Poyart, C; Pagnier, J

    1996-07-19

    In hemoglobin (Hb) S the hydrophobic mutated residue Val-beta6(A3) (donor site) closely interacts with the hydrophobic side groups of Phe-beta85(F1) and Leu-beta88(F4) (EF pocket, acceptor site) of a neighboring tetramer, resulting in decreased solubility and polymerization of the deoxy-Hb. The beta6(A3) residue is followed by two charged residues Glu-beta7(A4) and Lys-beta8(A5). This cluster has no attraction for the hydrophobic EF pocket. We have modified the beta7(A4) residue next to the donor site Val-beta6(A3), replacing the charged Glu by a hydrophobic Ala-(rHb betaE6V/E7A). The single mutant Glu-beta7 --> Ala-(rHb betaE7A) was also engineered. Both rHbs exhibit a heat instability and an increased oxygen affinity compared to Hb A and Hb S. There was a concentration dependence of the ligand binding properties (1-300 microM in heme) indicating an increased amount of dimers relative to Hb A. The deoxy form of rHb betaE6V/E7A polymerizes in vitro, with a decreased rate of polymer formation relative to Hb S, while the single mutant betaE7A does not polymerize in the same experimental conditions. The Glu-beta7(A4) --> Ala substitution does not increase the hydrophobic interaction between donor and acceptor site. We speculate that the loss of the normal saline bridge between Glu-beta7(A4) and Lys-beta132(H10) leads to an increased flexibility of the A helix and may account for the difference of the polymerization for this Hb S mutant. PMID:8663330

  18. [Protein-protein interactions of cytochromes P450 3A4 and 3A5 with their intermediate redox partners cytochromes b5].

    PubMed

    Gnedenko, O V; Ivanov, A S; Yablokov, E O; Usanov, S A; Mukha, D V; Sergeev, G V; Kuzikov, A V; Bulko, T V; Moskaleva, N E; Shumyantseva, V V; Archakov, A I

    2015-01-01

    Molecular interactions between proteins redox partners (cytochromes Р450 3А4, 3А5 and cytochrome b5) within the monooxygenase system, which is known to be involved in drug biotransformation, were investigated. Human cytochromes Р450 3А4 and 3А5 (CYP3A4 and CYP3A5) form complexes with various cytochromes b5: the microsomal (b5mc) and mitochondrial (b5om) forms of this protein, as well as with 2 "chimeric" proteins, b5(om-mc), b5(mc-om). Kinetic constants and equilibrium dissociation constants were determined by the SPR biosensor. Essential distinction between CYP3A4 and CYP3A5 was only observed upon their interactions with cytochrome b5om. Electroanalytical characteristics of electrodes with immobilized hemoproteins were obtained. The electrochemical analysis of CYP3A4, CYP3A5, b5mc, b5om, b5(om-mc), and b5(mc-om) immobilized on screen printed graphite electrodes modified with membranous matrix revealed that these proteins have very close reduction potentials -0.435  -0.350 V (vs. Ag/AgCl). Cytochrome b5mc was shown to be capable of stimulating the electrocatalytic activity of CYP3A4 in the presence of its substrate testosterone.

  19. Characterization of cytochrome P450 2A4 and 2A5-catalyzed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism.

    PubMed

    Felicia, N D; Rekha, G K; Murphy, S E

    2000-12-15

    The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung carcinogen in the A/J mouse, and is believed to be a causative agent for human lung cancer. NNK requires metabolic activation by alpha-hydroxylation to exert its carcinogenic potential. The human P450, 2A6 is a catalyst of this reaction. There are two closely related enzymes in the mouse, P450 2A4 and 2A5, which differ from each other by only 11 amino acids. In the present study these two mouse P450s were expressed in Spodoptera frugiperda (Sf9) cells using recombinant baculovirus. The catalysis of NNK metabolism by Sf9 microsomal fractions containing either P450 2A4 or 2A5 was determined. Both enzymes catalyzed the alpha-hydroxylation of NNK but with strikingly different efficiencies and specificities. P450 2A5 preferentially catalyzed NNK methyl hydroxylation, while P450 2A4 preferentially catalyzed methylene hydroxylation. The KM and Vmax for the former were 1.5 microM and 4.0 nmol/min/nmol P450, respectively, and for the latter 3.9 mM and 190 nmol/min/nmol P450. The mouse coumarin 7-hydroxylase, P450 2A5 is a significantly better catalyst of NNK alpha-hydroxylation than is the closely related human enzyme, P450 2A6.

  20. Individual and combined associations of genetic variants in CYP3A4, CYP3A5, and SLCO1B1 with simvastatin and simvastatin acid plasma concentrations

    PubMed Central

    Luzum, Jasmine A.; Theusch, Elizabeth; Taylor, Kent D.; Wang, Ann; Sadee, Wolfgang; Binkley, Philip F.; Krauss, Ronald M.; Medina, Marisa W.; Kitzmiller, Joseph P.

    2015-01-01

    Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism (CYP3A4*22 and CYP3A5*3) and transport (SLCO1B1 T521C) with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and concentrations were quantified by HPLC-MS/MS in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/day SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared to CYP3A4*1/*1 participants (p=0.006). SLCO1B1 521T/C and 521C/C participants had 71% (p<0.001) and 248% (p<0.001) higher 12-hour plasma SVA compared to SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (p=0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased plasma 12-hour concentrations of SV and SVA, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles. PMID:26164721

  1. Effects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in healthy young men.

    PubMed

    Delgado-Lista, Javier; Perez-Jimenez, Francisco; Ruano, Juan; Perez-Martinez, Pablo; Fuentes, Francisco; Criado-Garcia, Juan; Parnell, Laurence D; Garcia-Rios, Antonio; Ordovas, Jose M; Lopez-Miranda, Jose

    2010-01-01

    The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism.

  2. [CYP2D6, CYP3A5, and CYP3A4 gene polymorphism in Russian, Tatar, and Bashkir populations].

    PubMed

    Mustafina, O E; Tuktarova, I A; Karimov, D D; Somova, R sh; Nasibullin, T R

    2015-01-01

    The allele and genotype frequency distribution at polymorphic loci rs3892097 (184G>A) of CYP2D6 gene, rs776746 (6986A>G) of the CYP3A5 gene and rs2740574 (-392A>G) of the CYP3A4 gene in Russians, Tatars, and Bashkirs was examined. Samples were taken from residents of Bashkortostan Republic (1240 men and women aged from 20 to 109 years and consisted of 443 Russians, 517 Tatars, and 280 Bashkirs). Allele identification was conducted using PCR-RFLP or PCR with TaqMan probes. The "nonfunctional" allele rs3892097*A of the CYP2D6 gene was detected in populations of Russians, Tatars, and Bashkirs in 17.2, 9.5, and 7.1% cases, respectively. The rs776746*G allele of the CYP3A5 gene encoding the CYP3A5 isoenzyme with decreased activity was revealed with a frequency of 94.6% in populations of Russians, 94.3% in the Tatar population, and 91.5% in the Bashkir population. The share of the minor allele rs2740574*G of the CYP3A4 was 4.0% in populations of Russians, 0.5% in the Tatar population, and 0.9% in the Bashkir population. It has been previously shown that the rs3892097*A, rs776746*G, and rs2740574*G allele frequencies vary significantly in different world populations. Since allele variants of CYP2D6, CYP3A5, and CYP3A4 genes can play essential role in interindividual and in interethnic differences in the metabolism of many therapeutic agents, the obtained results could be used in the prognosis of pharmacotherapy efficacy in populations of Russians, Tatars, and Bashkirs.

  3. Three Novel Lantibiotics, Ticins A1, A3, and A4, Have Extremely Stable Properties and Are Promising Food Biopreservatives.

    PubMed

    Xin, Bingyue; Zheng, Jinshui; Xu, Ziya; Li, Congzhi; Ruan, Lifang; Peng, Donghai; Sun, Ming

    2015-10-01

    Lantibiotics are antimicrobial peptides with potential applications as the next generation of antimicrobials in the food industry and/or the pharmaceutical industry. Nisin has successfully been used as a food preservative for over 40 years, but its major drawback is its limited stability under neutral and alkaline pH conditions. To identify alternatives with better biochemical properties, we screened more than 100 strains of the Bacillus cereus group. Three novel lantibiotics, ticins A1 (4,062.98 Da), A3 (4,048.96 Da), and A4 (4,063.02 Da), which were highly thermostable (121°C for 30 min) and extremely pH tolerant (pH 2.0 to 9.0), were identified in Bacillus thuringiensis BMB3201. They all showed potent antimicrobial activities against all tested Gram-positive bacteria and greater activities than those of nisin A against Bacillus cereus and Listeria monocytogenes, two important foodborne pathogens. These three novel lantibiotics, with their extremely stable properties and potent antimicrobial activities, have the potential for use as biopreservatives.

  4. Three Novel Lantibiotics, Ticins A1, A3, and A4, Have Extremely Stable Properties and Are Promising Food Biopreservatives

    PubMed Central

    Xin, Bingyue; Zheng, Jinshui; Xu, Ziya; Li, Congzhi; Ruan, Lifang; Peng, Donghai

    2015-01-01

    Lantibiotics are antimicrobial peptides with potential applications as the next generation of antimicrobials in the food industry and/or the pharmaceutical industry. Nisin has successfully been used as a food preservative for over 40 years, but its major drawback is its limited stability under neutral and alkaline pH conditions. To identify alternatives with better biochemical properties, we screened more than 100 strains of the Bacillus cereus group. Three novel lantibiotics, ticins A1 (4,062.98 Da), A3 (4,048.96 Da), and A4 (4,063.02 Da), which were highly thermostable (121°C for 30 min) and extremely pH tolerant (pH 2.0 to 9.0), were identified in Bacillus thuringiensis BMB3201. They all showed potent antimicrobial activities against all tested Gram-positive bacteria and greater activities than those of nisin A against Bacillus cereus and Listeria monocytogenes, two important foodborne pathogens. These three novel lantibiotics, with their extremely stable properties and potent antimicrobial activities, have the potential for use as biopreservatives. PMID:26231642

  5. Three Novel Lantibiotics, Ticins A1, A3, and A4, Have Extremely Stable Properties and Are Promising Food Biopreservatives.

    PubMed

    Xin, Bingyue; Zheng, Jinshui; Xu, Ziya; Li, Congzhi; Ruan, Lifang; Peng, Donghai; Sun, Ming

    2015-10-01

    Lantibiotics are antimicrobial peptides with potential applications as the next generation of antimicrobials in the food industry and/or the pharmaceutical industry. Nisin has successfully been used as a food preservative for over 40 years, but its major drawback is its limited stability under neutral and alkaline pH conditions. To identify alternatives with better biochemical properties, we screened more than 100 strains of the Bacillus cereus group. Three novel lantibiotics, ticins A1 (4,062.98 Da), A3 (4,048.96 Da), and A4 (4,063.02 Da), which were highly thermostable (121°C for 30 min) and extremely pH tolerant (pH 2.0 to 9.0), were identified in Bacillus thuringiensis BMB3201. They all showed potent antimicrobial activities against all tested Gram-positive bacteria and greater activities than those of nisin A against Bacillus cereus and Listeria monocytogenes, two important foodborne pathogens. These three novel lantibiotics, with their extremely stable properties and potent antimicrobial activities, have the potential for use as biopreservatives. PMID:26231642

  6. Combined application of plasma mutagenesis and gene engineering leads to 5-oxomilbemycins A3/A4 as main components from Streptomyces bingchenggensis.

    PubMed

    Wang, Hai-Yan; Zhang, Ji; Zhang, Yue-Jing; Zhang, Bo; Liu, Chong-Xi; He, Hai-Rong; Wang, Xiang-Jing; Xiang, Wen-Sheng

    2014-12-01

    Milbemycin oxime has been commercialized as effective anthelmintics in the fields of animal health, agriculture, and human infections. Currently, milbemycin oxime is synthesized by a two-step chemical reaction, which involves the ketonization of milbemycins A3/A4 to yield the intermediates 5-oxomilbemycins A3/A4 using CrO3 as catalyst. Due to the low efficiency and environmental unfriendliness of the ketonization of milbemycins A3/A4, it is imperative to develop alternative strategies to produce 5-oxomilbemycins A3/A4. In this study, the atmospheric and room temperature plasma (ARTP) mutation system was first employed to treat milbemycin-producing strain Streptomyces bingchenggensis, and a mutant strain BC-120-4 producing milbemycins A3, A4, B2, and B3 as main components was obtained, which favors the construction of genetically engineered strains producing 5-oxomilbemycins. Importantly, the milbemycins A3/A4 yield of BC-120-4 reached 3,890 ± 52 g/l, which was approximately two times higher than that of the initial strain BC-109-6 (1,326 ± 37 g/l). The subsequent interruption of the gene milF encoding a C5-ketoreductase responsible for the ketonization of milbemycins led to strain BCJ60 (∆milF) with the production of 5-oxomilbemycins A3/A4 and the elimination of milbemycins A3, A4, B2, and B3. The high 5-oxomilbemycins A3/A4 yield (3,470 ± 147 g/l) and genetic stability of BCJ60 implied the potential use in industry to prepare 5-oxomilbemycins A3/A4 for the semisynthesis of milbemycins oxime. PMID:25081559

  7. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....50A-4 Section 1.50A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Rules for Computing Credit for Expenses of Work Incentive Programs § 1.50A-4 Exceptions to.... For purposes of the preceding sentence, a substantial reduction in the benefits of employment of...

  8. Insights into Eph receptor tyrosine kinase activation from crystal structures of the EphA4 ectodomain and its complex with ephrin-A5

    PubMed Central

    Xu, Kai; Tzvetkova-Robev, Dorothea; Xu, Yan; Goldgur, Yehuda; Chan, Yee-Peng; Himanen, Juha P.; Nikolov, Dimitar B.

    2013-01-01

    Eph receptor tyrosine kinases and their ephrin ligands mediate cell signaling during normal and oncogenic development. Eph signaling is initiated in a multistep process leading to the assembly of higher-order Eph/ephrin clusters that set off bidirectional signaling in interacting cells. Eph and ephrins are divided in two subclasses based on their abilities to bind and activate each other and on sequence conservation. EphA4 is an exception to the general rule because it can be activated by both A- and B-class ephrin ligands. Here we present high-resolution structures of the complete EphA4 ectodomain and its complexes with ephrin-A5. The structures reveal how ligand binding promotes conformational changes in the EphA4 ligand-binding domain allowing the formation of signaling clusters at the sites of cell–cell contact. In addition, the structural data, combined with structure-based mutagenesis, reveal a previously undescribed receptor–receptor interaction between the EphA4 ligand-binding and membrane-proximal fibronectin domains, which is functionally important for efficient receptor activation. PMID:23959867

  9. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) of § 1.50A-5 (relating to electing small business corporations), paragraph (a)(2) of § 1.50A-6... transferor (or in a case where the transferor is a partnership, estate, trust, or electing small business... the case of an electing small business corporation (as defined in section 1371(b)), an estate or...

  10. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  11. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

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

  12. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

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

  13. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

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

  14. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

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

  15. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Limitations on application of § 1.613A-3... Reconciliation Act of 1990) or the taxable income limitation contained in section 613A(d)(1); (ii) Any net...). Of that amount, $19.5×: EC08OC91.012 is tentatively allocated to property M, $29.25×: EC08OC91.013...

  16. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Limitations on application of § 1.613A-3... Reconciliation Act of 1990) or the taxable income limitation contained in section 613A(d)(1); (ii) Any net...). Of that amount, $19.5×: EC08OC91.012 is tentatively allocated to property M, $29.25×: EC08OC91.013...

  17. Identification of some clinical strains of CDC coryneform group A-3 and A-4 bacteria as Cellulomonas species and proposal of Cellulomonas hominis sp. nov. for some group A-3 strains.

    PubMed Central

    Funke, G; Ramos, C P; Collins, M D

    1995-01-01

    CDC coryneform group A-3 and A-4 bacteria were defined by Hollis and Weaver in 1981, but their taxonomic position is still unclear. By using biochemical and chemotaxonomical methods, four clinical strains belonging to CDC coryneform groups A-3 (n = 2) and A-4 (n = 2) were studied and could be assigned to the genus Cellulomonas, resulting in the first description of Cellulomonas strains isolated from clinical specimens. CDC coryneform group A-3 and A-4 strains were compared with the type strains of the seven species constituting the genus Cellulomonas at present as well as with the closely related species Oerskovia turbata, Oerskovia xanthineolytica, and Jonesia denitrificans, but their biochemical patterns were not compatible with the patterns of any of those species. Almost the entire sequences of the 16S rRNA genes of one representative strain of both CDC taxa were determined, and comparative sequence analysis confirmed the placement of the CDC coryneform group A-3 and A-4 strains studied in the Cellulomonas-Oerskovia subbranch of the actinomycetes. Both CDC taxa exhibited > 99% base pair homology within their 16S rDNAs. On the basis of phenotypic and molecular data, we formally propose a new species, Cellulomonas hominis sp. nov., for the CDC coryneform group A-3 bacteria examined. The type strain is DSM 9581. The precise taxonomic status of the CDC coryneform group A-4 strains studied remains to be established by quantitative DNA-DNA hybridizations. PMID:7559954

  18. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons.

    PubMed

    Wang, Qian-fei; Liu, Xin; O'Connell, Jeff; Peng, Ze; Krauss, Ronald M; Rainwater, David L; VandeBerg, John L; Rubin, Edward M; Cheng, Jan-Fang; Pennacchio, Len A

    2004-05-15

    Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well-established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well-characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL-cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human quantitative trait loci genes in a highly controlled non-human primate model.

  19. Monoester-Diterpene Aconitum Alkaloid Metabolism in Human Liver Microsomes: Predominant Role of CYP3A4 and CYP3A5

    PubMed Central

    Ye, Ling; Yang, Xiao-Shan; Lu, Lin-lin; Chen, Wei-Ying; Zeng, Shan; Yan, Tong-Meng; Dong, Ling-Na; Peng, Xiao-Juan; Shi, Jian; Liu, Zhong-Qiu

    2013-01-01

    Aconitum, widely used to treat rheumatoid arthritis for thousands of years, is a toxic herb that can frequently cause fatal cardiac poisoning. Aconitum toxicity could be decreased by properly hydrolyzing diester-diterpene alkaloids into monoester-diterpene alkaloids. Monoester-diterpene alkaloids, including benzoylaconine (BAC), benzoylmesaconine (BMA), and benzoylhypaconine (BHA), are the primary active and toxic constituents of processed Aconitum. Cytochrome P450 (CYP) enzymes protect the human body by functioning as the defense line that limits the invasion of toxicants. Our purposes were to identify the CYP metabolites of BAC, BMA, and BHA in human liver microsomes and to distinguish which isozymes are responsible for their metabolism through the use of chemical inhibitors, monoclonal antibodies, and cDNA-expressed CYP enzyme. High-resolution mass spectrometry was used to characterize the metabolites. A total of 7, 8, and 9 metabolites were detected for BAC, BMA, and BHA, respectively. The main metabolic pathways were demethylation, dehydrogenation, demethylation-dehydrogenation, hydroxylation and didemethylation, which produced less toxic metabolites by decomposing the group responsible for the toxicity of the parent compound. Taken together, the results of the chemical inhibitors, monoclonal antibodies, and cDNA-expressed CYP enzymes experiments demonstrated that CYP3A4 and CYP3A5 have essential functions in the metabolism of BAC, BMA, and BHA. PMID:23864901

  20. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons

    SciTech Connect

    Wang, Qian-fei; Liu, Xin; O'Connell, Jeff; Peng, Ze; Krauss, Ronald M.; Rainwater, David L.; VandeBerg, John L.; Rubin, Edward M.; Cheng, Jan-Fang; Pennacchio, Len A.

    2003-09-15

    Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human QTL genes in a highly controlled non-human primate model.

  1. Identifying and applying a highly selective probe to simultaneously determine the O-glucuronidation activity of human UGT1A3 and UGT1A4.

    PubMed

    Jiang, Li; Liang, Si-Cheng; Wang, Chao; Ge, Guang-Bo; Huo, Xiao-Kui; Qi, Xiao-Yi; Deng, Sa; Liu, Ke-Xin; Ma, Xiao-Chi

    2015-01-01

    Glucuronidation mediated by uridine 5'-diphospho (UDP)-glucuronosyltransferase is an important detoxification pathway. However, identifying a selective probe of UDP- glucuronosyltransferase is complicated because of the significant overlapping substrate specificity displayed by the enzyme. In this paper, desacetylcinobufagin (DACB) 3-O- and 16-O-glucuronidation were found to be isoform-specific probe reactions for UGT1A4 and UGT1A3, respectively. DACB was well characterized as a probe for simultaneously determining the catalytic activities of O-glucuronidation mediated by UGT1A3 and UGT1A4 from various enzyme sources, through a sensitive analysis method. PMID:25884245

  2. Functional genetic variation in the basal promoter of the organic cation/carnitine transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5).

    PubMed

    Tahara, Harunobu; Yee, Sook Wah; Urban, Thomas J; Hesselson, Stephanie; Castro, Richard A; Kawamoto, Michiko; Stryke, Doug; Johns, Susan J; Ferrin, Thomas E; Kwok, Pui-Yan; Giacomini, Kathleen M

    2009-04-01

    The organic cation/ergothioneine transporter OCTN1 (SLC22A4) and the high-affinity carnitine transporter OCTN2 (SLC22A5), play an important role in the disposition of xenobiotics and endogenous compounds. Here, we analyzed the sequence of the proximal promoter regions of OCTN1 and OCTN2 in four ethnic groups and determined the effects of the identified genetic variants on transcriptional activities and mRNA expression. Six variants were found in the proximal promoter of OCTN1, one of which showed high allele frequency ranging from 13 to 34% in samples from individuals with ancestries in Africa, Europe, China, and Mexico. OCTN1 haplotypes had similar activities as the reference in luciferase reporter assays. For OCTN2, three of the seven variants identified in the proximal promoter showed allele frequencies greater than 29.5% in all populations, with the exception of -207C>G (rs2631367) that was monomorphic in Asian Americans. OCTN2 haplotypes containing -207G, present in all populations, were associated with a gain of function in luciferase reporter assays. Consistent with reporter assays, OCTN2 mRNA expression levels in lymphoblastoid cell lines (LCLs) from gene expression analysis were greater in samples carrying a marker for -207G. This SNP seems to contribute to racial differences in OCTN2 mRNA expression levels in LCLs. Our study with healthy subjects (n = 16) homozygous for either -207C or -207G, showed no appreciable effect of this SNP on carnitine disposition. However, there were significant effects of gender on carnitine plasma levels (p < 0.01). Further in vivo studies of OCTN2 promoter variants on carnitine disposition and variation in drug response are warranted.

  3. MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset.

    PubMed

    Martinez-Chamorro, A; Moreno, A; Gómez-García, M; Cabello, M J; Martin, J; Lopez-Nevot, M Á

    2016-06-01

    Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.

  4. Identification of New Natural CphA Metallo-β-Lactamases CphA4 and CphA5 in Aeromonas veronii and Aeromonas hydrophila Isolates from Municipal Sewage in Central Italy

    PubMed Central

    Bottoni, Carlo; Marcoccia, Francesca; Compagnoni, Chiara; Colapietro, Martina; Sabatini, Alessia; Celenza, Giuseppe; Segatore, Bernardetta; Maturo, Maria Giovanna; Amicosante, Gianfranco

    2015-01-01

    Two new natural CphA metallo-β-lactamases, the CphA4 and CphA5 enzymes, were identified in water samples from municipal sewage in central Italy. Compared to CphA, the CphA4 and CphA5 enzymes showed numerous point mutations. These enzymes have a narrow spectrum of substrates focused on carbapenems only. CphA5 showed kcat values about 40-, 12-, and 97-fold higher than those observed for CphA4 versus imipenem, ertapenem, and biapenem, respectively. PMID:25987617

  5. Exploring the roles of UGT1A1 and UGT1A3 in oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor.

    PubMed

    Mosteller, Michael; Condreay, Lynn D; Harris, Elizabeth C; Ambery, Claire; Beerahee, Misba; Ghosh, Soumitra

    2014-12-01

    Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders. Substantial variability in the oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes, is largely unaccounted for by clinical variables. A study of 41 patients, 78% (32/41) of whom were non-Hispanic whites, with mild to moderate asthma identified an association of UGT1A1*28 and UGT1A3*2 with the oral clearance of GSK2190915 (P=3.8×10⁻⁴ and 1.2×10⁻⁵, respectively). However, in a subsequent replication study of 403 non-Hispanic white patients with asthma, we failed to observe a statistically significant association between oral clearance of GSK2190915 and either UGT1A1*28 or UGT1A3*2 (P>0.05). Therefore, genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified. PMID:25192553

  6. Human UGT1A4 and UGT1A3 Conjugate 25-Hydroxyvitamin D3: Metabolite Structure, Kinetics, Inducibility, and Interindividual Variability

    PubMed Central

    Wang, Zhican; Wong, Timothy; Hashizume, Takanori; Dickmann, Leslie Z.; Scian, Michele; Koszewski, Nicholas J.; Goff, Jesse P.; Horst, Ronald L.; Chaudhry, Amarjit S.; Schuetz, Erin G.

    2014-01-01

    25-Hydroxyvitamin D3 (25OHD3) is used as a clinical biomarker for assessment of vitamin D status. Blood levels of 25OHD3 represent a balance between its formation rate and clearance by several oxidative and conjugative processes. In the present study, the identity of human uridine 5′-diphosphoglucuronyltransferases (UGTs) capable of catalyzing the 25OHD3 glucuronidation reaction was investigated. Two isozymes, UGT1A4 and UGT1A3, were identified as the principal catalysts of 25OHD3 glucuronidation in human liver. Three 25OHD3 monoglucuronides (25OHD3-25-glucuronide, 25OHD3-3-glucuronide, and 5,6-trans-25OHD3-25-glucuronide) were generated by recombinant UGT1A4/UGT1A3, human liver microsomes, and human hepatocytes. The kinetics of 25OHD3 glucuronide formation in all systems tested conformed to the Michaelis-Menten model. An association between the UGT1A4*3 (Leu48Val) gene polymorphism with the rates of glucuronide formation was also investigated using human liver microsomes isolated from 80 genotyped livers. A variant allele dose effect was observed: the homozygous UGT1A4*3 livers (GG) had the highest glucuronidation activity, whereas the wild type (TT) had the lowest activity. Induction of UGT1A4 and UGT1A3 gene expression was also determined in human hepatocytes treated with pregnane X receptor/constitutive androstane receptor agonists, such as rifampin, carbamazepine, and phenobarbital. Although UGT mRNA levels were increased significantly by all of the known pregnane X receptor/constitutive androstane receptor agonists tested, rifampin, the most potent of the inducers, significantly induced total 25OHD3 glucuronide formation activity in human hepatocytes measured after 2, but not 4 and 24 hours, of incubation. Finally, the presence of 25OHD3-3-glucuronide in both human plasma and bile was confirmed, suggesting that the glucuronidation pathway might be physiologically relevant and contribute to vitamin D homeostasis in humans. PMID:24641623

  7. Frequency of COL4A3/COL4A4 Mutations amongst Families Segregating Glomerular Microscopic Hematuria and Evidence for Activation of the Unfolded Protein Response. Focal and Segmental Glomerulosclerosis Is a Frequent Development during Ageing

    PubMed Central

    Papazachariou, Louiza; Demosthenous, Panayiota; Pieri, Myrtani; Papagregoriou, Gregory; Savva, Isavella; Stavrou, Christoforos; Zavros, Michael; Athanasiou, Yiannis; Ioannou, Kyriakos; Patsias, Charalambos; Panagides, Alexia; Potamitis, Costas; Demetriou, Kyproula; Prikis, Marios; Hadjigavriel, Michael; Kkolou, Maria; Loukaidou, Panayiota; Pastelli, Androulla; Michael, Aristos; Lazarou, Akis; Arsali, Maria; Damianou, Loukas; Goutziamani, Ioanna; Soloukides, Andreas; Yioukas, Lakis; Elia, Avraam; Zouvani, Ioanna; Polycarpou, Polycarpos; Pierides, Alkis; Voskarides, Konstantinos; Deltas, Constantinos

    2014-01-01

    Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies. PMID:25514610

  8. Effectiveness of a combined in-office and take-home whitening system for teeth shades A3.5 to A4.

    PubMed

    Radz, Gary M

    2014-10-01

    As teeth whitening increases in popularity, dental professionals are challenged to select the proper materials and technique to create esthetically whitened smiles for their patients. This study examined nine subjects with baseline shades of A3.5 to A4 on four to six of their maxillary anterior teeth with the VITA Classical (VC) shade guide. All subjects received one session of in-office whitening (Philips Zoom WhiteSpeed), 3 weeks of at-home tray whitening (Zoom NiteWhite), and the option of a second WhiteSpeed treatment. Subjects achieved, on average, documented change of 11.1 shades. Only two subjects reported any sensitivity, thereby demonstrating the effectiveness of a combined whitening system, including both chairside and take-home whitening, and a sensitivity prevention protocol.

  9. Pharmacogenetics in American Indian Populations: Analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes

    PubMed Central

    Fohner, Alison; Muzquiz, LeeAnna I.; Austin, Melissa A.; Gaedigk, Andrea; Gordon, Adam; Thornton, Timothy; Rieder, Mark J.; Pershouse, Mark A.; Putnam, Elizabeth A.; Howlett, Kevin; Beatty, Patrick; Thummel, Kenneth E.; Woodahl, Erica L.

    2014-01-01

    Objectives Cytochrome P450 enzymes play a dominant role in drug elimination and variation in these genes is a major source of interindividual differences in drug response. Little is known, however, about pharmacogenetic variation in American Indian and Alaska Native (AI/AN) populations. We have developed a partnership with the Confederated Salish and Kootenai Tribes (CSKT) in northwestern Montana to address this knowledge gap. Methods We resequenced CYP2D6 in 187 CSKT subjects and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT subjects. Results We identified 67 variants in CYP2D6, 15 in CYP3A4, 10 in CYP3A5, and 41 in CYP2C9. The most common CYP2D6 alleles were CYP2D6*4 and *41 (20.86 and 11.23%, respectively). CYP2D6*3, *5, *6, *9, *10, *17, *28, *33, *35, *49, *1xN, *2xN, and *4xN frequencies were less than 2%. CYP3A5*3, CYP3A4*1G, and *1B were detected with frequencies of 92.47, 26.81, and 2.20%, respectively. Allelic variation in CYP2C9 was low: CYP2C9*2 (5.17%) and *3 (2.69%). In general, allele frequencies in CYP2D6, CYP2C9 and CYP3A5 were similar to those observed in European Americans. There was, however, a marked divergence in CYP3A4 for the CYP3A4*1G allele. We also observed low levels of linkage between CYP3A4*1G and CYP3A5*1 in the CSKT. The combination of nonfunctional CYP3A5*3 and putative reduced function CYP3A4*1G alleles may predict diminished clearance of CYP3A substrates. Conclusions These results highlight the importance of conducting pharmacogenomic research in AI/AN populations and demonstrate that extrapolation from other populations is not appropriate. This information could help to optimize drug therapy for the CSKT population. PMID:23778323

  10. Differential inhibition of cytochromes P450 3A4 and 3A5 by the newly synthesized coumarin derivatives 7-coumarin propargyl ether and 7-(4-trifluoromethyl)coumarin propargyl ether.

    PubMed

    Sridar, Chitra; Kent, Ute M; Noon, Kate; McCall, Alecia; Alworth, Bill; Foroozesh, Maryam; Hollenberg, Paul F

    2008-11-01

    The abilities of 7-coumarin propargyl ether (CPE) and 7-(4-trifluoromethyl)coumarin propargyl ether (TFCPE) to act as mechanism-based inactivators of P450 3A4 and 3A5 in the reconstituted system have been investigated using 7-benzyloxy-4-(trifluoromethyl)coumarin (BFC) and testosterone as probes. CPE inhibited the BFC O-debenzylation activity of P450 3A4 in a time-, concentration-, and NADPH-dependent manner characteristic of a mechanism-based inactivator with a half-maximal inactivation (K(I)) of 112 microM, a maximal rate of inactivation (k(inact)) of 0.05 min(-1), and a t(1/2) of 13.9 min. Similarly, TFCPE inhibited the BFC O-debenzylation activity of P450 3A4 in a time-, concentration-, and NADPH-dependent manner with a K(I) of 14 microM, a k(inact) of 0.04 min(-1), and a t(1/2) of 16.5 min. Parallel losses of P450 3A4 enzymatic activity and heme were observed with both compounds as measured by high-performance liquid chromatography and reduced CO spectra. Interestingly, neither compound inhibited the BFC O-debenzylation activity of P450 3A5. Reactive intermediates of CPE and TFCPE formed by P450 3A4 were trapped with glutathione, and the resulting adducts were identified using tandem mass spectral analysis. Metabolism studies using TFCPE resulted in the identification of a single metabolite that is formed by P450 3A4 but not by P450 3A5 and that may play a role in the mechanism-based inactivation.

  11. No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects

    PubMed Central

    González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A.

    2015-01-01

    Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world. PMID:26557993

  12. MiR-193a-3p and miR-193a-5p suppress the metastasis of human osteosarcoma cells by down-regulating Rab27B and SRR, respectively.

    PubMed

    Pu, Youguang; Zhao, Fangfang; Cai, Wenjing; Meng, Xianghui; Li, Yinpeng; Cai, Shanbao

    2016-04-01

    MicroRNAs have been identified as key players in the development and progression of osteosarcoma, which is the most common primary malignancy of bone. Sequencing-based miR-omic and quantitative real-time PCR analyses suggested that the expression of miR-193a-3p and miR-193a-5p was decreased by DNA methylation at their promoter region in a highly metastatic osteosarcoma cell line (MG63.2) relative to their expression in the less metastatic MG63 cell line. Further wound-healing and invasion assays demonstrated that both miR-193a-3p and miR-193a-5p suppressed osteosarcoma cell migration and invasion. Moreover, introducing miR-193a-3p and miR-193a-5p mimics into MG63.2 cells or antagomiRs into MG63 cells confirmed their critical roles in osteosarcoma metastasis. Additionally, bioinformatics prediction along with biochemical assay results clearly suggested that the secretory small GTPase Rab27B and serine racemase (SRR) were direct targets of miR-193a-3p and miR-193a-5p, respectively. These two targets are indeed involved in the miR-193a-3p- and miR-193a-5p-induced suppression of osteosarcoma cell migration and invasion. MiR-193a-3p and miR-193a-5p play important roles in osteosarcoma metastasis through down-regulation of the Rab27B and SRR genes and therefore may serve as useful biomarkers for the diagnosis of osteosarcoma and as potential candidates for the treatment of metastatic osteosarcoma.

  13. A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4.

    PubMed

    Hansen, M T; Forst, B; Cremers, N; Quagliata, L; Ambartsumian, N; Grum-Schwensen, B; Klingelhöfer, J; Abdul-Al, A; Herrmann, P; Osterland, M; Stein, U; Nielsen, G H; Scherer, P E; Lukanidin, E; Sleeman, J P; Grigorian, M

    2015-01-22

    S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression. PMID:24469032

  14. Anti-I-J alloantisera elicited by immunization of B10.A(3R) (I-Jb) mice with bone marrow-derived macrophages from B10.A(5R) (I-Jk) mice.

    PubMed

    Bradley, L M; Shiigi, S M; Malley, A

    1986-03-01

    In this paper we describe production of alloantisera specific for determinants encoded by I-J gene loci expressed on macrophages. B10.A(3R) (I-Jb) mice were hyperimmunized with pure macrophages grown in vitro from bone marrow stem cells of congenic B10.A(5R) mice. The antisera contained predominantly IgM antibody that was non-adherent to protein-A-Sepharose with a minor component of IgG1, and IgG2a antibodies that were adherent to protein-A-Sepharose. The protein-A non-adherent antibody completely blocked the in vitro generation of humoral immune responses to sheep erythrocytes by spleen cell from B10.A(5R) mice and from inbred strains that share the I-Jk haplotypes, but did not alter the responses of spleen cells of the I-Jb haplotype. In the presence of complement, both protein-A adherent and protein-A non-adherent antibodies eliminated the capacity of B10.A(5R) spleen cells to generate humoral and proliferative responses, but the functional activity of B10.A(3R) cells was unaffected. These data indicate the I-Jk specificity of the antisera. The capacity of the anti-macrophage antibody to block humoral immune induction was removed by absorption with bone marrow-derived macrophages from B10.A(5R) mice, but not from B10.A(3R) mice. Further, the B10.A(5R) macrophages completely restored the humoral responses of antibody- and complement-treated B10.A(5R) spleen cells, but B10.A(3R) macrophages showed only partial restoration that was consistent with a factor-mediated allogeneic effect. These data demonstrate the specificity of our anti-I-J sera for macrophages and indicate that bone marrow-derived macrophages express surface I-J encoded molecules.

  15. D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures

    PubMed Central

    Foster, Alan C.; Farnsworth, Jill; Lind, Genevieve E.; Li, Yong-Xin; Yang, Jia-Ying; Dang, Van; Penjwini, Mahmud; Viswanath, Veena; Staubli, Ursula; Kavanaugh, Michael P.

    2016-01-01

    N-methyl-D-aspartate (NMDA) receptors play critical roles in synaptic transmission and plasticity. Activation of NMDA receptors by synaptically released L-glutamate also requires occupancy of co-agonist binding sites in the tetrameric receptor by either glycine or D-serine. Although D-serine appears to be the predominant co-agonist at synaptic NMDA receptors, the transport mechanisms involved in D-serine homeostasis in brain are poorly understood. In this work we show that the SLC1 amino acid transporter family members SLC1A4 (ASCT1) and SLC1A5 (ASCT2) mediate homo- and hetero-exchange of D-serine with physiologically relevant kinetic parameters. In addition, the selectivity profile of D-serine uptake in cultured rat hippocampal astrocytes is consistent with uptake mediated by both ASCT1 and ASCT2. Together these data suggest that SLC1A4 (ASCT1) may represent an important route of Na-dependent D-serine flux in the brain that has the ability to regulate extracellular D-serine and thereby NMDA receptor activity. PMID:27272177

  16. Transient up-regulation of retinal EphA3 and EphA5, but not ephrin-A2, coincides with re-establishment of a topographic map during optic nerve regeneration in goldfish.

    PubMed

    King, Carolyn E; Wallace, Amy; Rodger, Jennifer; Bartlett, Carole; Beazley, Lyn D; Dunlop, Sarah A

    2003-10-01

    Eph tyrosine kinase receptors and their ligands, the ephrins, play a key role in the establishment of retinotectal topography during development. Tectal up-regulation of ephrin-A2 in goldfish, coincident with the reestablishment of a retinotectal map, suggests a similar role during optic nerve regeneration. Here we report a complementary study of EphA3, EphA5 and ephrin-A2 expression in the retina. EphA3 and EphA5 are transiently up-regulated as ascending naso-temporal gradients, whereas ephrin-A2 remains uniform. The expression profiles differ from those in developing chick and mouse, suggesting that different combinations of retinal Eph receptors and ligands can generate topographic guidance information.

  17. Electron impact mass spectral fragmentation of 3a,5-disubstituted 1, 3-diphenyl-3a,4,5,6-tetra-hydro-3H-1,2,4-triazolo[4,3-a][1, 5]benzo-diazepines.

    PubMed

    Xu, J; Zhang, Q; Wang, C

    2000-01-01

    The mass spectrometric behaviour of six 3a,5-disubstituted 1, 3-diphenyl-3a,4,5,6-tetrahydro-3H-1,2,4-triazolo[4,3-a][1, 5]benzodiazepines has been studied with the aid of mass-analyzed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization. All compounds show a tendency to eliminate (substituted) styrene molecules, aryl radicals, arylmethyl radicals or phenylnitrene (PhN:). All of the resulting fragment ions, except [M - PhN:](+.), could further undergo a reverse [2 + 3] cycloaddition. The [M - PhN:](+.) ions could further lose styrene derivatives and undergo a ring enlargement rearrangement. The molecular ions also show a tendency to eliminate a phenyl radical, and the [M - Ph](+) ions could eliminate styrene derivatives. The [M - R(1)CH = CH(2)](+.) ions could further lose NH(2) to yield stable tetracyclic 1,3-diphenyl-1,2,4-triazolo[4,3-d]phenanthridine ions, which could further lose benzonitrile, or undergo a reverse [2 + 3] cycloaddition. The molecular ions could also undergo a reverse [2 + 3] cycloaddition to produce N-phenylbenzonitrile imine ions and 2, 4-disubstituted 2,3-dihydro-1H-1,5-benzodiazepine ions, whose further fragmentations were also investigated.

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

    PubMed Central

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

    2007-01-01

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

  19. Excited state reaction dynamics of Ti(a5FJ) + O2 → TiO(A3Φ, B3Π, C3Δ) + O studied by a crossed-beam velocity map imaging technique

    NASA Astrophysics Data System (ADS)

    Honma, Kenji; Tanaka, Yuhki

    2015-04-01

    Oxidation reactions of the gas-phase titanium atom in its excited state with oxygen molecule, Ti(a5FJ) + O2 → TiO(A3Φ, B3Π, C3Δ) + O, were studied by a crossed-beam velocity map imaging technique at 14.3 kJ/mol of collision energy. Metastable excited Ti, Ti(a5FJ), was generated by an optical pumping method and the reaction products were detected by single photon-ionization followed by a time-of-flight mass analysis and a two dimensional detection. Three wavelengths were selected to ionize electronically excited TiO∗, TiO(A3Φ, B3Π, C3Δ). Time sliced images were measured, and angular and speed distributions of TiO∗ were determined. In all three ionization wavelengths, the angular distributions showed a forward-backward symmetry with low intensity at the sideway direction. The speed distributions were represented by the distributions based on the statistical energy partition into products. These results suggested that the reaction of Ti(a5FJ) to form TiO(B) and TiO(C) proceeds via a long-lived intermediate and confirmed that the mechanism proposed by the previous chemiluminescence study.

  20. Linkage approach and direct COL4A5 gene mutation screening in Alport syndrome

    SciTech Connect

    Turco, A.E.; Rossetti, S.; Biasi, O.

    1994-09-01

    Alport Syndrome (AS) is transmitted as an X-linked dominant trait in the majority of families, the defective gene being COL4A5 at Xq22. In the remaining cases AS appears to be autosomally inherited. Recently, mutations in COL4A3 and COL4A4 genes at 2q35-q37 were identified in families with autosomal recessive AS. Mutation detection screening is being performed by non-radioactive single stand conformation polymorphism (SSCP), heteroduplex analysis, and automated DNA sequencing in over 170 AS patients enrolled in the ongoing Italian Multicenter Study on AS. So far twenty-five different mutations have been found, including missense, splicing, and frameshifts. Moreover, by using six tightly linked COL4A5 informative makers, we have also typed two larger AS families, and have shown compatible sex-linked transmission in one other, suggesting autosomal recessive inheritance. In this latter three-generation COL4A5-unlinked family we are now looking for linkage and for mutations in the candidate COL4A3 and COL4A4 genes on chromosome 2q.

  1. A-3 Groundbreaking Ceremony

    NASA Technical Reports Server (NTRS)

    2007-01-01

    NASA officials and government leaders participated in a groundbreaking event for a new rocket engine test stand at NASA's Stennis Space Center, Miss. Pictured (left to right) are Deputy Associate Administrator for Exploration Systems Doug Cooke, Pratt & Whitney Rocketdyne President Jim Maser, Stennis Space Center Director Richard Gilbrech, NASA Associate Administrator for Exploration Systems Scott Horowitz, NASA Deputy Administrator Shana Dale, Mississippi Gov. Haley Barbour, Sen. Thad Cochran, Sen. Trent Lott, Rep. Gene Taylor, SSC's Deputy Director Gene Goldman, and SSC's A-3 Project Manager Lonnie Dutreix. Stennis' A-3 Test Stand will provide altitude testing for NASA's developing J-2X engine. That engine will power the upper stages of NASA's Ares I and Ares V rockets. A-3 is the first large test stand to be built at SSC since the site's inception in the 1960s.

  2. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within...

  3. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within...

  4. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within...

  5. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Awards. 59a.5 Section 59a.5 Public Health PUBLIC... for Establishing, Expanding, and Improving Basic Resources § 59a.5 Awards. (a) General. Within the limits of funds available, the Secretary may award grants to those applicants whose proposals...

  6. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Responsibilities. 168a.5 Section 168a.5 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.5 Responsibilities. (a) The Deputy Director,...

  7. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  8. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  9. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  10. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  11. 14 CFR 374a.5 - Exemption authority.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Exemption authority. 374a.5 Section 374a.5 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.5 Exemption authority....

  12. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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  13. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  14. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  15. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Relationships. 352a.5 Section 352a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.5 Relationships. (a) In the performance...

  16. 40 CFR Table A-5 to Subpart A of... - Supplier Category List for § 98.2(a)(4)

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt. A... deliver 460,000 thousand standard cubic feet or more of natural gas per year. Industrial greenhouse gas suppliers (subpart OO): (A) All producers of industrial greenhouse gases. (B) Importers of...

  17. 40 CFR Table A-5 to Subpart A of... - Supplier Category List for § 98.2(a)(4)

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt. A... deliver 460,000 thousand standard cubic feet or more of natural gas per year. Industrial greenhouse gas suppliers (subpart OO): (A) All producers of industrial greenhouse gases. (B) Importers of...

  18. 40 CFR Table A-5 to Subpart A of... - Supplier Category List for § 98.2(a)(4)

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt. A... deliver 460,000 thousand standard cubic feet or more of natural gas per year. Industrial greenhouse gas suppliers (subpart OO): (A) All producers of industrial greenhouse gases. (B) Importers of...

  19. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  20. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  1. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  2. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  3. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  4. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority...

  5. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... State shall follow the standards in E.O. 11652 and the provisions of 22 CFR 9.5 through 9.8. ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4,...

  6. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... State shall follow the standards in E.O. 11652 and the provisions of 22 CFR 9.5 through 9.8. ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4,...

  7. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority...

  8. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority...

  9. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority...

  10. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... State shall follow the standards in E.O. 11652 and the provisions of 22 CFR 9.5 through 9.8. ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4,...

  11. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... State shall follow the standards in E.O. 11652 and the provisions of 22 CFR 9.5 through 9.8. ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4,...

  12. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  13. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  14. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  15. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  16. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  17. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority...

  18. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... State shall follow the standards in E.O. 11652 and the provisions of 22 CFR 9.5 through 9.8. ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Classification. 9a.4 Section 9a.4 Foreign... ENERGY PROGRAMS; RELATED MATERIAL § 9a.4 Classification. (a) Section 1 of E.O. 11932, August 4,...

  19. 44 CFR Appendix A(5) to Part 61 - Appendix A(5) to Part 61

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Appendix A(5) to Part 61 A(5) Appendix A(5) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  20. Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels ...

  1. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.5 Responsibilities. (a) The Deputy Director, Defense Research and Engineering (Research and Advanced Technology) , shall: (1) Administer this part and issue DoD... representative of the Deputy Director, Defense Research and Engineering (Research and Advanced...

  2. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.5 Responsibilities. (a) The Deputy Director, Defense Research and Engineering (Research and Advanced Technology) , shall: (1) Administer this part and issue DoD... representative of the Deputy Director, Defense Research and Engineering (Research and Advanced...

  3. A3 Altitude Test Facility

    NASA Technical Reports Server (NTRS)

    Dulreix, Lionel J.

    2009-01-01

    This slide presentation shows drawings, diagrams and photographs of the A3 Altitude Test Facility. It includes a review of the A3 Facility requirements, and drawings of the various sections of the facility including Engine Deck and Superstructure, Test Cell and Thrust Takeout, Structure and Altitude Support Systems, Chemical Steam generators, and the subscale diffuser. There are also pictures of the construction site, and the facility under construction. A Diagram of the A3 Steam system schematic is also shown

  4. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Religious activities. 54a.4 Section 54a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS CHARITABLE CHOICE... FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR SUBSTANCE...

  5. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Religious activities. 54a.4 Section 54a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS CHARITABLE CHOICE REGULATIONS APPLICABLE TO STATES, LOCAL GOVERNMENTS AND RELIGIOUS ORGANIZATIONS RECEIVING...

  6. A-3 Construction Time Lapse

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A time lapse from start to finish of steel erection for the 235-foot tall A-3 Test Stand. Ground work for the stand was broken in August 2008 and the final structural steel beam was placed April 9, 2009.

  7. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Appendix A(4) to Part 61 A(4) Appendix A(4) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  8. A-3 First Tree Cutting

    NASA Technical Reports Server (NTRS)

    2007-01-01

    Tree clearing for the site of the new A-3 Test Stand at Stennis Space center began June 13. NASA's first new large rocket engine test stand to be built since the site's inception, A-3 construction begins a historic era for America's largest rocket engine test complex. The 300-foot-tall structure is scheduled for completion in August 2010. A-3 will perform altitude tests on the Constellation's J-2X engine that will power the upper stage of the Ares I crew launch vehicle and earth departure stage of the Ares V cargo launch vehicle. The Constellation Program, NASA's plan for carrying out the nation's Vision for Space Exploration, will return humans to the moon and eventually carry them to Mars and beyond.

  9. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee shall... of: (1) The Secretary of Labor, or his duly authorized representative; or (2) The Secretary of...

  10. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee shall... of: (1) The Secretary of Labor, or his duly authorized representative; or (2) The Secretary of...

  11. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee shall... of: (1) The Secretary of Labor, or his duly authorized representative; or (2) The Secretary of...

  12. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee shall... of: (1) The Secretary of Labor, or his duly authorized representative; or (2) The Secretary of...

  13. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee shall... of: (1) The Secretary of Labor, or his duly authorized representative; or (2) The Secretary of...

  14. 7 CFR 15a.4 - Assurance required.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.4 Assurance required. (a) General. Every application for Federal financial assistance for any education program or activity shall as condition of its approval... Federal financial assistance to a transferee which operates any education program or activity, and...

  15. 26 CFR 1.263(a)-4 - Amounts paid to acquire or create intangibles.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... providing wireless telecommunications services to customers. To induce customer B to enter into a 3-year non....263(a)-4 Section 1.263(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... performing services. Amounts paid in performing services under an agreement are treated as amounts that...

  16. A-3 steel work completed

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Stennis Space Center engineers celebrated a key milestone in construction of the A-3 Test Stand on April 9 - completion of structural steel work. Workers with Lafayette (La.) Steel Erector Inc. placed the last structural steel beam atop the stand during a noon ceremony attended by more than 100 workers and guests.

  17. Vessels installed at A-3

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Construction of the A-3 Test Stand approaches another milestone with delivery and installation of water, isopropyl alcohol (IPA) and liquid oxygen (LOX) tanks. The three LOX tanks shown on the left and the two IPA tanks shown on the right are all 35,000 gallons each. The four water tanks in the center are 39,000 gallons each.

  18. 44 CFR Appendix A(5) to Part 61 - Appendix A(5) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... notice sent to you in conjunction with the community inspection procedure established under 44 CFR 59.30... procedure set forth in National Flood Insurance Program Regulations (44 CFR 59.30). During the several years... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(5) to Part 61...

  19. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... entire fiscal year and not applied with respect to each short period included in a fiscal year. For... January 1, 1975, and ending May 31, 1975, is treated as a short taxable year. The depletion allowable pursuant to section 613A(c) without regard to section 613A(d)(1) for such short taxable year was $80x and...

  20. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... basis of property on sale). Example 7. In 1975 F owned producing properties M, N, O, P, Q, and R. With... have been $40x). With respect to property R, the allowable cost depletion was $40x (the allowable... allowable depletion with respect to properties N, O, Q, and R. (b) Retailers excluded. (1) Section...

  1. A-3 scientific results - extragalactic

    NASA Technical Reports Server (NTRS)

    Schwartz, D. A.

    1979-01-01

    The results of the HEAO A-3 experiment are summarized. Specific contributions of the experiment to extragalactic astronomy are emphasized. The discovery of relatively condensed X-ray emission in the cores of those clusters of galaxies which are dominated by a giant elliptical or cD galaxy, the discovery of extended X-ray emitting plasma in groups of galaxies, and the demonstration that BL Lac objects are a class of X-ray sources are among the topics discussed.

  2. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.5 Advice...

  3. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  4. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  5. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  6. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  7. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Counsel. 18a.5 Section 18a.5 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS (CONTINUED) DELEGATION OF RESPONSIBILITY IN CONNECTION WITH TITLE VI, CIVIL RIGHTS ACT OF 1964 § 18a.5 Delegation to the General Counsel. The General Counsel is delegated the responsibility, upon receipt...

  8. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  9. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 1 2013-04-01 2013-04-01 false Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  10. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 1 2011-04-01 2009-04-01 true Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  11. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 1 2014-04-01 2013-04-01 true Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  12. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 1 2012-04-01 2012-04-01 false Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  13. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  14. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  15. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Procedure for announcing meetings. 242a.5 Section 242a.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.5 Procedure...

  16. 7 CFR 1a.5 - Responsibility of the Inspector General.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Responsibility of the Inspector General. 1a.5 Section 1a.5 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.5 Responsibility of the Inspector General. The Inspector General shall: (a) Issue directives conforming to...

  17. 26 CFR 1.56A-5 - Tax carryovers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Tax carryovers. 1.56A-5 Section 1.56A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-5 Tax carryovers. (a) In...

  18. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  19. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  20. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  1. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  2. 26 CFR 1.409A-5 - Funding. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Funding. 1.409A-5 Section 1.409A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-5 Funding....

  3. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  4. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  5. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  6. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as black plate,...

  7. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers...

  8. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How will NIH evaluate applications? 52a.5 Section 52a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers...

  9. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... notice sent to you in conjunction with the community inspection procedure established under 44 CFR 59.30... procedure set forth in National Flood Insurance Program Regulations (44 CFR 59.30). During the several years... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(4) to Part 61...

  10. Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons.

    PubMed

    Zimmer, Geraldine; Garcez, Patricia; Rudolph, Judith; Niehage, Ronny; Weth, Franco; Lent, Roberto; Bolz, Jürgen

    2008-07-01

    Cortical interneurons are born in the germinative zones of the ganglionic eminences in the subpallium, and migrate tangentially in spatially and temporally well-defined corridors into the neocortex. Because ephrin-A5 is expressed in the ventricular zone (VZ) of the ganglionic eminences at these developmental stages, we examined the possible effects of this molecule on interneuron migration. Double-immunocytochemistry of dissociated neurons from the medial ganglionic eminences (MGE) revealed that calbindin-positive cells express the EphA4-receptor. In situ, EphA4 is strongly expressed in the subventricular zone of the ganglionic eminences. Using different in vitro assays, we found that ephrin-A5 acts as a repellent cue for MGE neurons. We then examined interneuron migration in slice overlay experiments, where MGE-derived explants from enhanced green fluorescent protein-expressing transgenic mice were homotopically grafted into host slices from wild-type littermate embryos. In these in vitro preparations, interneurons recapitulated in vivo cell migration in several respects. However, interneurons in brain slices also migrated in the VZ of the ganglionic eminences, a region that is strictly avoided in vivo. In situ hybridizations revealed that ephrin-A5 became downregulated in the VZ in vitro. When recombinant ephrin-A5-Fc was added to the slices, it preferentially bound to the VZ, and migrating MGE neurons avoided the VZ as in vivo. The restoration of the normal migration pathway in slices required ephrin-A5 clustering and signalling of Src family kinases. Together, these experiments suggest that ephrin-A5 acts as an inhibitory flank that contributes to define the pathway of migrating interneurons. PMID:18662335

  11. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How will NIH evaluate applications? 52a.5 Section... INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the... statute or NIH policy, applications are reviewed by appropriate national advisory councils or...

  12. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How will NIH evaluate applications? 52a.5 Section... INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the... statute or NIH policy, applications are reviewed by appropriate national advisory councils or...

  13. 42 CFR 52a.5 - How will NIH evaluate applications?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How will NIH evaluate applications? 52a.5 Section... INSTITUTES OF HEALTH CENTER GRANTS § 52a.5 How will NIH evaluate applications? (a) NIH considers the... statute or NIH policy, applications are reviewed by appropriate national advisory councils or...

  14. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Religious character and independence. 54a.5 Section 54a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS CHARITABLE... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR...

  15. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Duration of classification. 4a.5 Section 4a.5 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION..., except as provided in § 1.6(d) of E.O. 12958. Under E.O. 12958, information may be exempted...

  16. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Material. 178.33a-5 Section 178.33a-5 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS SPECIFICATIONS FOR...

  17. 42 CFR 68a.5 - Who is ineligible to participate?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is ineligible to participate? 68a.5 Section 68a... INDIVIDUALS FROM DISADVANTAGED BACKGROUNDS (CR-LRP) § 68a.5 Who is ineligible to participate? The following... Government, a State, or other entity, unless a deferral is granted for the length of his/her...

  18. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  19. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  20. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  1. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  2. 42 CFR 65a.5 - How to apply.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How to apply. 65a.5 Section 65a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING...

  3. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Open meetings. 242a.3 Section 242a.3 National... § 242a.3 Open meetings. (a) Members shall not jointly conduct or dispose of business of the Board of... Regents or any committee of the Board shall be open to public observation subject to the...

  4. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.3 Classification levels. Information...

  5. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.3 Classification levels. Information...

  6. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.3 Classification levels. Information...

  7. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.3 Classification levels. Information...

  8. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Open meetings. 242a.3 Section 242a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.3 Open meetings. (a) Members shall...

  9. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  10. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2014-07-01 2014-07-01 false Mission. 383a.3 Section 383a.3 National...

  11. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2013-07-01 2013-07-01 false Mission. 383a.3 Section 383a.3 National...

  12. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2012-07-01 2012-07-01 false Mission. 383a.3 Section 383a.3 National...

  13. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  14. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Open meetings. 242a.3 Section 242a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.3 Open meetings. (a) Members shall...

  15. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Open meetings. 242a.3 Section 242a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.3 Open meetings. (a) Members shall...

  16. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Open meetings. 242a.3 Section 242a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.3 Open meetings. (a) Members shall...

  17. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  18. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  19. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Definitions. 374a.3 Section 374a.3 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions....

  20. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Definitions. 374a.3 Section 374a.3 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions....

  1. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Definitions. 374a.3 Section 374a.3 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions....

  2. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Definitions. 374a.3 Section 374a.3 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions....

  3. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Definitions. 374a.3 Section 374a.3 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions....

  4. CYP3A5 mediates bioactivation and cytotoxicity of tetrandrine.

    PubMed

    Tian, Ye; Shen, Shuijie; Jiang, Yan; Shen, Qi; Zeng, Su; Zheng, Jiang

    2016-07-01

    Tetrandrine is a diaryl ether-type bisbenzylisoquinoline alkaloid and has shown multiple pharmacological activities. Our early work demonstrated that tetrandrine produced acute pulmonary toxicity and that tetrandrine was biotransformed to a quinone methide-derived metabolite mediated by CYP3A enzymes. The formation of the reactive intermediate is suggested to be responsible for the pulmonary toxicity induced by tetrandrine. In the present study, a WI-38-based Cyp3a5 transgenic cell line (WI-38/Cyp3a5) was established to investigate the role of CYP3A5 in tetrandrine-induced cytotoxicity. The transgenic cells were found to be more susceptible to the cytotoxicity of tetrandrine than the wild-type cells (WI-38/Vector). WI-38/Cyp3a5 cells showed higher cellular ROS levels, higher LDH activities in culture media, but lower cellular GSH contents than those observed in WI-38/Vector cells after exposure to tetrandrine. And severer apoptosis were observed in WI-38/Cyp3a5 cells after treatment with tetrandrine: WI-38/Cyp3a5 cells had higher proportion of early and late apoptotic cells, higher expression levels of caspase-3, but lower level of Bcl-2 than WI-38/Vector cells. This study provided strong evidence that CYP3A5 participated in tetrandrine-induced cytotoxicity. PMID:26302866

  5. Pharmacogenetic biomarkers: cytochrome P450 3A5.

    PubMed

    MacPhee, Iain A M

    2012-09-01

    The immunosuppressive drugs used for solid organ transplantation all have a narrow therapeutic index with wide variation between individuals in the blood concentration achieved by a given dose. Therapeutic drug monitoring is employed routinely but may not allow optimisation of drug exposure during the critical period two to three days following transplantation. A key factor in the inter-individual variability for tacrolimus, and probably sirolimus, is whether an individual is genetically predicted to express the drug metabolising enzyme cytochrome P450 3A5 (CYP3A5). Individuals predicted to express CYP3A5 by possession of at least one wild-type CYP3A5*1 allele require 1.5-2 times higher doses of tacrolimus to achieve target blood concentrations than individuals homozygous for the CYP3A5*3 allele who are functional non-expressers of CYP3A5. Planning the initial tacrolimus dose based on the CYP3A5 genotype has been shown to allow more rapid achievement of target blood concentrations after transplantation than a standard dose given to all patients. However, it remains to be demonstrated that use of this approach as an adjunct to therapeutic drug monitoring can reduce either efficacy failure (transplant rejection) or toxicity. Use of a pharmacogenetic approach to dosing sirolimus awaits testing and it is unlikely to be useful for ciclosporin or everolimus.

  6. 17 CFR 240.17a-4 - Records to be preserved by certain exchange members, brokers and dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... for a period of not less than six years, the first two years in an easily accessible place, all... years in an easily accessible place: (1) All records required to be made pursuant to § 240.17a-3(a)(4... the account. (d) Every member, broker and dealer subject to § 240.17a-3 shall preserve during the...

  7. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, et seq., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  8. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  9. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, ET SEQ., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  10. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... DISCRETIONARY FUNDING UNDER TITLE V OF THE PUBLIC HEALTH SERVICE ACT, 42 U.S.C. 290aa, et seq., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.5 Religious character and independence. A...

  11. 42 CFR 68a.4 - Who is eligible to participate?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible to participate? 68a.4 Section 68a.4... DISADVANTAGED BACKGROUNDS (CR-LRP) § 68a.4 Who is eligible to participate? To be eligible to participate in the... the Program is contingent, in part, upon employment with NIH, a Program contract may not be awarded...

  12. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Responsibilities and functions. 352a.4 Section 352a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense...

  13. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... § 809a.4 Use of Government facilities. Commanders are prohibited from authorizing demonstrations...

  14. Plantaricin IIA-1A5 from Lactobacillus plantarum IIA-1A5 displays bactericidal activity against Staphylococcus aureus.

    PubMed

    Arief, I Isnafia; Budiman, C; Jenie, B Sri Laksmi; Andreas, E; Yuneni, A

    2015-01-01

    Plantaricin IIA-1A5 is a bacteriocin produced by Lactobacillus plantarum IIA-1A5 isolated from Indonesian beef. This research aimed to identify the genes involved in plantaricin IIA-1A5 production and examine its mode of action against Staphylococcus aureus. It has been reported that a bacteriocin structural gene, plnW, is present in genome of L. plantarum IIA-1A5. Here, we reported the presence of additional genes responsible for plantaricin precursor (plnA and plnEF) and a gene encoding the quorum sensor of histidine kinase (plnB). It indicates that genes involved in production of plantaricin IIA-1A5 are organized in at least two bacteriocin operons (plnABCD, plnEFI) and a structural plnW gene. Purified plantaricin IIA-1A5 yielded a single band in SDS-PAGE with apparent size of 6.4 kDa. Amino acid composition of purified plantaricin IIA-1A5 was mainly composed of cationic glutamic acid and cysteine that allowed the formation of disulphide bonds, suggesting plantaricin IIA-1A5 belongs to the pediocin-subclass of class II bacteriocins. Plantaricin IIA-1A5 displayed remarkable antibacterial activity against S. aureus, which was initiated by the adsorption of plantaricin IIA-1A5 onto the cell membrane of S. aureus. The adsorption is hypothesised to be facilitated by non-ionic interactions as it is reduced by the presence of organic solvents or detergents. This adsorption promoted leakage of cellular metabolites through the cell membrane of S. aureus, as indicated by the release of genetic and proteinaceous material of S. aureus observed at 260 and 280 nm, respectively. The leakage also promoted the release of divalent (Ca(2+), Mg(2+)) and monovalent (K(+)) cations. The release of these intracellular components might be due to pores formed in the cell membrane of S. aureus by plantaricin IIA-1A5 as shown by scanning electron microscopy. Altogether, the mode of action of plantaricin IIA-1A5 against S. aureus seems to be bactericidal as indicated by lysis of the cell

  15. The Redox-A(3) Reaction.

    PubMed

    Seidel, Daniel

    2014-06-01

    This Highlight details the recent emergence of a new type of A(3) reaction (three-component condensation of an amine, an aldehyde and an alkyne). In contrast to the classic A(3) coupling process, the redox-A(3) reaction incorporates an iminium isomerization step and leads to amine α-alkynylation. The overall transformation is redox-neutral by virtue of a combined reductive N-alkylation/oxidative C-H bond functionalization.

  16. A3 Subscale Diffuser Test Article Design

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.

    2009-01-01

    This paper gives a detailed description of the design of the A3 Subscale Diffuser Test (SDT) Article Design. The subscale diffuser is a geometrically accurate scale model of the A3 altitude rocket facility. It was designed and built to support the SDT risk mitigation project located at the E3 facility at Stennis Space Center, MS (SSC) supporting the design and construction of the A3 facility at SSC. The subscale test article is outfitted with a large array of instrumentation to support the design verification of the A3 facility. The mechanical design of the subscale diffuser and test instrumentation are described here

  17. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION... E.O. 12958. The levels established by E.O. 12958 (Top Secret, Secret, and Confidential) are the...

  18. 38 CFR 8a.3 - Effective date.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Effective date. 8a.3 Section 8a.3 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... effective August 11, 1971, if on that date, the eligible veteran was obligated under a mortgage loan,...

  19. 38 CFR 8a.3 - Effective date.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Effective date. 8a.3 Section 8a.3 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... effective August 11, 1971, if on that date, the eligible veteran was obligated under a mortgage loan,...

  20. 38 CFR 8a.3 - Effective date.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Effective date. 8a.3 Section 8a.3 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... effective August 11, 1971, if on that date, the eligible veteran was obligated under a mortgage loan,...

  1. 38 CFR 8a.3 - Effective date.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Effective date. 8a.3 Section 8a.3 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... effective August 11, 1971, if on that date, the eligible veteran was obligated under a mortgage loan,...

  2. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  3. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  4. Plexin a4 expression in adult rat cranial nerves.

    PubMed

    Gutekunst, Claire-Anne; Gross, Robert E

    2014-11-01

    PlexinsA1-A4 participate in class 3 semaphorin signaling as co-receptors to neuropilin 1 and 2. PlexinA4 is the latest member of the PlexinA subfamily to be identified. In previous studies, we described the expression of PlexinA4 in the brain and spinal cord of the adult rat. Here, antibodies to PlexinA4 were used to reveal immunolabeling in most of the cranial nerve surveyed. Labeling was found in the olfactory, optic, oculomotor, trochlear, trigeminal, abducens, facial, vestibulocochlear, glossopharyngeal, vagus, and hypoglossal nerves. This is the first detailed description of the cellular and subcellular distribution of PlexinA4 in the adult cranial nerves. The findings will set the basis for future studies on the potential role of PlexinA4 in regeneration and repair of the adult central and peripheral nervous system.

  5. 26 CFR 1.408A-5 - Recharacterized contributions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... April 1, 2003, edition of 26 CFR part 1). Q-3. What is the effect of recharacterizing a contribution... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Recharacterized contributions. 1.408A-5 Section... Recharacterized contributions. This section sets forth the following questions and answers that provide...

  6. 42 CFR 68a.5 - Who is ineligible to participate?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... INDIVIDUALS FROM DISADVANTAGED BACKGROUNDS (CR-LRP) § 68a.5 Who is ineligible to participate? The following individuals are ineligible for CR-LRP participation: (a) Persons who are not eligible applicants as specified... obligation under the CR-LRP. The following are examples of programs which have a service...

  7. 7 CFR 15a.5 - Effect of other requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.5 Effect of other requirements. (a) Effect of...); and any other act of Congress or Federal regulation. (b) Effect of State or local law or other requirements. The obligation to comply with this part is not obviated or alleviated by any State or local...

  8. The PreA4(695) precursor protein of Alzheimer's disease A4 amyloid is encoded by 16 exons.

    PubMed

    Lemaire, H G; Salbaum, J M; Multhaup, G; Kang, J; Bayney, R M; Unterbeck, A; Beyreuther, K; Müller-Hill, B

    1989-01-25

    Alzheimer's disease (AD) is characterized by the cerebral deposition of fibrillar aggregates of the amyloid A4 protein. Complementary DNA's coding for the precursor of the amyloid A4 protein have been described. In order to identify the structure of the precursor gene relevant clones from several human genomic libraries were isolated. Sequence analysis of the various clones revealed 16 exons to encode the 695 residue precursor protein (PreA4(695] of Alzheimer's disease amyloid A4 protein. The DNA sequence coding for the amyloid A4 protein is interrupted by an intron. This finding supports the idea that amyloid A4 protein arises by incomplete proteolysis of a larger precursor, and not by aberrant splicing.

  9. Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells.

    PubMed

    Wu, Jing-Jing; Ge, Guang-Bo; He, Yu-Qi; Wang, Ping; Dai, Zi-Ru; Ning, Jing; Hu, Liang-Hai; Yang, Ling

    2016-01-01

    Nearly half of prescription medicines are metabolized by human cytochrome P450 (CYP) 3A. CYP3A4 and 3A5 are two major isoforms of human CYP3A and share most of the substrate spectrum. A very limited previous study distinguished the activity of CYP3A4 and CYP3A5, identifying the challenge in predicting CYP3A-mediated drug clearance and drug-drug interaction. In the present study, we introduced gomisin A (GA) with a dibenzocyclooctadiene skeleton as a novel selective probe of CYP3A4. The major metabolite of GA was fully characterized as 8-hydroxylated GA by LC-MS and NMR. CYP3A4 was assigned as the predominant isozyme involved in GA 8-hydroxylation by reaction phenotyping assays, chemical inhibition assays, and correlation studies. GA 8-hydroxylation in both recombinant human CYP3A4 and human liver microsomes followed classic Michaelis-Menten kinetics. The intrinsic clearance values indicated that CYP3A4 contributed 12.8-fold more than CYP3A5 to GA 8-hydroxylation. Molecular docking studies indicated different hydrogen bonds and π-π interactions between CYP3A4 and CYP3A5, which might result in the different catalytic activity for GA 8-hydroxylation. Furthermore, GA exhibited a stronger inhibitory activity towards CYP3A4 than CYP3A5, which further suggested a preferred selectivity of CYP3A4 for the transformation of GA. More importantly, GA has been successfully applied to selectively monitor the modulation of CYP3A4 activities by the inducer rifampin in hepG2 cells, which is consistent with the level change of CYP3A4 mRNA expression. In summary, our results suggested that GA could be used as a novel probe for the selective sensing of CYP3A4 in tissue and cell preparations.

  10. Steel erected at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Workers erect the first fabricated steel girders to arrive at the A-3 Test Stand at Stennis Space Center. Steel work began at the construction site Oct. 29 and is scheduled to continue into next spring.

  11. Nuclear Data Sheets for A = 3

    NASA Astrophysics Data System (ADS)

    Purcell, J. E.; Sheu, C. G.

    2015-12-01

    Compilation of information about the structure of A = 3 systems. This review mainly summarizes the work presented in (2010Pu04) and has updates of mass, lifetime and nuclear moment data as noted in the text.

  12. Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism.

    PubMed

    Zhang, Youcai; Csanaky, Iván L; Selwyn, Felcy Pavithra; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2013-08-01

    Organic anion transporting polypeptides (human: OATPs; rodent: Oatps) were thought to have important functions in bile acid (BA) transport. Oatp1a1, 1a4, and 1b2 are the three major Oatp1 family members in rodent liver. Our previous studies have characterized the BA homeostasis in Oatp1a1-null and Oatp1b2-null mice. The present study investigated the physiological role of Oatp1a4 in BA homeostasis by using Oatp1a4-null mice. Oatp1a4 expression is female-predominant in livers of mice, and thereby it was expected that female Oatp1a4-null mice will have more prominent changes than males. Interestingly, the present study demonstrated that female Oatp1a4-null mice had no significant alterations in BA concentrations in serum or liver, though they had increased mRNA of hepatic BA efflux transporters (Mrp4 and Ostα/β) and ileal BA transporters (Asbt and Ostα/β). In contrast, male Oatp1a4-null mice showed significantly altered BA homeostasis, including increased concentrations of deoxycholic acid (DCA) in serum, liver and intestinal contents. After feeding a DCA-supplemented diet, male but not female Oatp1a4-null mice had higher concentrations of DCA in serum and livers than their WT controls. This suggested that Oatp1a4 is important for intestinal absorption of secondary BAs in male mice. Furthermore, loss of Oatp1a4 function did not decrease BA accumulation in serum or livers of bile-duct-ligated mice, suggesting that Oatp1a4 is not likely a BA uptake transporter. In summary, the present study for the first time demonstrates that Oatp1a4 does not appear to mediate the hepatic uptake of BAs, but plays an important male-predominant role in secondary BA metabolism in mice.

  13. 49 CFR 178.33a-4 - Duties of inspector.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Duties of inspector. 178.33a-4 Section 178.33a-4 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  14. 49 CFR 178.33a-4 - Duties of inspector.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Duties of inspector. 178.33a-4 Section 178.33a-4 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  15. 49 CFR 178.33a-4 - Duties of inspector.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Duties of inspector. 178.33a-4 Section 178.33a-4 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  16. 49 CFR 178.33a-4 - Duties of inspector.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Duties of inspector. 178.33a-4 Section 178.33a-4 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  17. 12 CFR 708a.4 - Disclosures and communications to members.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... SAVINGS. If your credit union converts to a bank, you may experience changes in your loan and savings... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Disclosures and communications to members. 708a.4 Section 708a.4 Banks and Banking NATIONAL CREDIT UNION ADMINISTRATION REGULATIONS AFFECTING...

  18. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  19. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  20. 26 CFR 1.167(a)-4 - Leased property.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 2 2011-04-01 2011-04-01 false Leased property. 1.167(a)-4 Section 1.167(a)-4... property. Capital expenditures made by a lessee for the erection of buildings or the construction of other permanent improvements on leased property are recoverable through allowances for depreciation...

  1. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the...

  2. 26 CFR 1.6038A-4 - Monetary penalty.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Monetary penalty. 1.6038A-4 Section 1.6038A-4... maintaining records under section 6038A if the taxpayer has a reasonable belief that it is not owned by a 25... know that it is owned by a 25-percent foreign shareholder. For example, a reporting corporation...

  3. 26 CFR 1.6038A-4 - Monetary penalty.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Monetary penalty. 1.6038A-4 Section 1.6038A-4... maintaining records under section 6038A if the taxpayer has a reasonable belief that it is not owned by a 25... know that it is owned by a 25-percent foreign shareholder. For example, a reporting corporation...

  4. 26 CFR 1.6038A-4 - Monetary penalty.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Monetary penalty. 1.6038A-4 Section 1.6038A-4... maintaining records under section 6038A if the taxpayer has a reasonable belief that it is not owned by a 25... know that it is owned by a 25-percent foreign shareholder. For example, a reporting corporation...

  5. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  6. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  7. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  8. Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

    PubMed

    Ma, Zhong-lin; Yan, Xiao-jing; Zhao, Lei; Zhou, Jiu-jiu; Pang, Wan; Kai, Zhen-peng; Wu, Fan-hong

    2016-02-01

    Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.

  9. Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

    PubMed

    Ma, Zhong-lin; Yan, Xiao-jing; Zhao, Lei; Zhou, Jiu-jiu; Pang, Wan; Kai, Zhen-peng; Wu, Fan-hong

    2016-02-01

    Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management. PMID:26711170

  10. Child with Sotos phenotype and a 5:15 translocation

    SciTech Connect

    Maround, C.; Schmerler, S.; Hutcheon, R.G.

    1994-04-15

    The authors report on a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between the long arms of chromosome 5 and chromosome 15 [46,XX,t(5,15)(q35;q22)]. They suggest a relationship between genetic material at 5q35 or 15q22 and the expression of an autosomal dominant gene. 18 refs., 2 figs.

  11. Lepton mixing in A 5 family symmetry and generalized CP

    NASA Astrophysics Data System (ADS)

    Li, Cai-Chang; Ding, Gui-Jun

    2015-05-01

    We study lepton mixing patterns which can be derived from the A 5 family symmetry and generalized CP. We find five phenomenologically interesting mixing patterns for which one column of the PMNS matrix is (the first column of the golden ratio mixing), (the second column of the golden ratio mixing), or . The three lepton mixing angles are determined in terms of a single real parameter θ, and agreement with experimental data can be achieved for certain values of θ. The Dirac CP violating phase is predicted to be trivial or maximal while Majorana phases are trivial. We construct a supersymmetric model based on A 5 family symmetry and generalized CP. The lepton mixing is exactly the golden ratio pattern at leading order, and the mixing patterns of case III and case IV are reproduced after higher order corrections are considered.

  12. Tracheobronchopathia osteochondroplastica in a 5 year-old girl.

    PubMed

    Sant'Anna, Clemax Couto; Pires-de-Mello, Paulo; Morgado, Maria de Fátima; March, Maria de Fátima Pombo

    2012-12-01

    Tracheobronchopathia osteochondroplastica (TO) is considered an orphan disease with exceptional occurrence in children. We report a 5 year old female child who was referred to us with chronic cough and recurrent pneumonia. After several investigations, bronchoscopy showed multiple nodules in the tracheobronchial lumen, whose distribution was consistent with TO. The patient was followed for four years, with no change in the pattern of the disease.

  13. Optimized synthesis of phosphorothioate oligodeoxyribonucleotides substituted with a 5′-protected thiol function and a 3′-amino group

    PubMed Central

    Aubert, Yves; Bourgerie, Sylvain; Meunier, Laurent; Mayer, Roger; Roche, Annie-Claude; Monsigny, Michel; Thuong, Nguyen T.; Asseline, Ulysse

    2000-01-01

    A new deprotection procedure enables a medium scale preparation of phosphodiester and phosphorothioate oligonucleotides substituted with a protected thiol function at their 5′-ends and an amino group at their 3′-ends in good yield (up to 72 OD units/µmol for a 19mer phosphorothioate). Syntheses of 3′-amino-substituted oligonucleotides were carried out on a modified support. A linker containing the thioacetyl moiety was manually coupled in two steps by first adding its phosphoramidite derivative in the presence of tetrazole followed by either oxidation or sulfurization to afford the bis-derivatized oligonucleotide bound to the support. Deprotection was achieved by treating the fully protected oligonucleotide with a mixture of 2,2′-dithiodipyridine and concentrated aqueous ammonia in the presence of phenol and methanol. This procedure enables (i) cleavage of the oligonucleotide from the support, releasing the oligonucleotide with a free amino group at its 3′-end, (ii) deprotection of the phosphate groups and the amino functions of the nucleic bases, as well as (iii) transformation of the 5′-terminal S-acetyl function into a dithiopyridyl group. The bis-derivatized phosphorothioate oligomer was further substituted through a two-step procedure: first, the 3′-amino group was reacted with fluorescein isothiocyanate to yield a fluoresceinylated oligonucleotide; the 5′-dithiopyridyl group was then quantitatively reduced to give a free thiol group which was then substituted by reaction with an Nα-bromoacetyl derivative of a signal peptide containing a KDEL sequence to afford a fluoresceinylated peptide–oligonucleotide conjugate. PMID:10637335

  14. Neutrino masses and mixing in A5 with flavor antisymmetry

    NASA Astrophysics Data System (ADS)

    Joshipura, Anjan S.; Nath, Newton

    2016-08-01

    We discuss the consequences of assuming that the (Majorana) neutrino mass matrix Mν and the charged lepton mass matrix Ml satisfy SνTMνSν=-Mν and Tl†MlMl†Tl=MlMl† with respect to some discrete groups Sν and Tl contained in A5. These assumptions lead to a neutrino mass spectrum with two degenerate and one massless neutrino and also constrain mixing among them. We derive possible mixing patterns following from the choices Sν=Z2 , Z2×Z2 , and Tl=Z2,Z2×Z2,Z3,Z5 as subgroups of A5. One predicts the maximal atmospheric neutrino mixing angle θ23 and μ -τ reflection symmetry in a large number of cases, but it is also possible to obtain nonmaximal values for θ23. Only the third column of the neutrino mixing matrix can be obtained at the leading order due to degeneracy in masses of two of the neutrinos. We take up a specific example within the A5 group and identify Higgs vacuum expectation values which realize the above assumptions. Nonleading terms present in this example are shown to lead to splitting among degenerate pairs and a consistent description of both neutrino masses and mixing angles.

  15. Homotropic cooperativity of monomeric cytochrome P450 3A4

    SciTech Connect

    Baas, Bradley J.; Denisov, Ilia G.; Sligar, Stephen G.

    2010-11-16

    Mechanistic studies of mammalian cytochrome P450s are often obscured by the phase heterogeneity of solubilized preparations of membrane enzymes. The various protein-protein aggregation states of microsomes, detergent solubilized cytochrome or a family of aqueous multimeric complexes can effect measured substrate binding events as well as subsequent steps in the reaction cycle. In addition, these P450 monooxygenases are normally found in a membrane environment and the bilayer composition and dynamics can also effect these catalytic steps. Here, we describe the structural and functional characterization of a homogeneous monomeric population of cytochrome P450 3A4 (CYP 3A4) in a soluble nanoscale membrane bilayer, or Nanodisc [Nano Lett. 2 (2002) 853]. Cytochrome P450 3A4:Nanodisc assemblies were formed and purified to yield a 1:1 ratio of CYP 3A4 to Nanodisc. Solution small angle X-ray scattering was used to structurally characterize this monomeric CYP 3A4 in the membrane bilayer. The purified CYP 3A4:Nanodiscs showed a heretofore undescribed high level of homotropic cooperativity in the binding of testosterone. Soluble CYP 3A4:Nanodisc retains its known function and shows prototypic hydroxylation of testosterone when driven by hydrogen peroxide. This represents the first functional characterization of a true monomeric preparation of cytochrome P450 monooxygenase in a phospholipid bilayer and elucidates new properties of the monomeric form.

  16. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4 How... coordination with other libraries and related facilities, and (d) Potential for testing or demonstration of...

  17. Air density measurement with a falling A4 sheet

    NASA Astrophysics Data System (ADS)

    Oladyshkin, Ivan V.; Oladyshkina, Anastasia A.

    2016-09-01

    We propose a simple experiment on the air density measurement which does not require any special equipment: just an A4 sheet of paper, a stopwatch and a ruler. The discussed method uses the most basic air resistance model.

  18. INTERIOR VIEW WITH CASTING MACHINE AND A 4' DUCTILE IRON ...

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

    INTERIOR VIEW WITH CASTING MACHINE AND A 4' DUCTILE IRON PIPE BEING CENTRIFUGALLY CAST, AS OPERATOR WATCHES TO ENSURE QUALITY. - McWane Cast Iron Pipe Company, Pipe Casting Area, 1201 Vanderbilt Road, Birmingham, Jefferson County, AL

  19. INTERIOR VIEW WITH CASTING MACHINE AND A 4" DUCTILE IRON ...

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

    INTERIOR VIEW WITH CASTING MACHINE AND A 4" DUCTILE IRON PIPE BEING EXTRACTED FROM CASTING MACHINE - McWane Cast Iron Pipe Company, Pipe Casting Area, 1201 Vanderbilt Road, Birmingham, Jefferson County, AL

  20. Electromagnetic energy dispersion in a 5D universe

    SciTech Connect

    Hartnett, John G.

    2010-06-15

    Electromagnetism is analyzed in a 5D expanding universe. Compared to the usual 4D description of electrodynamics it can be viewed as adding effective charge and current densities to the universe that are static in time. These lead to effective polarization and magnetization of the vacuum, which is most significant at high redshift. Electromagnetic waves propagate but group and phase velocities are dispersive. This introduces a new energy scale to the cosmos. And as a result electromagnetic waves propagate with superluminal speeds but no energy is transmitted faster than the canonical speed of light c.

  1. Pineal anlage tumor in a 5-month-old boy.

    PubMed

    Olaya, Joffre E; Raghavan, Ravi; Totaro, Laura; Zouros, Alexander

    2010-06-01

    Pineal tumors are rare neoplasms that are categorized into pineoblastomas, pineocytomas, and pineal parenchymal tumors of intermediate differentiation. Pineal anlage tumors are primary pineal tumors with neuroepithelial and ectomesenchymal differentiation and without endodermal differentiation. The authors review the literature and report the case of a 5-month-old boy with a pineal anlage tumor. This is only the sixth case of a pineal anlage tumor reported in the English-language literature adding to the understanding of this tumor's presentation, immunomorphological and molecular characteristics, embryological origin, radiological appearance, treatment outcome, and prognosis.

  2. 26 CFR 1.401(a)(4)-12 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit... that is within the transition period defined in section 410(b)(6)(C)(ii). In addition, in the case of a... transition period defined in section 410(b)(6)(C)(ii). Actuarial equivalent. An amount or benefit is...

  3. Structure and nucleosome interaction of the yeast NuA4 and Piccolo-NuA4 histone acetyltransferase complexes.

    PubMed

    Chittuluru, Johnathan R; Chaban, Yuriy; Monnet-Saksouk, Julie; Carrozza, Michael J; Sapountzi, Vasileia; Selleck, William; Huang, Jiehuan; Utley, Rhea T; Cramet, Myriam; Allard, Stephane; Cai, Gang; Workman, Jerry L; Fried, Michael G; Tan, Song; Côté, Jacques; Asturias, Francisco J

    2011-10-09

    We have used EM and biochemistry to characterize the structure of NuA4, an essential yeast histone acetyltransferase (HAT) complex conserved throughout eukaryotes, and we have determined the interaction of NuA4 with the nucleosome core particle (NCP). The ATM-related Tra1 subunit, which is shared with the SAGA coactivator complex, forms a large domain joined to a second region that accommodates the catalytic subcomplex Piccolo and other NuA4 subunits. EM analysis of a NuA4-NCP complex shows the NCP bound at the periphery of NuA4. EM characterization of Piccolo and Piccolo-NCP provided further information about subunit organization and confirmed that histone acetylation requires minimal contact with the NCP. A small conserved region at the N terminus of Piccolo subunit enhancer of Polycomb-like 1 (Epl1) is essential for NCP interaction, whereas the subunit yeast homolog of mammalian Ing1 2 (Yng2) apparently positions Piccolo for efficient acetylation of histone H4 or histone H2A tails. Taken together, these results provide an understanding of the NuA4 subunit organization and the NuA4-NCP interactions.

  4. Steel erected at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Fabricated steel began arriving by truck Oct. 24 for construction of the A-3 Test Stand that will be used to test the engine for the nation's next generation of moon rockets. Within days workers from Lafayette Steel Erector Inc. began assembling the 16 steel stages needed on the foundation and footings poured in the previous year.

  5. A3 Subscale Rocket Hot Fire Testing

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.; Yen, J.

    2009-01-01

    This paper gives a description of the methodology and results of J2-X Subscale Simulator (JSS) hot fire testing supporting the A3 Subscale Diffuser Test (SDT) project at the E3 test facility at Stennis Space Center, MS (SSC). The A3 subscale diffuser is a geometrically accurate scale model of the A3 altitude simulating rocket test facility. This paper focuses on the methods used to operate the facility and obtain the data to support the aerodynamic verification of the A3 rocket diffuser design and experimental data quantifying the heat flux throughout the facility. The JSS was operated at both 80% and 100% power levels and at gimbal angle from 0 to 7 degrees to verify the simulated altitude produced by the rocket-rocket diffuser combination. This was done with various secondary GN purge loads to quantify the pumping performance of the rocket diffuser. Also, special tests were conducted to obtain detailed heat flux measurements in the rocket diffuser at various gimbal angles and in the facility elbow where the flow turns from vertical to horizontal upstream of the 2nd stage steam ejector.

  6. A 3 x 2 Achievement Goal Model

    ERIC Educational Resources Information Center

    Elliot, Andrew J.; Murayama, Kou; Pekrun, Reinhard

    2011-01-01

    In the present research, a 3 x 2 model of achievement goals is proposed and tested. The model is rooted in the definition and valence components of competence, and encompasses 6 goal constructs: task-approach, task-avoidance, self-approach, self-avoidance, other-approach, and other-avoidance. The results from 2 studies provided strong support for…

  7. 32 CFR 809a.3 - Unauthorized entry.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy § 809a.3... by the commander of a military installation or facility, which includes the parameters for authorized entry to or exit from a military installation, is legally enforceable against all persons whether or...

  8. 32 CFR 809a.3 - Unauthorized entry.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy § 809a.3... by the commander of a military installation or facility, which includes the parameters for authorized entry to or exit from a military installation, is legally enforceable against all persons whether or...

  9. 75 FR 9140 - Airworthiness Directives; International Aero Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-01

    ...- 7117, fax: (781) 238-7199. SUPPLEMENTARY INFORMATION: On February 12, 2010 (75 FR 6860), we published a proposed AD, FR Doc. 2010-2999, in the Federal Register. That AD applies to IAE V2500-A1, V2522-A5, V2524... Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5,...

  10. SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice

    PubMed Central

    Li, Xiangming; Sanneman, Joel D.; Harbidge, Donald G.; Zhou, Fei; Ito, Taku; Nelson, Raoul; Picard, Nicolas; Chambrey, Régine; Eladari, Dominique; Miesner, Tracy; Griffith, Andrew J.; Marcus, Daniel C.; Wangemann, Philine

    2013-01-01

    Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4 Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4 Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4. PMID:23874234

  11. A 5-D hyperchaotic Rikitake dynamo system with hidden attractors

    NASA Astrophysics Data System (ADS)

    Vaidyanathan, S.; Pham, V.-T.; Volos, C. K.

    2015-07-01

    This paper presents a 5-D hyperchaotic Rikitake dynamo system with three positive Lyapunov exponents which is derived by adding two state feedback controls to the famous 3-D Rikitake two-disk dynamo system. It is noted that the proposed hyperchaotic system has no equilibrium points and hence it exhibits hidden attractors. In addition, the qualitative properties, as well as the adaptive synchronization of the hyperchaotic Rikitake dynamo system with unknown system parameters, are discussed in details. The main results are proved using Lyapunov stability theory and numerical simulations are shown using MATLAB. Moreover, an electronic circuit realization in SPICE has been detailed to confirm the feasibility of the theoretical 5-D hyperchaotic Rikitake dynamo model.

  12. Characterization of the human ephrin-A4 promoter.

    PubMed Central

    Munthe, Else; Aasheim, Hans-Christian

    2002-01-01

    Expression of the ephrin-A4 ligand, a family member of ligands binding the Eph receptor tyrosine kinases, is induced after an antigen-receptor stimulation of lymphocytes. To understand the transcription regulation of the ephrin-A4 gene, its promoter was identified and regulating elements were characterized. The ephrin-A4 promoter contains cis elements directing the cell-specific expression. By deletion studies, three specific regions, which were contributing to the transcription activity in lymphoid cells, were localized. In one of these regions, an inverted CCAAT box was identified and shown to bind the transcription activator nuclear factor-Y (NF-Y). The importance of NF-Y binding for the ephrin-A4 promoter activity is shown by a total abrogation of promoter activity after destruction of its binding site. NF-Y binding and activity are also crucially dependent on the integrity of the surrounding sequence. In addition, electrophoretic mobility-shift assay and serial-mutation analysis of the two remaining regulating regions revealed cis regulatory elements contributing to the transcription activity of the ephrin-A4 promoter. PMID:12030849

  13. Interactions between CYP3A4 and Dietary Polyphenols

    PubMed Central

    Basheer, Loai; Kerem, Zohar

    2015-01-01

    The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols. PMID:26180597

  14. Interactions between CYP3A4 and Dietary Polyphenols.

    PubMed

    Basheer, Loai; Kerem, Zohar

    2015-01-01

    The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols. PMID:26180597

  15. TMS delivered for A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A state-of-the-art thrust measurement system for the A-3 Test Stand under construction at NASA's John C. Stennis Space Center was delivered March 17. Once completed, the A-3 stand (seen in background) will allow simulated high-altitude testing on the next generation of rocket engines for America's space program. Work on the stand began in 2007, with activation scheduled for 2012. The stand is the first major test structure to be built at Stennis since the 1960s. The recently delivered TMS was fabricated by Thrust Measurement Systems in Illinois. It is an advanced calibration system capable of measuring vertical and horizontal thrust loads with an accuracy within 0.15 percent at 225,000 pounds.

  16. A 3-Vinyl Cephem Derivative, a Useful Intermediate in the Synthesis of Cepham Antibiotics, from Aspergillus awamori Associated with Banana Fruit.

    PubMed

    Bandara, H M S K H; Kumar, N Savitri; Jayasinghe, Lalith; Masubuti, Hironori; Fujimoto, Yoshinori

    2015-10-01

    Aspergillus awamori was isolated from a diseased banana fruit, Musa acuminata cv. Ambul. The fungus was fermented in potato dextrose broth and on potato dextrose agar media and the fungal media were extracted with EtOAc. Chromatographic separation of the EtOAc extracts furnished 4-methoxybenzyl 7-phenylacetamido-3-vinyl-3-cephem-4-carboxylate (1), along with three naphtho-γ-pyrones, flavasperone (2), foncesinone A (3) and aurasperone A (4), and three alkaloids, aspernigrin A (5), pestalamide C (6) and nigragillin (7). Compound 1, a known key intermediate in the chemical synthesis of cepham antibiotics, was isolated from a natural source for the first time. Compound 1 is the first 3-vinyl cephem derivative of microbial origin. PMID:26669099

  17. Priapism Induced by Boceprevir-CYP3A4 Inhibition and α-Adrenergic Blockade: Case Report

    PubMed Central

    Hammond, Kyle P.; Nielsen, Craig; Linnebur, Sunny A.; Langness, Jacob A.; Ray, Graham; Maroni, Paul; Kiser, Jennifer J.

    2014-01-01

    A 44-year-old white man presented to the emergency department with a 3-day history of priapism requiring a surgically performed distal penile shunt. A drug–drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin, and/or quetiapine, resulting in additional α-adrenergic blockade. PMID:24092799

  18. Priapism induced by boceprevir-CYP3A4 inhibition and α-adrenergic blockade: case report.

    PubMed

    Hammond, Kyle P; Nielsen, Craig; Linnebur, Sunny A; Langness, Jacob A; Ray, Graham; Maroni, Paul; Kiser, Jennifer J

    2014-01-01

    A 44-year-old white man presented to the emergency department with a 3-day history of priapism requiring a surgically performed distal penile shunt. A drug-drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin, and/or quetiapine, resulting in additional α-adrenergic blockade.

  19. Acrodermatitis enteropathica: a novel SLC39A4 gene mutation found in a patient with an early-onset.

    PubMed

    Santiago, Felicidade; Matos, José; Moreno, Ana; Schmitt, Sébastien; Bézieau, Stéphane; Tellechea, Oscar

    2011-01-01

    We report the case of a 3-month-old full-term, breast-fed infant with clinical and laboratorial findings consistent with acrodermatitis enteropathica. In addition, the mother had low zinc levels in her breast milk. Mutation analysis revealed a novel insertion in the SLC39A4 gene.

  20. 17 CFR 240.17a-4 - Records to be preserved by certain exchange members, brokers and dealers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... for a period of not less than six years, the first two years in an easily accessible place, all... years in an easily accessible place: (1) All records required to be made pursuant to § 240.17a-3(a)(4... reconciliations. (3) All bills receivable or payable (or copies thereof), paid or unpaid, relating to the...

  1. Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population.

    PubMed

    Chen, Zhengshuai; Li, Jingjie; Chen, Peng; Wang, Fengjiao; Zhang, Ning; Yang, Min; Jin, Tianbo; Chen, Chao

    2016-09-01

    1.  Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. 2. We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions. 3. We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C > T in exon 1, two mutations 32120C > G and 32245T > C in 3'-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype "TTAGGT" was the most prevalent with 0.781. 4. Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs. PMID:26739429

  2. Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population.

    PubMed

    Chen, Zhengshuai; Li, Jingjie; Chen, Peng; Wang, Fengjiao; Zhang, Ning; Yang, Min; Jin, Tianbo; Chen, Chao

    2016-09-01

    1.  Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. 2. We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions. 3. We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C > T in exon 1, two mutations 32120C > G and 32245T > C in 3'-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype "TTAGGT" was the most prevalent with 0.781. 4. Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs.

  3. Apolipoprotein A5: A newly identified gene impacting plasmatriglyceride levels in humans and mice

    SciTech Connect

    Pennacchio, Len A.; Rubin, Edward M.

    2002-09-15

    Apolipoprotein A5 (APOA5) is a newly described member of theapolipoprotein gene family whose initial discovery arose from comparativesequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functionalstudies in mice indicated that alteration in the level of APOA5significantly impacted plasma triglyceride concentrations. Miceover-expressing human APOA5 displayed significantly reducedtriglycerides, while mice lacking apoA5 had a large increase in thislipid parameter. Studies in humans have also suggested an important rolefor APOA5 in determining plasma triglyceride concentrations. In theseexperiments, polymorphisms in the human gene were found to define severalcommon haplotypes that were associated with significant changes intriglyceride concentrations in multiple populations. Several separateclinical studies have provided consistent and strong support for theeffect with 24 percent of Caucasians, 35 percent of African-Americans and53 percent of Hispanics carrying APOA5 haplotypes associated withincreased plasma triglyceride levels. In summary, APOA5 represents anewly discovered gene involved in triglyceride metabolism in both humansand mice whose mechanism of action remains to be deciphered.

  4. Structure and nucleosome interaction of the yeast NuA4 and Piccolo-NuA4 histone acetyltransferase complexes

    PubMed Central

    Chittuluru, Johnathan R.; Chaban, Yuriy; Monnet-Saksouk, Julie; Carrozza, Michael J.; Sapountzi, Vasileia; Selleck, William; Huang, Jiehuan; Utley, Rhea T.; Cramet, Myriam; Allard, Stephane; Cai, Gang; Workman, Jerry L.; Fried, Michael G.; Tan, Song; Côté, Jacques; Asturias, Francisco J.

    2011-01-01

    We have used electron microscopy (EM) and biochemistry to characterize the structure and nucleosome core particle (NCP) interaction of NuA4, an essential yeast histone acetyltransferase (HAT) complex conserved throughout eukaryotes. The ATM-related Tra1 subunit, shared with the SAGA coactivator, forms a large domain joined to a second portion that accommodates the Piccolo catalytic subcomplex and other NuA4 subunits. EM analysis of an NuA4–NCP complex shows the NCP bound at NuA4's periphery. EM characterization of Piccolo and Piccolo–NCP provided further information about subunit organization and confirmed that histone acetylation requires minimal contact with the NCP. A small conserved region at the N-terminus of Piccolo subunit Epl1 is essential for NCP interaction, whereas subunit Yng2 apparently positions Piccolo for efficient acetylation of H4 or H2A tails. Taken together, these results provide an understanding of NuA4 subunit organization and NCP interactions. PMID:21984211

  5. 75 FR 71373 - Airworthiness Directives; International Aero Engines V2500-A1, V2522-A5, V2524-A5, V2525-D5...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-23

    ..., 2000 (65 FR 19477-78). Examining the AD Docket You may examine the AD docket on the Internet at http... ``significant rule'' under the DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3... Aero Engines (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5,...

  6. 75 FR 12971 - Airworthiness Directives; International Aero Engines (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-18

    ... (74 FR 19904), and a supplemental proposed AD on December 23, 2009 (74 FR 68192). That action proposed... 12866; (2) Is not a ``significant rule'' under DOT Regulatory Policies and Procedures (44 FR 11034... Engines (IAE) V2500- A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5,...

  7. The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients.

    PubMed

    de Jonge, H; Elens, L; de Loor, H; van Schaik, R H; Kuypers, D R J

    2015-04-01

    Tacrolimus, a dual substrate of CYP3A4 and CYP3A5 has a narrow therapeutic index and is characterized by high between-subject variability in oral bioavailability. This study investigated the effects of the recently described CYP3A4*22 intron 6 C>T single nucleotide polymorphism on in vivo CYP3A4 activity as measured by midazolam (MDZ) clearance and tacrolimus pharmacokinetics in two cohorts of renal allograft recipients, taking into account the CYP3A5*1/*3 genotype and other determinants of drug disposition. In CYP3A5 non-expressers, the presence of one CYP3A4*22T-allele was associated with a 31.7-33.6% reduction in MDZ apparent oral clearance, reflecting reduced in vivo CYP3A4 activity. In addition, at ⩾12 months after transplantation, steady-state clearance of tacrolimus was 36.8% decreased compared with homozygous CYP3A4*22CC-wild type patients, leading to 50% lower dose requirements. Both concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP3A4*22T-allele.

  8. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have...

  9. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have...

  10. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have...

  11. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have...

  12. 32 CFR 168a.4 - Policy and procedures.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.4 Policy and procedures. (a) Sponsoring... to pursue graduate degrees in science, engineering, or other fields of study that are designated, in... members of groups (including minorities, women, and disabled persons) that historically have...

  13. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the research... research project and the general research methods to be used. (e) The date on which research will begin or... PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any...

  14. Framing Retention for Institutional Improvement: A 4 Ps Framework

    ERIC Educational Resources Information Center

    Kalsbeek, David H.

    2013-01-01

    A 4 Ps framework for student retention strategy is a construct for reframing the retention discussion in a way that enables institutional improvement by challenging some conventional wisdom and prevailing perspectives that have characterized retention strategy for years. It opens new possibilities for action and improvement by suggesting that…

  15. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of...

  16. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of...

  17. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of...

  18. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of...

  19. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... eastern daylight-saving time, whichever is in effect at the principal office of the Commission on the date... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Calculation of time. 260.7a-4... time. Saturdays, Sundays and holidays shall be counted in computing the effective date of...

  20. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Use considered sale. 48.4161(a)-4 Section 48... sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or importer thereof, see section 4218 relating to use by a manufacturer being considered a sale, and...

  1. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Use considered sale. 48.4161(a)-4 Section 48... sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or importer thereof, see section 4218 relating to use by a manufacturer being considered a sale, and...

  2. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Use considered sale. 48.4161(a)-4 Section 48... sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or importer thereof, see section 4218 relating to use by a manufacturer being considered a sale, and...

  3. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Use considered sale. 48.4161(a)-4 Section 48... sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or importer thereof, see section 4218 relating to use by a manufacturer being considered a sale, and...

  4. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4 How... Secretary's evaluation shall consider the scope of library or related services for the population and... coordination with other libraries and related facilities, and (d) Potential for testing or demonstration of...

  5. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the research... research project and the general research methods to be used. (e) The date on which research will begin or... PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any...

  6. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the research... research project and the general research methods to be used. (e) The date on which research will begin or... PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any...

  7. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the research... research project and the general research methods to be used. (e) The date on which research will begin or... PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any...

  8. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense Finance and Accounting Service (DFAS), is the principal DoD executive for finance and accounting requirements, systems, and functions identified in DoD Directive 5118.3, 1...

  9. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense Finance and Accounting Service (DFAS), is the principal DoD executive for finance and accounting requirements, systems, and functions identified in DoD Directive 5118.3, 1...

  10. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense Finance and Accounting Service (DFAS), is the principal DoD executive for finance and accounting requirements, systems, and functions identified in DoD Directive 5118.3, 1...

  11. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4 How... Secretary's evaluation shall consider the scope of library or related services for the population and purposes served by the applicant. This evaluation shall include consideration of the following...

  12. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4 How... Secretary's evaluation shall consider the scope of library or related services for the population and purposes served by the applicant. This evaluation shall include consideration of the following...

  13. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4 How... Secretary's evaluation shall consider the scope of library or related services for the population and purposes served by the applicant. This evaluation shall include consideration of the following...

  14. Annexin A5 multitasking: a potentially novel antiatherothrombotic agent?

    PubMed

    Cederholm, Anna; Frostegård, Johan

    2007-06-01

    Atherothrombosis, formed on an underlying atherosclerotic plaque, is the key pathogenic mechanism behind the majority of clinically evident cardiovascular ischemic diseases including acute coronary artery disease, cerebrovascular and peripheral arterial occlusion. Annexin A5 (ANXA5; previously annexin V), a member of the annexin superfamily, is a protein with potent and unique antithrombotic properties. The antithrombotic effect exerted by ANXA5 is thought to be mediated mainly by mechanical shielding of phospholipids, phosphatidylserine in particular, thereby reducing their availability for coagulation reactions. However, other intriguing properties of ANXA5 potentially contributing to its antithrombotic function, especially downregulation of surface expressed tissue factor, or interaction with additional ligands involved in hemostasis such as sulfatide and heparin, as well as upregulation of urokinase-type plasminogen activator were reported. The biological significance of ANXA5 as a member of endogenous antithrombotic system in vivo has been suggested recently for the large vasculature and for placental microcirculation. Antiatherothrombotic potential of ANXA5 deserves further attention and careful studies in order to determine its true physiological impact as well as its possible therapeutic applications.

  15. Natural history of alcoholic myopathy: a 5-year study.

    PubMed

    Estruch, R; Sacanella, E; Fernández-Solá, J; Nicolás, J M; Rubin, E; Urbano-Márquez, A

    1998-12-01

    Chronic myopathy is a common complication of alcoholism, but its natural history has not been well described. We, therefore, studied muscle structure and function in a 5-year study of 30 chronic alcoholics who became abstinent and 20 who relapsed, and 40 control subjects. The mean strength of the abstaining alcoholics increased from 18.6 to 23.2 kg; but, after 5 years, they were still substantially weaker than controls. In a subset who showed histological myopathy, the strength of half of the patients remained two standard deviations below that of controls. Alcoholics who relapsed tended to become progressively weaker (21.7 kg vs. 18.2 kg) and develop histological evidence of myopathy. Thus, continued alcohol abuse was generally reflected in deterioration of muscle strength and the appearance of histological injury to muscle. Importantly, almost half of the sober patients did not recover to normal levels, indicating that alcoholic myopathy is only partially reversible. We also unexpectedly found that, in some alcoholics, a substantial reduction in the amount of alcohol consumed may be as effective as complete abstinence in improving muscle strength or preventing its deterioration.

  16. Nearly free electrons in a 5d delafossite oxide metal

    PubMed Central

    Kushwaha, Pallavi; Sunko, Veronika; Moll, Philip J. W.; Bawden, Lewis; Riley, Jonathon M.; Nandi, Nabhanila; Rosner, Helge; Schmidt, Marcus P.; Arnold, Frank; Hassinger, Elena; Kim, Timur K.; Hoesch, Moritz; Mackenzie, Andrew P.; King, Phil D. C.

    2015-01-01

    Understanding the role of electron correlations in strong spin-orbit transition-metal oxides is key to the realization of numerous exotic phases including spin-orbit–assisted Mott insulators, correlated topological solids, and prospective new high-temperature superconductors. To date, most attention has been focused on the 5d iridium-based oxides. We instead consider the Pt-based delafossite oxide PtCoO2. Our transport measurements, performed on single-crystal samples etched to well-defined geometries using focused ion beam techniques, yield a room temperature resistivity of only 2.1 microhm·cm (μΩ-cm), establishing PtCoO2 as the most conductive oxide known. From angle-resolved photoemission and density functional theory, we show that the underlying Fermi surface is a single cylinder of nearly hexagonal cross-section, with very weak dispersion along kz. Despite being predominantly composed of d-orbital character, the conduction band is remarkably steep, with an average effective mass of only 1.14me. Moreover, the sharp spectral features observed in photoemission remain well defined with little additional broadening for more than 500 meV below EF, pointing to suppressed electron-electron scattering. Together, our findings establish PtCoO2 as a model nearly-free–electron system in a 5d delafossite transition-metal oxide. PMID:26601308

  17. Glucose Regulates the Expression of the Apolipoprotein A5 Gene

    SciTech Connect

    Fruchart, Jamila; Nowak, Maxime; Helleboid-Chapman, Audrey; Jakel, Heidelinde; Moitrot, Emmanuelle; Rommens, Corinne; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart, Jean-Charles

    2008-04-07

    The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.

  18. A 3-d modular gripper design tool

    SciTech Connect

    Brown, R.G.; Brost, R.C.

    1997-02-01

    Modular fixturing kits are sets of components used for flexible, rapid construction of fixtures. A modular vise is a parallel-jaw vise, each jaw of which is a modular fixture plate with a regular grid of precisely positioned holes. To fixture a part, one places pins in some of the holes so that when the vise is closed, the part is reliably located and completely constrained. The modular vise concept can be adapted easily to the design of modular parallel-jaw grippers for robots. By attaching a grid-plate to each jaw of a parallel-jaw gripper, one gains the ability to easily construct high-quality grasps for a wide variety of parts from a standard set of hardware. Wallack and Canny developed an algorithm for planning planar grasp configurations for the modular vise. In this paper, the authors expand this work to produce a 3-d fixture/gripper design tool. They describe several analyses they have added to the planar algorithm, including a 3-d grasp quality metric based on force information, 3-d geometric loading analysis, and inter-gripper interference analysis. Finally, the authors describe two applications of their code. One of these is an internal application at Sandia, while the other shows a potential use of the code for designing part of an agile assembly line.

  19. The A 3Π state of SO

    NASA Astrophysics Data System (ADS)

    Elks, John M. F.; Western, Colin M.

    1999-04-01

    Laser induced fluorescence and 1+1 resonance enhanced multiphoton ionisation spectra of the A 3Π-X3Σ- transition of SO radicals prepared by an electric discharge in a supersonic jet expansion are presented. Rotational constants are given for A state vibrational levels with v'=0-13, extending to within 190 cm-1 of the A state dissociation limit. The Rydberg-Klein-Rees curve derived from these constants shows significant anharmonicity, even around the equilibrium geometry. In addition, several small local perturbations of the rotational structure are observed. Collision free fluorescence lifetimes are determined for the complete range of vibrational states, and are found to fall smoothly from 29.5 μs for v'=0 to 6.45 μs for v'=12. Combining these data with earlier measurements leads to a better determination of the A-X transition dipole moment over the range 1.4-2.0 Å.

  20. A 4D Hyperspherical Interpretation of q-Space

    PubMed Central

    Hosseinbor, A. Pasha; Chung, Moo K.; Wu, Yu-Chien; Alexander, Andrew L.; Bendlin, Barbara B.

    2014-01-01

    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH). Using this orthonormal basis, we analytically derive several quantitative indices and numerically estimate the diffusion ODF. Importantly, we derive the integral transform describing the relationship between the diffusion signal and propagator on a hypersphere. We also show that the HSH basis expends less fitting parameters than other well-established methods to achieve comparable signal and better ODF reconstructions. All in all, this work provides a new way of looking at q-space. PMID:24505799

  1. A 5-year experience with an elective scholarly concentrations program

    PubMed Central

    George, Paul; Green, Emily P.; Park, Yoon S.; Gruppuso, Philip A.

    2015-01-01

    Problem Programs that encourage scholarly activities beyond the core curriculum and traditional biomedical research are now commonplace among US medical schools. Few studies have generated outcome data for these programs. The goal of the present study was to address this gap. Intervention The Scholarly Concentration (SC) Program, established in 2006 at the Warren Alpert Medical School of Brown University, is a 4-year elective program that not only encourages students to pursue scholarly work that may include traditional biomedical research but also seeks to broaden students’ focus to include less traditional areas. We compared characteristics and academic performance of SC students and non-SC students for the graduating classes of 2010–2014. Context Approximately one-third of our students opt to complete an SC during their 4-year undergraduate medical education. Because this program is additional to the regular MD curriculum, we sought to investigate whether SC students sustained the academic achievement of non-SC students while at the same time producing scholarly work as part of the program. Outcome Over 5 years, 35% of students elected to enter the program and approximately 81% of these students completed the program. The parameters that were similar for both SC and non-SC students were age at matriculation, admission route, proportion of undergraduate science majors, and number of undergraduate science courses. Most academic indicators, including United States Medical Licensing Examinations scores, were similar for the two groups; however, SC students achieved more honors in the six core clerkships and were more likely to be inducted into the medical school's two honor societies. Residency specialties selected by graduates in the two groups were similar. SC students published an average of 1.3 peer-reviewed manuscripts per student, higher than the 0.8 manuscripts per non-SC student (p=0.013). Conclusions An elective, interdisciplinary scholarly program with

  2. Towards a complete A4 × SU(5) SUSY GUT

    NASA Astrophysics Data System (ADS)

    Björkeroth, Fredrik; de Anda, Francisco J.; de Medeiros Varzielas, Ivo; King, Stephen F.

    2015-06-01

    We propose a renormalisable model based on A 4 family symmetry with an SU(5) grand unified theory (GUT) which leads to the minimal supersymmetric standard model (MSSM) with a ℤ9 × ℤ6 symmetry provides the fermion mass hierarchy in both the quark and lepton sectors, while ℤ {4/ R } symmetry is broken to ℤ {2/ R }, identified as usual R-parity. Proton decay is highly sup-pressed by these symmetries. The strong CP problem is solved in a similar way to the Nelson-Barr mechanism. We discuss both the A 4 and SU(5) symmetry breaking sectors, including doublet-triplet splitting, Higgs mixing and the origin of the μ term. The model provides an excellent fit (better than one sigma) to all quark and lepton (including neu-trino) masses and mixing with spontaneous CP violation. With the A 4 vacuum alignments, (0, 1, 1) and (1, 3, 1), the model predicts the entire PMNS mixing matrix with no free pa-rameters, up to a relative phase, selected to be 2π/3 from a choice of the nine complex roots of unity, which is identified as the leptogenesis phase. The model predicts a normal neutrino mass hierarchy with leptonic angles θ{13/ ι } ≈ 8.7∘, θ{12/ ι } ≈ 34∘, θ{23/ ι } ≈ 46∘ and an oscillation phase δ ι ≈ - 87∘.

  3. 26 CFR 1.509(a)-4 - Supporting organizations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... publicly supported organizations, the distinguishing feature is the presence of common supervision or control among the governing bodies of all organizations involved, such as the presence of common directors... in section 509(a)(3)(B), presupposes a substantial degree of direction over the policies,...

  4. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation.

    PubMed

    Zhu, Yanlin; Wang, Fen; Li, Quan; Zhu, Mingshe; Du, Alicia; Tang, Wei; Chen, Weiqing

    2014-02-01

    Amlodipine is a commonly prescribed calcium channel blocker for the treatment of hypertension and ischemic heart disease. The drug is slowly cleared in humans primarily via dehydrogenation of its dihydropyridine moiety to a pyridine derivative (M9). Results from clinical drug-drug interaction studies suggest that CYP3A4/5 mediate metabolism of amlodipine. However, attempts to identify a role of CYP3A5 in amlodipine metabolism in humans based on its pharmacokinetic differences between CYP3A5 expressers and nonexpressers failed. Objectives of this study were to determine the metabolite profile of amlodipine (a racemic mixture and S-isomer) in human liver microsomes (HLM), and to identify the cytochrome P450 (P450) enzyme(s) involved in the M9 formation. Liquid chromatography/mass spectrometry analysis showed that amlodipine was mainly converted to M9 in HLM incubation. M9 underwent further O-demethylation, O-dealkylation, and oxidative deamination to various pyridine derivatives. This observation is consistent with amlodipine metabolism in humans. Incubations of amlodipine with HLM in the presence of selective P450 inhibitors showed that both ketoconazole (an inhibitor of CYP3A4/5) and CYP3cide (an inhibitor of CYP3A4) completely blocked the M9 formation, whereas chemical inhibitors of other P450 enzymes had little effect. Furthermore, metabolism of amlodipine in expressed human P450 enzymes showed that only CYP3A4 had significant activity in amlodipine dehydrogenation. Metabolite profiles and P450 reaction phenotyping data of a racemic mixture and S-isomer of amlodipine were very similar. The results from this study suggest that CYP3A4, rather than CYP3A5, plays a key role in metabolic clearance of amlodipine in humans. PMID:24301608

  5. An A 4 × {{{Z}}_4} model for neutrino mixing

    NASA Astrophysics Data System (ADS)

    BenTov, Yoni; He, Xiao-Gang; Zee, A.

    2012-12-01

    The A 4 × U(1) flavor model of He, Keum, and Volkas is extended to provide a minimal modification to tribimaximal mixing that accommodates a nonzero reactor angle θ 13 0.1. The sequestering problem is circumvented by forbidding superheavy scales and large coupling constants which would otherwise generate sizable RG flows. The model is compatible with (but does not require) a stable or metastable dark matter candidate in the form of a complex scalar field with unit charge under a discrete subgroup {{{Z}}_4} of the U(1) flavor symmetry.

  6. Clinical neosporosis in a 4-week-old Hereford calf.

    PubMed

    Dubey, J P; Janovitz, E B; Skowronek, A J

    1992-06-01

    Most reports of neosporosis associated with abortion in cattle are in dairy cattle and infected calves do not survive beyond 7 days of age. This paper reports neosporosis in a 4-week-old Hereford calf. The calf was full term and appeared clinically normal at birth. At 2 weeks of age, the calf had weakened and was unable to nurse unassisted. The calf was killed at 4 weeks because of paralysis. The primary lesions were in the brain and were associated with Neospora caninum tachyzoites. The diagnosis was confirmed by immunohistochemical staining with anti-Neospora rabbit serum.

  7. A 3-d modular gripper design tool

    SciTech Connect

    Brown, R.G.; Brost, R.C.

    1997-01-01

    Modular fixturing kits are precisely machined sets of components used for flexible, short-turnaround construction of fixtures for a variety of manufacturing purposes. A modular vise is a parallel-jaw vise, where each jaw is a modular fixture plate with a regular grid of precisely positioned holes. A modular vise can be used to locate and hold parts for machining, assembly, and inspection tasks. To fixture a part, one places pins in some of the holes so that when the vise is closed, the part is reliably located and completely constrained. The modular vise concept can be adapted easily to the design of modular parallel-jaw grippers for robots. By attaching a grid plate to each jaw of a parallel-jaw gripper, the authors gain the ability to easily construct high-quality grasps for a wide variety of parts from a standard set of hardware. Wallack and Canny developed a previous algorithm for planning planar grasp configurations for the modular vise. In this paper, the authors expand this work to produce a 3-d fixture/gripper design tool. They describe several analyses added to the planar algorithm to improve its utility, including a three-dimensional grasp quality metric based on geometric and force information, three-dimensional geometric loading analysis, and inter-gripper interference analysis to determine the compatibility of multiple grasps for handing the part from one gripper to another. Finally, the authors describe two applications which combine the utility of modular vise-style grasping with inter-gripper interference: The first is the design of a flexible part-handling subsystem for a part cleaning workcell under development at Sandia National Laboratories; the second is the automatic design of grippers that support the assembly of multiple products on a single assembly line.

  8. Charge symmetry breaking in the A = 4 hypernuclei

    NASA Astrophysics Data System (ADS)

    Gazda, Daniel; Gal, Avraham

    2016-10-01

    Charge symmetry breaking (CSB) in the Λ-nucleon strong interaction generates a charge dependence of Λ separation energies in mirror hypernuclei, which in the case of the A = 4 mirror hypernuclei 0+ ground states is sizable, ΔBΛJ=0 ≡BΛJ=0 (He4Λ) -BΛJ=0 (H4Λ) = 230 ± 90 keV, and of opposite sign to that induced by the Coulomb repulsion in light hypernuclei. Recent ab initio calculations of the (H4Λ, He4Λ) mirror hypernuclei 0g.s.+ and 1exc+ levels have demonstrated that a Λ -Σ0 mixing CSB model due to Dalitz and von Hippel (1964) is capable of reproducing this large value of ΔBΛJ=0. These calculations are discussed here with emphasis placed on the leading-order chiral EFT hyperon-nucleon Bonn-Jülich strong-interaction potential model used and the no-core shell-model calculational scheme applied. The role of one-pion exchange in producing sizable CSB level splittings in the A = 4 mirror hypernuclei is discussed.

  9. A 4D Hyperspherical Interpretation of q-Space

    PubMed Central

    Hosseinbor, A. Pasha; Chung, Moo K.; Wu, Yu-Chien; Bendlin, Barbara B.; Alexander, Andrew L.

    2015-01-01

    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH). Using this orthonormal basis, we derive several well-established q-space indices and numerically estimate the diffusion orientation distribution function (dODF). We also derive the integral transform describing the relationship between the diffusion signal and propagator on a hypersphere. Most importantly, we will demonstrate that for hybrid diffusion imaging (HYDI) acquisitions low order linear expansion of the HSH basis is sufficient to characterize diffusion in neural tissue. In fact, the HSH basis achieves comparable signal and better dODF reconstructions than other well-established methods, such as Bessel Fourier orientation reconstruction (BFOR), using fewer fitting parameters. All in all, this work provides a new way of looking at q-space. PMID:25624043

  10. Spontaneous CP violation in A4 flavor symmetry and leptogenesis

    NASA Astrophysics Data System (ADS)

    Ahn, Y. H.; Kang, Sin Kyu; Kim, C. S.

    2013-06-01

    We propose a simple renormalizable model for the spontaneous CP violation based on SU(2)L×U(1)Y×A4 symmetry in a radiative seesaw mechanism, which can be guaranteed by an extra Z2 symmetry. In our model CP is spontaneously broken at high energies, after the breaking of flavor symmetry, by a complex vacuum expectation value of the A4 triplet and gauge-singlet scalar field. We show that the spontaneously generated CP phase could become a natural source of leptogenesis, and also investigate CP violation at low energies in the lepton sector and show how the CP phases in the Pontecorvo-Maki-Nakagawa-Sakata formalism could arise through a spontaneous symmetry-breaking mechanism. As a numerical study, interestingly, we show that the normal mass hierarchy favors relatively large values of θ13, large deviations from maximality of θ23<π/4, and the Dirac-CP phase 0°≤δCP≤50° and 300°≤δCP≤360°. For the inverted hierarchy case, the experimentally measured values of θ13 favors θ23>π/4 and discrete values of δCP around 100°, 135°, 255°, and 300°. Finally, with a successful leptogenesis our numerical results give more predictive values on the Dirac CP phase: for the normal mass hierarchy 1°≲δCP≲10° and for inverted one δCP˜100°, 135°, 300°.

  11. Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia

    PubMed Central

    Okyere, Benjamin; Giridhar, Kaavya; Hazy, Amanda; Chen, Miao; Keimig, David; Bielitz, Robert C.; Xie, Hehuang; He, Jia-Qiang; Huckle, William R.; Theus, Michelle H.

    2016-01-01

    Leptomeningeal anastomoses play a critical role in regulating vascular re-perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p-Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of EC-specific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction. PMID:27467069

  12. Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia.

    PubMed

    Okyere, Benjamin; Giridhar, Kaavya; Hazy, Amanda; Chen, Miao; Keimig, David; Bielitz, Robert C; Xie, Hehuang; He, Jia-Qiang; Huckle, William R; Theus, Michelle H

    2016-01-01

    Leptomeningeal anastomoses play a critical role in regulating vascular re-perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p-Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of EC-specific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction. PMID:27467069

  13. Multifocal tumoral calcinosis in a 4-year-old girl

    PubMed Central

    Sayar, Ilyas; Peker, Kemal; Kapısız, Alparslan; Bostancı, Isıl Esen; Gürbüzel, Mehmet; Isik, Arda; Peker, Necla Aydın

    2014-01-01

    Patient: Female, 4 Final Diagnosis: Tumoral calcinosis Symptoms: Hard immobile mass Medication: — Clinical Procedure: — Specialty: Surgery Objective: Congenital defects Background: Tumoral calcinosis is an uncommon condition associated with the deposition of painless calcific masses. It is more common in childhood or early adolescence of African-American females. Case Report: We present a case of a 4-year-old girl with tumoral calcinosis treated surgically. The case is rather rare in terms of the age of the patient and the localization of the masses (gluteal site). In our patient, the biochemical findings were normal, except for hyperphosphatemia and elevated alkaline phosphatase. Conclusions: Total excision appears to lead to a good clinical outcome and a low incidence of local relapse. PMID:24644527

  14. Organising evidence for environmental management decisions: a '4S' hierarchy.

    PubMed

    Dicks, Lynn V; Walsh, Jessica C; Sutherland, William J

    2014-11-01

    Making decisions informed by the best-available science is an objective for many organisations managing the environment or natural resources. Yet, available science is still not widely used in environmental policy and practice. We describe a '4S' hierarchy for organising relevant science to inform decisions. This hierarchy has already revolutionised clinical practice. It is beginning to emerge for environmental management, although all four levels need substantial development before environmental decision-makers can reliably and efficiently find the evidence they need. We expose common bypass routes that currently lead to poor or biased representation of scientific knowledge. We argue that the least developed level of the hierarchy is that closest to decision-makers, placing synthesised scientific knowledge into environmental decision support systems.

  15. Rectal bleeding in a 4-month-old boy

    SciTech Connect

    Dutro, J.A.; Santanello, S.A.; Unger, F.; Goodwin, C.D.

    1986-10-24

    A case of bleeding Meckel's diverticulum is described in an infant. A 4-month-old boy was seen initially with a 24-hour history of painless hematochezia. His parents had noted two episodes of maroon-colored stool that did not appear to be associated with any abdominal distress. His medical history was unremarkable, with normal growth and development. Physical examination revealed a well-nourished, well-hydrated infant in no apparent distress. Vital signs were normal. Rectal examination revealed no masses, but bright-red blood was noted on the examining finger. Findings from the remainder of the examination were normal. An upright roentgenogram of the abdomen was obtained and demonstrated no abnormalities. The abdominal technetium scan was abnormal. An exploratory laparotomy was performed later on the day of admission.

  16. Acoustic noise reduction in a 4 T MRI scanner.

    PubMed

    Mechefske, Chris K; Geris, Ryan; Gati, Joseph S; Rutt, Brian K

    2002-01-01

    High-field, high-speed magnetic resonance imaging (MRI) can generate high levels of noise. There is ongoing concern in the medical and imaging research communities regarding the detrimental effects of high acoustic levels on auditory function, patient anxiety, verbal communication between patients and health care workers and ultimately MR image quality. In order to effectively suppress the noise levels inside MRI scanners, the sound field needs to be accurately measured and characterized. This paper presents the results of measurements of the sound radiation from a gradient coil cylinder within a 4 T MRI scanner under a variety of conditions. These measurement results show: (1) that noise levels can be significantly reduced through the use of an appropriately designed passive acoustic liner; and (2) the true noise levels that are experienced by patients during echo planar imaging.

  17. Organising evidence for environmental management decisions: a '4S' hierarchy.

    PubMed

    Dicks, Lynn V; Walsh, Jessica C; Sutherland, William J

    2014-11-01

    Making decisions informed by the best-available science is an objective for many organisations managing the environment or natural resources. Yet, available science is still not widely used in environmental policy and practice. We describe a '4S' hierarchy for organising relevant science to inform decisions. This hierarchy has already revolutionised clinical practice. It is beginning to emerge for environmental management, although all four levels need substantial development before environmental decision-makers can reliably and efficiently find the evidence they need. We expose common bypass routes that currently lead to poor or biased representation of scientific knowledge. We argue that the least developed level of the hierarchy is that closest to decision-makers, placing synthesised scientific knowledge into environmental decision support systems. PMID:25280588

  18. Acoustic noise reduction in a 4 T MRI scanner.

    PubMed

    Mechefske, Chris K; Geris, Ryan; Gati, Joseph S; Rutt, Brian K

    2002-01-01

    High-field, high-speed magnetic resonance imaging (MRI) can generate high levels of noise. There is ongoing concern in the medical and imaging research communities regarding the detrimental effects of high acoustic levels on auditory function, patient anxiety, verbal communication between patients and health care workers and ultimately MR image quality. In order to effectively suppress the noise levels inside MRI scanners, the sound field needs to be accurately measured and characterized. This paper presents the results of measurements of the sound radiation from a gradient coil cylinder within a 4 T MRI scanner under a variety of conditions. These measurement results show: (1) that noise levels can be significantly reduced through the use of an appropriately designed passive acoustic liner; and (2) the true noise levels that are experienced by patients during echo planar imaging. PMID:11755093

  19. RS-A4 relaxation of flavor and CP violation

    NASA Astrophysics Data System (ADS)

    Kadosh, Avihay

    2013-03-01

    I discuss a model based on an A4 bulk flavor symmetry in the Randall-Sundrum (RS) setup. After discussing the setup and leading order results for the masses and mixings of quarks and leptons, I elaborate on the effect of higher order "cross-talk" corrections, their contributions to flavor violating processes and the resulting constraints on the model parameter space and the Kaluza-Klein (KK) mass scale. In addition, I present a systematic study of higher order corrections to the PMNS matrix in light of the recent measurements of θ 13 > 0 by RENO and Daya Bay. Finally, I also comment on the model new physics contributions to B_{s,d}toμ+μ^- and μ → eγ, in light of the new upper bounds recently set by the LHCb and MEG experiment.

  20. Genetic regulation of expression of leukotriene A4 hydrolase

    PubMed Central

    Castaldi, Peter; Cho, Michael H.; Blalock, J. Edwin; Gaggar, Amit

    2016-01-01

    In chronic inflammatory lung disorders such as chronic obstructive pulmonary disease (COPD), the concurrent organ-specific and systemic inflammatory responses lead to airway remodelling and vascular dysfunction. Although a major common risk factor for COPD, cigarette smoke alone cannot explain the progression of this disease; there is increasing evidence that genetic predisposition also plays a role in COPD susceptibility and progression. A key enzyme in chronic lung inflammation is leukotriene A4 hydrolase (LTA4H). With its aminopeptidase activity, LTA4H degrades the neutrophil chemoattractant tripeptide PGP. In this study, we used the luciferase reporter gene analysis system and quantitative trait locus analysis to explore the impact of single-nucleotide polymorphisms (SNPs) in the putative promoter region of LTA4H on LTA4H expression. We show that not only is the putative promoter of LTA4H larger than previously reported but also that SNPs in the expanded promoter region regulate expression of LTA4H both in cell-based systems and in peripheral blood samples from human subjects. These findings provide significant evidence for an active region upstream of the previously reported LTA4H promoter, which may have implications related to ongoing inflammatory processes in chronic lung disease. PMID:27730172

  1. Aerodynamic analysis of Audi A4 Sedan using CFD

    NASA Astrophysics Data System (ADS)

    Birwa, S. K.; Rathi, N.; Gupta, R.

    2013-04-01

    This paper presents the aerodynamic influence of velocity and ground clearance for Audi A4 Sedan. The topology of the test vehicle was modeled using CATIA P3 V5 R17. ANSYS FLUENT 12 was the CFD solver employed in this study. The distribution of pressure and velocity was obtained. The velocities were 30, 40, 50 and 60 m/s and ground clearances were 76.2 mm,101.6 mm,127 mm and 152.4 mm. The simulation results were compared with the available resources. It was found that the drag coefficient decreases with the velocity increasing from 30 to 60 m/s and increases with the ground clearance from 101.6 mm to 152.4 mm. Further decrease in ground clearance showed no effect on the value of coefficient of drag. The lift coefficient was found to decrease firstly with ground clearance from 152.4 mm to 101.6 mm, and then increase from 101.6 mm to 76.2 mm. Both the lift coefficient and drag coefficient was found to be minimum for the ground clearance of 101.6 mm as designed by the company.

  2. Curved optical tubes in a 4Pi focusing system.

    PubMed

    Yan, Shaohui; Yu, Xianghua; Li, Manman; Yao, Baoli

    2015-08-24

    We demonstrate the possibility of creating curved optical tubes in a 4Pi focusing system. The focal fields of such optical tubes have interesting properties: the energy is concentered in the neighborhood of a prescribed three-dimensional (3D) curve while the cross section is of hollow shape. The creation of these optical tubes is based on the annular focal spot of a vortex beam, which is employed as a building block. An optical tube is thus obtained by covering the central-axis curve of the tube by various such building blocks. Each building block has a certain orientation and position, realized by a rotation plus a certain translation. The spatial spectrum (the input field as well) of the optical tube is obtained by linearly superposing the spectrum of each transformed building block. The curve is rather arbitrary. Three examples of optical tubes: a torus, a solenoid and a trefoil knot are given, showing a good agreement with the expected results. PMID:26368256

  3. The promoter of Alzheimer's disease amyloid A4 precursor gene.

    PubMed

    Salbaum, J M; Weidemann, A; Lemaire, H G; Masters, C L; Beyreuther, K

    1988-09-01

    The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.

  4. Combretastatin A4 disodium phosphate-induced myocardial injury.

    PubMed

    Tochinai, Ryota; Nagata, Yuriko; Ando, Minoru; Hata, Chie; Suzuki, Tomo; Asakawa, Naoyuki; Yoshizawa, Kazuhiko; Uchida, Kazumi; Kado, Shoichi; Kobayashi, Toshihide; Kaneko, Kimiyuki; Kuwahara, Masayoshi

    2016-07-01

    Histopathological and electrocardiographic features of myocardial lesions induced by combretastatin A4 disodium phosphate (CA4DP) were evaluated, and the relation between myocardial lesions and vascular changes and the direct toxic effect of CA4DP on cardiomyocytes were discussed. We induced myocardial lesions by administration of CA4DP to rats and evaluated myocardial damage by histopathologic examination and electrocardiography. We evaluated blood pressure (BP) of CA4DP-treated rats and effects of CA4DP on cellular impedance-based contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). The results revealed multifocal myocardial necrosis with a predilection for the interventricular septum and subendocardial regions of the apex of the left ventricular wall, injury of capillaries, morphological change of the ST junction, and QT interval prolongation. The histopathological profile of myocardial lesions suggested that CA4DP induced a lack of myocardial blood flow. CA4DP increased the diastolic BP and showed direct effects on hiPS-CMs. These results suggest that CA4DP induces dysfunction of small arteries and capillaries and has direct toxicity in cardiomyocytes. Therefore, it is thought that CA4DP induced capillary and myocardial injury due to collapse of the microcirculation in the myocardium. Moreover, the direct toxic effect of CA4DP on cardiomyocytes induced myocardial lesions in a coordinated manner. PMID:27559241

  5. A 4 GHz digital receiver using the Uniboard platform

    NASA Astrophysics Data System (ADS)

    Comoretto, Giovanni; Russo, Antonietta; Quertier, Benjamin; Cais, Philippe; Camino, Pascal

    2012-09-01

    The Uniboard is a general purpose board, developed as a part of the Radionet FP7 program, that hosts 8 Altera StratixIV FPGAs interconnected by high speed links. It can be used standalone or as a part of a more complex system. The Digital receiver application uses a single Uniboard to implement a flexible packetization of a wideband signal in the frequency domain. It accepts a 4 GHz (8 GS/s) input bandwidth and provides up to 64 output bands. The bandwidth and position of each output band can be independently adjusted. The input signal is first analyzed by a polyphase filterbank, that splits the input band into 32 sub-bands with a bandwidth of 190 MHz and a spacing of 128 MHz. The overlap among adjacent bands allows the positioning of the output bands without dead regions. This filterbank is followed by an array of digitally defined downconverters, each one composed of a mixer/LO and a variable decimation filter. The filter band can be adjusted in binary steps from 1 to 128 MHz. Using tap recirculation, the filter shape remains constant over this whole range, with about 60 dB of stopband rejection and 90% usable passband. The output bands are packetized according to the VDIF VLBI standard, over eight 10G Ethernet links. Further processing can be done either on board, or in a cluster of conventional PCs. In addition, high speed ADC are in-house developed (ASIC 65nm CMOS STmicroelectronics) to feed the Uniboard card with 8GS/s, 4GHz BW, 3bits samples.

  6. Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance.

    PubMed

    Mammen, Cherry; Rupps, Rosemarie; Trnka, Peter; Boerkoel, Cornelius F

    2012-02-01

    We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. PMID:22245519

  7. 26 CFR 1.643(a)-5 - Tax-exempt interest.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax-exempt interest. 1.643(a)-5 Section 1.643(a)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.643(a)-5 Tax-exempt interest. (a) There...

  8. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  9. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  10. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  11. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  12. 42 CFR 63a.5 - How to apply for a training grant.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How to apply for a training grant. 63a.5 Section 63a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.5 How to apply for a training...

  13. 26 CFR 1.643(a)-5 - Tax-exempt interest.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax-exempt interest. 1.643(a)-5 Section 1.643(a)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.643(a)-5 Tax-exempt interest....

  14. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.

    PubMed

    Fang, J; Bourin, M; Baker, G B

    1999-02-01

    Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 microM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg144, CYP2C9-cys144, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol(-1) CYP min(-1), respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat.

  15. 26 CFR 1.512(a)-3 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true 1.512(a)-3 Section 1.512(a)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.512(a)-3...

  16. 26 CFR 1.468A-3 - Ruling amount.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 6 2011-04-01 2011-04-01 false Ruling amount. 1.468A-3 Section 1.468A-3...) INCOME TAXES (CONTINUED) Taxable Year for Which Deductions Taken § 1.468A-3 Ruling amount. (a) In general... schedule of ruling amounts for the nuclear decommissioning fund that includes a ruling amount for...

  17. 26 CFR 48.4061(a)-3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Definitions. 48.4061(a)-3 Section 48.4061(a)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE... Fuel Automotive and Related Items § 48.4061(a)-3 Definitions. For purposes of the tax imposed...

  18. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible to apply? 52a.3 Section 52a.3... OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit agency, institution, or consortium of agencies is eligible to apply for a grant under sections 409C, 414, 417,...

  19. 42 CFR 68a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible to apply? 68a.3 Section 68a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS... DISADVANTAGED BACKGROUNDS (CR-LRP) § 68a.3 Who is eligible to apply? To be eligible to apply to the CR-LRP,...

  20. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  1. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  2. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  3. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  4. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  5. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  6. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  7. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  8. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  9. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit...

  10. Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

    SciTech Connect

    Kim, Sangsoo Daniel; Antenos, Monica; Squires, E. James; Kirby, Gordon M.

    2013-07-15

    Bilirubin (BR) has recently been identified as the first endogenous substrate for cytochrome P450 2A5 (CYP2A5) and it has been suggested that CYP2A5 plays a major role in BR clearance as an alternative mechanism to BR conjugation by uridine-diphosphate glucuronyltransferase 1A1. This study investigated the mechanisms of Cyp2a5 gene regulation by BR and the cytoprotective role of CYP2A5 in BR hepatotoxicity. BR induced CYP2A5 expression at the mRNA and protein levels in a dose-dependent manner in primary mouse hepatocytes. BR treatment also caused nuclear translocation of Nuclear factor-E2 p45-related factor 2 (Nrf2) in hepatocytes. In reporter assays, BR treatment of primary hepatocytes transfected with a Cyp2a5 promoter-luciferase reporter construct resulted in a 2-fold induction of Cyp2a5 reporter activity. Furthermore, cotransfection of the hepatocytes with a Nrf2 expression vector without BR treatment resulted in an increase in Cyp2a5 reporter activity of approximately 2-fold and BR treatment of Nrf2 cotransfectants further increased reporter activity by 4-fold. In addition, site-directed mutation of the ARE in the reporter construct completely abolished both the BR- and Nrf2-mediated increases in reporter activity. The cytoprotective role of CYP2A5 against BR-mediated apoptosis was also examined in Hepa 1–6 cells that lack endogenous CYP2A5. Transient overexpression of CYP2A5 partially blocked BR-induced caspase-3 cleavage in Hepa 1–6 cells. Furthermore, in vitro degradation of BR was increased by microsomes from Hepa 1–6 cells overexpressing CYP2A5 compared to control cells transfected with an empty vector. Collectively, these results suggest that Nrf2-mediated CYP2A5 transactivation in response to BR may provide an additional mechanism for adaptive cytoprotection against BR hepatotoxicity. - Highlights: • The mechanism of Cyp2a5 gene regulation by BR was investigated. • The cytoprotective role of CYP2A5 in BR hepatotoxicity was determined. • BR

  11. Accumulation of dioxins and induction of cytochrome P450 1A4/1A5 enzyme activities in common cormorants from Lake Biwa, Japan: temporal trends and validation of national regulation on dioxins emission.

    PubMed

    Kubota, Akira; Watanabe, Michio X; Kim, Eun-Young; Yoneda, Kumiko; Tanabe, Shinsuke; Iwata, Hisato

    2012-09-01

    To validate the outcome of the national regulation on dioxins emission implemented in 1999, this study investigated temporal trends of chlorinated dioxins and related compounds (DRCs) in liver of common cormorants (Phalacrocorax carbo) collected from Lake Biwa, Japan between 2001 and 2008, as a part of the "Survey on the State of Dioxins Accumulation in Wildlife" conducted by the Ministry of the Environment, Japan. We also measured a biomarker of DRCs exposure, the cytochrome P450 1A (CYP1A)-dependent O-dealkylation activity of alkoxyresorufins (AROD), including methoxy-, ethoxy-, pentoxy- and benzyloxy-resorufins in the samples over 2001-2007. Neither TEQ nor AROD activity showed any clear declining trend over the time period, although the emission of DRCs during the corresponding period was estimated to be apparently decreasing. Our data indicate that the concentration of recalcitrant DRCs in the cormorant during 2001-2008 was scarcely affected by the national regulation on dioxins emission. PMID:22610036

  12. Accelerated radiation damage test facility using a 5 MV tandem ion accelerator

    NASA Astrophysics Data System (ADS)

    Wady, P. T.; Draude, A.; Shubeita, S. M.; Smith, A. D.; Mason, N.; Pimblott, S. M.; Jimenez-Melero, E.

    2016-01-01

    We have developed a new irradiation facility that allows to perform accelerated damage tests of nuclear reactor materials at temperatures up to 400 °C using the intense proton (<100 μA) and heavy ion (≈10 μA) beams produced by a 5 MV tandem ion accelerator. The dedicated beam line for radiation damage studies comprises: (1) beam diagnosis and focusing optical components, (2) a scanning and slit system that allows uniform irradiation of a sample area of 0.5-6 cm2, and (3) a sample stage designed to be able to monitor in-situ the sample temperature, current deposited on the sample, and the gamma spectrum of potential radio-active nuclides produced during the sample irradiation. The beam line capabilities have been tested by irradiating a 20Cr-25Ni-Nb stabilised stainless steel with a 3 MeV proton beam to a dose level of 3 dpa. The irradiation temperature was 356 °C, with a maximum range in temperature values of ±6 °C within the first 24 h of continuous irradiation. The sample stage is connected to ground through an electrometer to measure accurately the charge deposited on the sample. The charge can be integrated in hardware during irradiation, and this methodology removes uncertainties due to fluctuations in beam current. The measured gamma spectrum allowed the identification of the main radioactive nuclides produced during the proton bombardment from the lifetimes and gamma emissions. This dedicated radiation damage beam line is hosted by the Dalton Cumbrian Facility of the University of Manchester.

  13. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., transfers, and buybacks. (10) Vesting. (11) Crediting service. (12) Governmental plans. (13) Employee stock... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table...(a)(4)-13. § 1.401(a)(4)-1Nondiscrimination requirements of section 401(a)(4) (a) In general....

  14. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., transfers, and buybacks. (10) Vesting. (11) Crediting service. (12) Governmental plans. (13) Employee stock... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table...(a)(4)-13. § 1.401(a)(4)-1Nondiscrimination requirements of section 401(a)(4) (a) In general....

  15. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., transfers, and buybacks. (10) Vesting. (11) Crediting service. (12) Governmental plans. (13) Employee stock... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table...(a)(4)-13. § 1.401(a)(4)-1Nondiscrimination requirements of section 401(a)(4) (a) In general....

  16. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ..., transfers, and buybacks. (10) Vesting. (11) Crediting service. (12) Governmental plans. (13) Employee stock... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table...(a)(4)-13. § 1.401(a)(4)-1Nondiscrimination requirements of section 401(a)(4) (a) In general....

  17. Outdoor transmission measurement at 26 GHz: Results of a 4 year trial in Prague

    NASA Astrophysics Data System (ADS)

    Thorvaldsen, Per; Henne, Ingvar

    2016-05-01

    This paper presents the results from a field trial that was performed during a 4 year period on a 5.5 km long radio link path operating at 26 GHz in Prague. The purpose was to investigate the amount of attenuation due to precipitation and its yearly variations. The attenuation of the radio link signal and the rain rate were measured. The measured attenuation results are compared to the models given by the International Telecommunication Union (ITU). The propagation measurements show large yearly variations due to variability in rain rate from one year to another. The measured results are in agreement with the ITU long-term statistical rain attenuation model if the measured rain rate for the individual year is used. For the worst year the number of fades, the fade duration, the fade speed, the worst month statistics, and the polarization correlation are presented. The measurements presented will add to the current knowledge of fading due to precipitation, and some of the results, such as the fade duration distributions, are new knowledge.

  18. PTP-PEST controls EphA3 activation and ephrin-induced cytoskeletal remodelling.

    PubMed

    Mansour, Mariam; Nievergall, Eva; Gegenbauer, Kristina; Llerena, Carmen; Atapattu, Lakmali; Hallé, Maxime; Tremblay, Michel L; Janes, Peter W; Lackmann, Martin

    2016-01-15

    Eph receptors and their corresponding membrane-bound ephrin ligands regulate cell positioning and establish tissue patterns during embryonic and oncogenic development. Emerging evidence suggests that assembly of polymeric Eph signalling clusters relies on cytoskeletal reorganisation and underlies regulation by protein tyrosine phosphatases (PTPs). PTP-PEST (also known as PTPN12) is a central regulator of actin cytoskeletal dynamics. Here, we demonstrate that an N-terminal fragment of PTP-PEST, generated through an ephrinA5-triggered and spatially confined cleavage mediated by caspase-3, attenuates EphA3 receptor activation and its internalisation. Isolation of EphA3 receptor signalling clusters within intact plasma membrane fragments obtained by detergent-free cell fractionation reveals that stimulation of cells with ephrin triggers effective recruitment of this catalytically active truncated form of PTP-PEST together with key cytoskeletal and focal adhesion proteins. Importantly, modulation of actin polymerisation using pharmacological and dominant-negative approaches affects EphA3 phosphorylation in a similar manner to overexpression of PTP-PEST. We conclude that PTP-PEST regulates EphA3 activation both by affecting cytoskeletal remodelling and through its direct action as a PTP controlling EphA3 phosphorylation, indicating its multifaceted regulation of Eph signalling. PMID:26644181

  19. Inhibition of A5 Neurons Facilitates the Occurrence of REM Sleep-Like Episodes in Urethane-Anesthetized Rats: A New Role for Noradrenergic A5 Neurons?

    PubMed

    Fenik, Victor B; Marchenko, Vitaliy; Davies, Richard O; Kubin, Leszek

    2012-01-01

    When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α(2)-adrenergic agonist clonidine (20-40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5-5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5

  20. Inhibition of A5 Neurons Facilitates the Occurrence of REM Sleep-Like Episodes in Urethane-Anesthetized Rats: A New Role for Noradrenergic A5 Neurons?

    PubMed Central

    Fenik, Victor B.; Marchenko, Vitaliy; Davies, Richard O.; Kubin, Leszek

    2012-01-01

    When rapid eye movement (REM) sleep occurs, noradrenergic cells become silent, with the abolition of activity in locus coeruleus (LC) neurons seen as a key event permissive for the occurrence of REM sleep. However, it is not known whether silencing of other than LC noradrenergic neurons contributes to the generation of REM sleep. In urethane-anesthetized rats, stereotyped REM sleep-like episodes can be repeatedly elicited by injections of the cholinergic agonist, carbachol, into a discrete region of the dorsomedial pons. We used this preparation to test whether inhibition of ventrolateral pontine noradrenergic A5 neurons only, or together with LC neurons, also can elicit REM sleep-like effects. To silence noradrenergic cells, we sequentially injected the α2-adrenergic agonist clonidine (20–40 nl, 0.75 mM) into both A5 regions and then the LC. In two rats, successful bilateral clonidine injections into the A5 region elicited the characteristic REM sleep-like episodes (hippocampal theta rhythm, suppression of hypoglossal nerve activity, reduced respiratory rate). In five rats, bilateral clonidine injections into the A5 region and then into one LC triggered REM sleep-like episodes, and in two rats injections into both A5 and then both LC were needed to elicit the effect. In contrast, in three rats, uni- or bilateral clonidine injections only into the LC had no effect, and clonidine injections placed in another six rats outside of the A5 and/or LC regions were without effect. The REM sleep-like episodes elicited by clonidine had similar magnitude of suppression of hypoglossal nerve activity (by 75%), similar pattern of hippocampal changes, and similar durations (2.5–5.3 min) to the episodes triggered in the same preparation by carbachol injections into the dorsomedial pontine reticular formation. Thus, silencing of A5 cells may importantly enable the occurrence of REM sleep-like episodes, at least under anesthesia. This is a new role for noradrenergic A5

  1. 26 CFR 1.613A-5 - Election under section 613A(c)(4).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Election under section 613A(c)(4). 1.613A-5 Section 1.613A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4). The election under section 613A(c)(4) is...

  2. Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism

    PubMed Central

    Belkhir, Leïla; Elens, Laure; Zech, Francis; Panin, Nadtha; Vincent, Anne; Yombi, Jean Cyr

    2016-01-01

    Objectives To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations. Methods 135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed. Results 45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566–2290] versus 1737ng/ml [CI95%: 1468–2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3–2165] versus 3141ng/ml [CI95%:2042–4831], p = 0.007). Conclusions Interaction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its

  3. Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population.

    PubMed

    Suarez-Kurtz, Guilherme; Vargens, Daniela D; Santoro, Ana Beatriz; Hutz, Mara H; de Moraes, Maria Elisabete; Pena, Sérgio D J; Ribeiro-dos-Santos, Ândrea; Romano-Silva, Marco A; Struchiner, Claudio José

    2014-01-01

    The influence of self-reported "race/color", geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black ("race/color" categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the

  4. Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population.

    PubMed

    Suarez-Kurtz, Guilherme; Vargens, Daniela D; Santoro, Ana Beatriz; Hutz, Mara H; de Moraes, Maria Elisabete; Pena, Sérgio D J; Ribeiro-dos-Santos, Ândrea; Romano-Silva, Marco A; Struchiner, Claudio José

    2014-01-01

    The influence of self-reported "race/color", geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black ("race/color" categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the

  5. Global Pharmacogenomics: Distribution of CYP3A5 Polymorphisms and Phenotypes in the Brazilian Population

    PubMed Central

    Suarez-Kurtz, Guilherme; Vargens, Daniela D.; Santoro, Ana Beatriz; Hutz, Mara H.; de Moraes, Maria Elisabete; Pena, Sérgio D. J.; Ribeiro-dos-Santos, Ândrea; Romano-Silva, Marco A.; Struchiner, Claudio José

    2014-01-01

    The influence of self-reported “race/color”, geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black (“race/color” categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity

  6. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... established by the Department of Education under the Higher Education Act of 1965 and set forth in 34 CFR 674... 26 Internal Revenue 1 2014-04-01 2013-04-01 true Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In...

  7. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... established by the Department of Education under the Higher Education Act of 1965 and set forth in 34 CFR 674... 26 Internal Revenue 1 2012-04-01 2012-04-01 false Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In...

  8. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... established by the Department of Education under the Higher Education Act of 1965 and set forth in 34 CFR 674... 26 Internal Revenue 1 2011-04-01 2009-04-01 true Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In...

  9. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... established by the Department of Education under the Higher Education Act of 1965 and set forth in 34 CFR 674... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In...

  10. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... established by the Department of Education under the Higher Education Act of 1965 and set forth in 34 CFR 674... 26 Internal Revenue 1 2013-04-01 2013-04-01 false Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In...

  11. An Overview of the A-3 Subscale Diffuser Test Project

    NASA Technical Reports Server (NTRS)

    Ryan, James E.; Mulkey, Christopher; Raines, Nickey; Saunders, Grady P.

    2008-01-01

    The Subscale Diffuser Test (SDT) Project comprised a series of tests of a subscale model of SSC s A-3 Test Stand diffuser. SDT was conducted at NASA s Stennis Space Center (SSC) Apr 2007 - Jan 2008. Purpose of SDT was to mitigate design risk for the A-3 diffuser. Initial scope of the SDT project successfully completed in Jan 2008. Follow-on A-3 risk mitigation testing being planned/considered. This presentation presents an overview of the SDT project.

  12. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  13. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  14. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  15. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  16. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  17. Pharmacology and therapeutic applications of A3 receptor subtype.

    PubMed

    Fishman, Pnina; Bar-Yehuda, Sara

    2003-01-01

    The present study summarizes the biological effects elicit upon A(3) adenosine receptor (A(3)AR) activation in normal and tumor cells. Anti-inflamatory response is mediated upon A(3)AR activation in neutrophils, eosinophils and macrophages via direct effect on cell degranulation or the production of anti-inflamatory cytokines. In basophils, which highly express A(3)AR, degranulation and mediator release upon receptor activation lead to pro-inflammatory effects resulting in bronchospasm and asthma. In other normal cells such as cardiomyocytes, neuronal cells and bone marrow cells A(1)AR activation induces cytoprotective effects in vitro. In vivo, A(3)AR agonists act as cardio- and neuroprotective agents and attenuate ischemic damage. Furthermore, agonists to A(3)AR induce granulocyte colony stimulating factor (G-CSF) production and myeloprotective effect in chemotherapy treated mice. Interestingly, A(3)AR agonists inhibit tumor cell growth both in vitro and in vivo through a cytostatic effect mediated via the de-regulation of the Wnt signaling pathway. The variety of activities elicit by A(3)AR agonists suggest their potential use as therapeutic agents in inflammation, brain/cardiac ischemia and cancer. Antagonists to A(3)AR may be implemented to the therapy of asthma and additional allergic conditions.

  18. High-throughput screening of dipeptide utilization mediated by the ABC transporter DppBCDF and its substrate-binding proteins DppA1-A5 in Pseudomonas aeruginosa.

    PubMed

    Pletzer, Daniel; Lafon, Corinne; Braun, Yvonne; Köhler, Thilo; Page, Malcolm G P; Mourez, Michael; Weingart, Helge

    2014-01-01

    In this study, we show that the dppBCDF operon of Pseudomonas aeruginosa PA14 encodes an ABC transporter responsible for the utilization of di/tripeptides. The substrate specificity of ABC transporters is determined by its associated substrate-binding proteins (SBPs). Whereas in E. coli only one protein, DppA, determines the specificity of the transporter, five orthologous SBPs, DppA1-A5 are present in P. aeruginosa. Multiple SBPs might broaden the substrate specificity by increasing the transporter capacity. We utilized the Biolog phenotype MicroArray technology to investigate utilization of di/tripeptides in mutants lacking either the transport machinery or all of the five SBPs. This high-throughput method enabled us to screen hundreds of dipeptides with various side-chains, and subsequently, to determine the substrate profile of the dipeptide permease. The substrate spectrum of the SBPs was elucidated by complementation of a penta mutant, deficient of all five SBPs, with plasmids carrying individual SBPs. It became apparent that some dipeptides were utilized with different affinity for each SBP. We found that DppA2 shows the highest flexibility on substrate recognition and that DppA2 and DppA4 have a higher tendency to utilize tripeptides. DppA5 was not able to complement the penta mutant under our screening conditions. Phaseolotoxin, a toxic tripeptide inhibiting the enzyme ornithine carbamoyltransferase, is also transported into P. aeruginosa via the DppBCDF permease. The SBP DppA1, and with much greater extend DppA3, are responsible for delivering the toxin to the permease. Our results provide a first overview of the substrate pattern of the ABC dipeptide transport machinery in P. aeruginosa. PMID:25338022

  19. Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa

    PubMed Central

    2013-01-01

    Background Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago. Results We estimate that ~43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A5*3 as ~76,400 years and CYP3A5*6 as ~218,400 years. Finally we report that global CYP3A5 expression

  20. Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease.

    PubMed

    Börgeson, Emma; Johnson, Andrew M F; Lee, Yun Sok; Till, Andreas; Syed, Gulam Hussain; Ali-Shah, Syed Tasadaque; Guiry, Patrick J; Dalli, Jesmond; Colas, Romain A; Serhan, Charles N; Sharma, Kumar; Godson, Catherine

    2015-07-01

    The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c(+) M1-macrophages (MΦs), while restoring CD206(+) M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies.

  1. Space-charge driven emittance growth in a 3D mismatched anisotropic beam

    SciTech Connect

    Qiang, J.; Ryne, R.D.; Hofmann, I.

    2002-12-03

    In this paper we present a 3D simulation study of the emittance growth in a mismatched anisotropic beam. The equipartitioning driven by a 4th order space-charge resonance can be significantly modified by the presence of mismatch oscillation and halo formation. This causes emittance growth in both the longitudinal and transverse directions which could drive the beam even further away from equipartition. The averaged emittance growth per degree freedom follows the upper bound of the 2D free energy limit plus the contributions from equipartitioning.

  2. 17 CFR 240.17a-5 - Reports to be made by certain brokers and dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... or carries customer accounts shall file Part I of Form X-17A-5 (§ 249.617 of this chapter) within 10... clears transactions or carries customer accounts shall file Part II of Form X-17A-5 (§ 249.617 of this... chapter). (iii) Every broker or dealer who does not carry nor clear transactions nor carry...

  3. 26 CFR 20.2056A-5 - Imposition of section 2056A estate tax.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Imposition of section 2056A estate tax. 20.2056A-5 Section 20.2056A-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable...

  4. Membrane repair of human skeletal muscle cells requires Annexin-A5.

    PubMed

    Carmeille, Romain; Bouvet, Flora; Tan, Sisareuth; Croissant, Coralie; Gounou, Céline; Mamchaoui, Kamel; Mouly, Vincent; Brisson, Alain R; Bouter, Anthony

    2016-09-01

    Defect in membrane repair contributes to the development of limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. In healthy skeletal muscle, unraveling membrane repair mechanisms requires to establish an exhaustive list of the components of the resealing machinery. Here we show that human myotubes rendered deficient for Annexin-A5 (AnxA5) suffer from a severe defect in membrane resealing. This defect is rescued by the addition of recombinant AnxA5 while an AnxA5 mutant, which is unable to form 2D protein arrays, has no effect. Using correlative light and electron microscopy, we show that AnxA5 binds to the edges of the torn membrane, as early as a few seconds after sarcolemma injury, where it probably self-assembles into 2D arrays. In addition, we observed that membrane resealing is associated with the presence of a cluster of lipid vesicles at the wounded site. AnxA5 is present at the surface of these vesicles and may thus participate in plugging the cell membrane disruption. Finally, we show that AnxA5 behaves similarly in myotubes from a muscle cell line established from a patient suffering from LGMD2B, a myopathy due to dysferlin mutations, which indicates that trafficking of AnxA5 during sarcolemma damage is independent of the presence of dysferlin. PMID:27286750

  5. Orphan nuclear receptor Nur77 participates in human apolipoprotein A5 gene expression

    SciTech Connect

    Song, Kwang-Hoon

    2010-01-29

    The orphan nuclear receptor Nur77 (NR4A1) has been reported to play a crucial role in the modulation of diverse metabolic processes in liver. Here, we reported the identification of human apolipoprotein A5 (ApoA5), which implicated in lowering plasma triglyceride levels, as a novel target gene of Nur77. Nur77 induced the human ApoA5 promoter activity. Using 5'-deletion and mutagenesis of human ApoA5 promoter analysis and chromatin immunoprecipitation assays, it was shown that Nur77 directly regulated human ApoA5 gene expression by binding to a Nur77 response element (AAAGGTCA) located in the proximal human ApoA5 promoter region. In addition, we demonstrated that blocking of Nur77 transcriptional activity via overexpression of dominant negative Nur77 suppressed human ApoA5 promoter activity and mRNA expression in human hepatoma cells, HepG2. Taken together, our results demonstrated that Nur77 is a novel regulator of human ApoA5 gene expression and provide a new insight into the role of this orphan nuclear receptor in lipoprotein metabolism and triglyceride homeostasis.

  6. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Contents of application; research projects in which drugs will be administered. 2a.5 Section 2a.5 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH... (21 U.S.C. 872(d)) and 21 CFR 1316.22. If the request is in such form, and is supported by...

  7. 42 CFR 68a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible to apply? 68a.3 Section 68a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL RESEARCH LOAN REPAYMENT PROGRAM FOR INDIVIDUALS...

  8. 42 CFR 68a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible to apply? 68a.3 Section 68a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL RESEARCH LOAN REPAYMENT PROGRAM FOR INDIVIDUALS...

  9. Using Toyota's A3 Thinking for Analyzing MBA Business Cases

    ERIC Educational Resources Information Center

    Anderson, Joe S.; Morgan, James N.; Williams, Susan K.

    2011-01-01

    A3 Thinking is fundamental to Toyota's benchmark management philosophy and to their lean production system. It is used to solve problems, gain agreement, mentor team members, and lead organizational improvements. A structured problem-solving approach, A3 Thinking builds improvement opportunities through experience. We used "The Toyota…

  10. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management. (a... 32 National Defense 2 2010-07-01 2010-07-01 false Organization and management. 352a.3 Section 352a..., selected by the Secretary of Defense, and such subordinate organizational elements as are established...

  11. 49 CFR 178.33a-3 - Inspection.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Inspection. 178.33a-3 Section 178.33a-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  12. 49 CFR 178.33a-3 - Inspection.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Inspection. 178.33a-3 Section 178.33a-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  13. 49 CFR 178.33a-3 - Inspection.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Inspection. 178.33a-3 Section 178.33a-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  14. 49 CFR 178.33a-3 - Inspection.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Inspection. 178.33a-3 Section 178.33a-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications for...

  15. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  16. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  17. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  18. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  19. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  20. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definition of Underserved Rural Community. 5a.3... PROVISIONS RURAL PHYSICIAN TRAINING GRANT PROGRAM § 5a.3 Definition of Underserved Rural Community. Underserved Rural Community means a community: (a) Located in: (1) A non-Metropolitan County or...

  1. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2)...

  2. 26 CFR 1.6038A-3 - Record maintenance.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Record maintenance. 1.6038A-3 Section 1.6038A-3... remaining 70 percent of RC stock is held by persons that are not 25-percent foreign shareholders. It is... products or services within such industry segment is $25 million or more in the taxable year. (ii) Form...

  3. 26 CFR 1.6038A-3 - Record maintenance.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Record maintenance. 1.6038A-3 Section 1.6038A-3... remaining 70 percent of RC stock is held by persons that are not 25-percent foreign shareholders. It is... products or services within such industry segment is $25 million or more in the taxable year. (ii) Form...

  4. 26 CFR 1.6038A-3 - Record maintenance.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Record maintenance. 1.6038A-3 Section 1.6038A-3... remaining 70 percent of RC stock is held by persons that are not 25-percent foreign shareholders. It is... products or services within such industry segment is $25 million or more in the taxable year. (ii) Form...

  5. The independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and the metabolism of atorvastatin

    PubMed Central

    Liu, Ju-E; Ren, Bin; Tang, Lan; Tang, Qian-Jie; Liu, Xiao-Ying; Li, Xin; Bai, Xue; Zhong, Wan-Ping; Meng, Jin-Xiu; Lin, Hao-Ming; Wu, Hong; Chen, Ji-Yan; Zhong, Shi-Long

    2016-01-01

    To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism, the relationships among three levels of factors, namely (1) clinical characteristics, CYP3A4/5 genotypes, and miRNAs, (2) CYP3A4 and CYP3A5 mRNAs, and (3) CYP3A activity, as well as their individual impacts on atorvastatin metabolism, were assessed in 55 human liver tissues. MiR-27b, miR-206, and CYP3A4 mRNA respectively accounted for 20.0%, 5.8%, and 9.5% of the interindividual variations in CYP3A activity. MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA (partial R2 = 0.12, P = 0.002) and CYP3A5 mRNA (partial R2 = 0.09, P = 0.005) but not CYP3A activity or atorvastatin metabolism. CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism, explaining the majority of the variance in reduction of atorvastatin (60.0%) and formation of ortho-hydroxy atorvastatin (78.8%) and para-hydroxy atorvastatin (83.9%). MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3′-UTR, while miR-142 was found to indirectly repress CYP3A activity. Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality. PMID:27211076

  6. The independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and the metabolism of atorvastatin.

    PubMed

    Liu, Ju-E; Ren, Bin; Tang, Lan; Tang, Qian-Jie; Liu, Xiao-Ying; Li, Xin; Bai, Xue; Zhong, Wan-Ping; Meng, Jin-Xiu; Lin, Hao-Ming; Wu, Hong; Chen, Ji-Yan; Zhong, Shi-Long

    2016-01-01

    To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism, the relationships among three levels of factors, namely (1) clinical characteristics, CYP3A4/5 genotypes, and miRNAs, (2) CYP3A4 and CYP3A5 mRNAs, and (3) CYP3A activity, as well as their individual impacts on atorvastatin metabolism, were assessed in 55 human liver tissues. MiR-27b, miR-206, and CYP3A4 mRNA respectively accounted for 20.0%, 5.8%, and 9.5% of the interindividual variations in CYP3A activity. MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA (partial R(2) = 0.12, P = 0.002) and CYP3A5 mRNA (partial R(2) = 0.09, P = 0.005) but not CYP3A activity or atorvastatin metabolism. CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism, explaining the majority of the variance in reduction of atorvastatin (60.0%) and formation of ortho-hydroxy atorvastatin (78.8%) and para-hydroxy atorvastatin (83.9%). MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3'-UTR, while miR-142 was found to indirectly repress CYP3A activity. Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality. PMID:27211076

  7. EphrinA5 suppresses colon cancer development by negatively regulating epidermal growth factor receptor stability.

    PubMed

    Wang, Tong-Hong; Chang, Junn-Liang; Ho, Jar-Yi; Wu, Hsiao-Chun; Chen, Tse-Ching

    2012-01-01

    Colon cancer is one of the most common human cancers worldwide. Owing to its aggressiveness and lethality, it is necessary to determine the mechanisms regulating the carcinogenesis of colon cancer. EphrinA5 has been reported to act as a putative tumor suppressor in glioma; however, little is known concerning the role of this protein in the context of colon cancer. To elucidate the biological significance of ephrinA5 in colon cancer, we examined ephrinA5 and epidermal growth factor receptor (EGFR) expression profiles in both colon cancer and normal tissues, using immunohistochemistry on a 96-spot tissue microarray. Gain-of-function and loss-of-function experiments were performed on the human colon cancer cell lines SW480 and WiDr to determine the biological effects of ephrinA5 in relation to cell proliferation, survival, and migration. It was found that ephrinA5 mRNA and protein levels were significantly reduced in colon cancer as compared with normal colon tissue specimens. EphrinA5 expression was also negatively associated with tumor differentiation and clinical stage. In colon cancer cell line models, ephrinA5 exerted an inhibitory effect on EGFR by promoting c-Cbl-mediated EGFR ubiquitination and degradation. EphrinA5 did not affect the transcriptional regulation of EGFR mRNA expression in colon cancer cells. Expression of ephrinA5 suppressed colon cancer cell proliferation, migration, and chemotherapeutic resistance. In conclusion, ephrinA5 inhibited colon cancer progression by promoting c-Cbl-mediated EGFR degradation. Our findings identify a novel mechanism that could be utilized to improve the therapeutic efficiency of EGFR-targeting strategies.

  8. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.

    PubMed

    Hong, Feng; Si, Chuanping; Gao, Pengfei; Cederbaum, Arthur I; Xiong, Huabao; Lu, Yongke

    2016-01-01

    Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison. Acute and subchronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1 (-/-) mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5 (-/-) mice developed comparable acute liver injury induced by a single injection of CCL4 as well as subchronic liver injury including fibrosis induced by 1 month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5 (-/-) mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5 (-/-) mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for 1 month, while subchronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5 (-/-) mice, liver fibrosis was more severe in cyp2a5 (-/-) mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it does not affect CCL4 hepatotoxicity.

  9. Giant mucocele originating from the middle concha in a 5-year-old child: a case report

    PubMed Central

    2013-01-01

    Introduction Mucoceles are mucus-filled, epithelial-lined sacs that slowly develop in the paranasal sinuses when sinus or concha bullosa drainage is obstructed by inflammatory processes, trauma, or prior surgery. They are extremely rare in children. Symptoms usually arise from the nasal obstruction or compression of neighboring structures. Case presentation This case report describes a 5-year-old Turkish boy with a 3-year history of nasal obstruction. A computed tomography scan showed a well-defined soft tissue density lesion, seemingly originating in the region of the middle concha and was suggestive of a middle concha mucocele. The mass was removed by endoscopic sinus surgery. Conclusions In the case of a child presenting with nasal obstruction, mucocele should be remembered in the differential diagnosis of intranasal tumors. Computed tomography and magnetic resonance imaging are helpful in making the diagnosis and endoscopic nasal surgery has proven successful in the treatment. PMID:24284013

  10. Structure–Activity Relationships of N6-Benzyladenosine-5′-uronamides as A3-Selective Adenosine Agonists†

    PubMed Central

    Gallo-Rodriguez, Carola; Ji, Xiao-duo; Melman, Neli; Siegman, Barry D.; Sanders, Lawrence H.; Orlina, Jeraldine; Fischer, Bilha; Pu, Quanlong; Olah, Mark E.; van Galen, Philip J. M.; Stiles, Gary L.; Jacobson, Kenneth A.

    2015-01-01

    Adenosine analogues modified at the 5′-position as uronamides and/or as N6-benzyl derivatives were synthesized. These derivatives were examined for affinity in radioligand binding assays at the newly discovered rat brain A3 adenosine receptor and at rat brain A1 and A2a receptors. 5′-Uronamide substituents favored A3 selectivity in the order N-methyl > N-ethyl ∞ unsubstituted carboxamide > N-cyclopropyl. 5′-(N-Methylcarboxamido)-N6-benzyladenosine was 37–56-fold more selective for A3 receptors. Potency at A3 receptors was enhanced upon substitution of the benzyl substituent with nitro and other groups. 5′-N-Methyluronamides and N6-(3-substituted-benzyl)adenosines are optimal for potency and selectivity at A3 receptors. A series of 3-(halobenzyl)-5′-N-ethyluronamide derivatives showed the order of potency at A1 and A2a receptors of I ~ Br > Cl > F. At A3 receptors the 3-F derivative was weaker than the other halo derivatives. 5′-N-Methyl-N6-(3-iodobenzyl)adenosine displayed a Ki value of 1.1 nM at A3 receptors and selectivity versus A1 and A2a receptors of 50-fold. A series of methoxybenzyl derivatives showed that a 4-methoxy group best favored A3 selectivity. A 4-sulfobenzyl derivative was a specific ligand at A3 receptors of moderate potency. An aryl amino derivative was prepared as a probe for radioiodination and receptor cross-linking. PMID:8126704

  11. Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

    SciTech Connect

    Abu-Bakar, A'edah; Arthur, Dionne Maioha; Aganovic, Simona; Ng, Jack C.; Lang, Matti A.

    2011-11-15

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic 'BR oxidase'. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible 'BR oxidase' where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced. -- Highlights: Black-Right-Pointing-Pointer CYP2A5 metabolizes bilirubin to biliverdin and dipyrroles. Black-Right-Pointing-Pointer Bilirubin increased the hepatic CYP2A5 protein and activity levels. Black-Right-Pointing-Pointer Bilirubin does not change the hepatic CYP2A5

  12. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  13. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  14. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  15. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  16. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  17. 42 CFR 85a.4 - Procedures for initiating investigations of places of employment.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... of employment. 85a.4 Section 85a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES OCCUPATIONAL SAFETY AND HEALTH INVESTIGATIONS OF PLACES OF EMPLOYMENT § 85a.4 Procedures for initiating investigations of...

  18. 42 CFR 85a.4 - Procedures for initiating investigations of places of employment.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... of employment. 85a.4 Section 85a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES OCCUPATIONAL SAFETY AND HEALTH INVESTIGATIONS OF PLACES OF EMPLOYMENT § 85a.4 Procedures for initiating investigations of...

  19. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  20. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  1. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  2. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  3. 42 CFR 51a.4 - How is application made for Federal funding?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How is application made for Federal funding? 51a.4 Section 51a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.4 How is application made for Federal funding? An...

  4. 42 CFR 51a.4 - How is application made for Federal funding?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How is application made for Federal funding? 51a.4 Section 51a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.4 How is application made for Federal funding? An...

  5. 42 CFR 51a.4 - How is application made for Federal funding?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How is application made for Federal funding? 51a.4 Section 51a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.4 How is application made for Federal funding? An...

  6. 42 CFR 51a.4 - How is application made for Federal funding?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How is application made for Federal funding? 51a.4 Section 51a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS PROJECT GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.4 How is application made for Federal funding? An...

  7. A Fhit-mimetic peptide suppresses annexin A4-mediated chemoresistance to paclitaxel in lung cancer cells

    PubMed Central

    Ngankeu, Apollinaire; Ortuso, Francesco; Lovat, Francesca; Pinton, Sandra; D'Agostino, Sabrina; Zanesi, Nicola; Aqeilan, Rami I.; Campiglia, Pietro; Novellino, Ettore; Alcaro, Stefano; Croce, Carlo M.; Trapasso, Francesco

    2016-01-01

    We recently reported that Fhit is in a molecular complex with annexin A4 (ANXA4); following to their binding, Fhit delocalizes ANXA4 from plasma membrane to cytosol in paclitaxel-resistant lung cancer cells, thus restoring their chemosensitivity to the drug. Here, we demonstrate that Fhit physically interacts with A4 through its N-terminus; molecular dynamics simulations were performed on a 3D Fhit model to rationalize its mechanism of action. This approach allowed for the identification of the QHLIKPS heptapeptide (position 7 to 13 of the wild-type Fhit protein) as the smallest Fhit sequence still able to preserve its ability to bind ANXA4. Interestingly, Fhit peptide also recapitulates the property of the native protein in inhibiting Annexin A4 translocation from cytosol to plasma membrane in A549 and Calu-2 lung cancer cells treated with paclitaxel. Finally, the combination of Tat-Fhit peptide and paclitaxel synergistically increases the apoptotic rate of cultured lung cancer cells and blocks in vivo tumor formation. Our findings address to the identification of chemically simplified Fhit derivatives that mimic Fhit tumor suppressor functions; intriguingly, this approach might lead to the generation of novel anticancer drugs to be used in combination with conventional therapies in Fhit-negative tumors to prevent or delay chemoresistance. PMID:27166255

  8. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL.

    PubMed

    Baraniskin, Alexander; Birkenkamp-Demtroder, Karin; Maghnouj, Abdelouahid; Zöllner, Hannah; Munding, Johanna; Klein-Scory, Susanne; Reinacher-Schick, Anke; Schwarte-Waldhoff, Irmgard; Schmiegel, Wolff; Hahn, Stephan A

    2012-04-01

    MicroRNAs (miRNAs) are small non-coding RNAs that are involved in different biological processes by suppressing target gene expression. Altered expression of miR-30a-5p has been reported in colon carcinoma. To elucidate its potential biological role in colon cancer, miR-30a-5p was overexpressed via a lentiviral vector system in two different colon cancer cell lines. This induced in both lines miR-30a-5p-mediated growth inhibition, attributable to a cell cycle arrest at the G(1) phase and an induction of apoptosis. Combining global gene expression analyses of miR-30a-5p transgenic line HCT116 with in silico miRNA target prediction, we identified the denticleless protein homolog (DTL) as a potential miRNA-30a-5p target. Subsequent reporter gene assays confirmed the predicted miR-30a-5p binding site in the 3'untranslated region of DTL. Importantly, overexpression of DTL in HCT116 cells partially rescued these cells from miR-30a-5p-mediated growth suppression. In addition, TP53 and CDKN1A expression were increased in miR-30a-5p-overexpressing HCT116 cells, suggesting that miR-30a-5p is able to modulate the cell cycle via a DTL-TP53-CDKN1A regulatory circuit. Finally, 379 colorectal cancer tissues were screened for DTL expression and DTL was found to be overexpressed in 95.8% of human colorectal cancers compared with normal colon mucosa. In conclusion, our data identified miR-30a-5p as a tumor-suppressing miRNA in colon cancer cells exerting its function via modulation of DTL expression, which is frequently overexpressed in colorectal cancer. Thus, our data suggest that restoring miR-30a-5p function may prove useful as therapeutic strategy for tumors with reduced miR-30a-5p expression.

  9. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing

    PubMed Central

    Birdwell, Kelly A.; Decker, Brian; Barbarino, Julia M.; Peterson, Josh F.; Stein, C. Michael; Sadee, Wolfgang; Wang, Danxin; Vinks, Alexander A.; He, Yijing; Swen, Jesse J.; Leeder, J. Steven; van Schaik, RHN; Thummel, Kenneth E.; Klein, Teri E.; Caudle, Kelly E.; MacPhee, Iain A.M.

    2015-01-01

    Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared to those who are CYP3A5 non-expressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org). PMID:25801146

  10. A 3D digital medical photography system in paediatric medicine.

    PubMed

    Williams, Susanne K; Ellis, Lloyd A; Williams, Gigi

    2008-01-01

    In 2004, traditional clinical photography services at the Educational Resource Centre were extended using new technology. This paper describes the establishment of a 3D digital imaging system in a paediatric setting at the Royal Children's Hospital, Melbourne.

  11. Distinct neurological disorders with ATP1A3 mutations

    PubMed Central

    Heinzen, Erin L.; Arzimanoglou, Alexis; Brashear, Allison; Clapcote, Steven J.; Gurrieri, Fiorella; Goldstein, David B.; Jóhannesson, Sigurður H.; Mikati, Mohamad A.; Neville, Brian; Nicole, Sophie; Ozelius, Laurie J.; Poulsen, Hanne; Schyns, Tsveta; Sweadner, Kathleen J.; van den Maagdenberg, Arn; Vilsen, Bente

    2014-01-01

    Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na+/K+-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in vitro and animal model systems, and the role of Na+/K+-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases. PMID:24739246

  12. Distinct neurological disorders with ATP1A3 mutations.

    PubMed

    Heinzen, Erin L; Arzimanoglou, Alexis; Brashear, Allison; Clapcote, Steven J; Gurrieri, Fiorella; Goldstein, David B; Jóhannesson, Sigurður H; Mikati, Mohamad A; Neville, Brian; Nicole, Sophie; Ozelius, Laurie J; Poulsen, Hanne; Schyns, Tsveta; Sweadner, Kathleen J; van den Maagdenberg, Arn; Vilsen, Bente

    2014-05-01

    Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases. PMID:24739246

  13. 10. NAVFAC Drawing 6101591 (814A5) (1978), 'Various Repairs to Building ...

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

    10. NAVFAC Drawing 6101591 (814-A-5) (1978), 'Various Repairs to Building 814, Sections and Miscellaneous Details' - Mare Island Naval Shipyard, Chemical Cleaning Facility, North of Fourteenth Street, between California & Railroad Avenue, Vallejo, Solano County, CA

  14. Isolation of Copper from a 5-Cent Coin: An Example of Electrorefining

    ERIC Educational Resources Information Center

    Sogo, Steven G.

    2004-01-01

    Copper is isolated from a 5-cent coin with the help of electrolysis. This experiment is useful for conceptual understanding of the significance of reduction potentials in situation of competition for electrons.

  15. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  16. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  17. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  18. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... section 401(a)(5) by section 1111(b) of the Tax Reform Act of 1986 (TRA '86) apply, a plan must be... account pre-existing guidance and the amendments made by TRA '86 to related provisions of the...

  19. Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer*

    PubMed Central

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; Liu, Diane D.; Lee, J. Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R. M.; Lobb, Roy R.; Edelman, Martin J.; Sidman, Richard L.; Wistuba, Ignacio I.; Arap, Wadih; Pasqualini, Renata

    2015-01-01

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications. PMID:25623065

  20. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    SciTech Connect

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; Liu, Diane D.; Lee, J. Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R. M.; Lobb, Roy R.; Edelman, Martin J.; Sidman, Richard L.; Wistuba, Ignacio I.; Arap, Wadih; Pasqualini, Renata

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.

  1. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    DOE PAGES

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; et al

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lungmore » cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.« less

  2. [Local injection of bleomycin A 5 in children with hemangiomas. Analysis of 210 cases].

    PubMed

    Zheng, Q T

    1991-05-01

    210 children with hemangiomas were treated by local injection of Bleomycin A5. Bleomycin A5 was effective in all patients with strawberry and mixed hemangiomas, 91.2% of patients with cavernous hemangiomas, 44.4% of patients with port-wine stain. There was no response in pampiniform hemangioma. The therapeutic mechanism, indications and complications of the new method for treatment of hemangioma are discussed. PMID:1717207

  3. 26 CFR 1.613A-5 - Election under section 613A(c)(4).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Election under section 613A(c)(4). 1.613A-5... TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4). The election under section 613A(c)(4) is an annual election which the taxpayer may make by...

  4. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  5. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  6. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  7. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section...

  8. Evaluation of a 4D cone-beam CT reconstruction approach using a simulation framework.

    PubMed

    Hartl, Alexander; Yaniv, Ziv

    2009-01-01

    Current image-guided navigation systems for thoracic abdominal interventions utilize three dimensional (3D) images acquired at breath-hold. As a result they can only provide guidance at a specific point in the respiratory cycle. The intervention is thus performed in a gated manner, with the physician advancing only when the patient is at the same respiratory cycle in which the 3D image was acquired. To enable a more continuous workflow we propose to use 4D image data. We describe an approach to constructing a set of 4D images from a diagnostic CT acquired at breath-hold and a set of intraoperative cone-beam CT (CBCT) projection images acquired while the patient is freely breathing. Our approach is based on an initial reconstruction of a gated 4D CBCT data set. The 3D CBCT images for each respiratory phase are then non-rigidly registered to the diagnostic CT data. Finally the diagnostic CT is deformed based on the registration results, providing a 4D data set with sufficient quality for navigation purposes. In this work we evaluate the proposed reconstruction approach using a simulation framework. A 3D CBCT dataset of an anthropomorphic phantom is deformed using internal motion data acquired from an animal model to create a ground truth 4D CBCT image. Simulated projection images are then created from the 4D image and the known CBCT scan parameters. Finally, the original 3D CBCT and the simulated X-ray images are used as input to our reconstruction method. The resulting 4D data set is then compared to the known ground truth by normalized cross correlation(NCC). We show that the deformed diagnostic CTs are of better quality than the gated reconstructions with a mean NCC value of 0.94 versus a mean 0.81 for the reconstructions. PMID:19964143

  9. Ephrin-A5 regulates inter-male aggression in mice.

    PubMed

    Sheleg, Michal; Yochum, Carrie L; Richardson, Jason R; Wagner, George C; Zhou, Renping

    2015-06-01

    The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5(-/-)) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5(-/-) mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5(-/-) mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice.

  10. Impaired osteoblast differentiation in Annexin A2- and -A5-deficient cells

    SciTech Connect

    Genetos, Damian C.; Wong, Alice; Weber, Thomas J.; Karin, Norman J.; Yellowley, Clare E.

    2014-09-15

    Annexins are a class of calcium-binding proteins with diverse functions in the regulation of lipid rafts inflammation,fibrinolysis, transcriptional programming and ion transport. Within bone, they are well-characterized as components of mineralizing matrix vesicles, although little else is known as to their function during osteogenesis. We generated annexin A2 (AnxA2)- or annexin A5 (AnxA5)-knockdown pre-osteoblasts, and asked whether proliferation or osteogenic differentiation was altered in knockdown cells, compared to vector controls. We report that DNA content, a marker of proliferation, was significantly reduced in both AnxA2 and AnxA5 knockdown cells. Alkaline phosphatase expression and staining activity were also suppressed in AnxA2- or AnxA5-knockdown after 14 days of culture. The pattern of osteogenic gene expression was altered in knockdown cells, with Col1a1 expressed more rapidly in knock-down cells, compared to controls. In contrast, Runx2, Ibsp, and Bglap all revealed decreased expression after 14 days of culture. Using a murine fracture model, we demonstrate that AnxA2 and AnxA5 are rapidly expressed within the fracture callus. These data demonstrate that AnxA2 and AnxA5 can influence bone formation via regulation of osteoprogenitor proliferation and differentiation in addition to their well-studied function in matrix vesicles.

  11. Purine derivatives as ligands for A3 adenosine receptors.

    PubMed

    Joshi, Bhalchandra V; Jacobson, Kenneth A

    2005-01-01

    Selective agonists and antagonists for A3 adenosine receptors (ARs) are being explored for the treatment of a variety of disorders, including brain and heart ischemic conditions, cancer, and rheumatoid arthritis. This review covers both the structure activity relationships of nucleoside agonist ligands and selected antagonists acting at this receptor and the routes of synthesis. Highly selective agonists have been designed, using both empirical approaches and a semi-rational approach based on molecular modeling. The prototypical A3 agonists IB-MECA 10 and the more receptor-subtype-selective Cl-IB-MECA 11, both of which have affinity in binding to the receptor of approximately 1 nM, have been used widely as pharmacological probes in the elucidation of the physiological role of this receptor. In addition to the exploration of the effects of structural modification of the adenine and ribose moieties on A3AR affinity, the effects of these structural changes on the intrinsic efficacy have also been studied in a systematic fashion. Key structural features determining A3AR interaction include the N6-benzyl group, 2-position substitution such as halo, substitution of ribose (e.g., the (N)-methanocarba ring system, various 2'- and 3'-substitutions and 4'-thio substitution of oxygen). Conformational studies of the ribose moiety and its equivalents indicate that the ring oxygen is not required and the North (N) ring conformation is preferred in binding to the A3AR. Using these observations, a series of ring constrained (N)-methanocarba 5'-uronamide derivatives was recently reported to be highly selective A3AR agonists, the most notable amongst them was MRS3558 113 having a Ki value in binding to the human A3 receptor of 0.3 nM. PMID:16305531

  12. Metabolism of aflatoxin B{sub 1} in Turkey liver microsomes: The relative roles of cytochromes P450 1A5 and 3A37

    SciTech Connect

    Rawal, Sumit; Coulombe, Roger A.

    2011-08-01

    The extreme sensitivity of turkeys to aflatoxin B{sub 1} (AFB{sub 1}) is associated with efficient epoxidation by hepatic cytochromes P450 (P450) 1A5 and 3A37 to exo-aflatoxin B{sub 1}-8,9-epoxide (exo-AFBO). The combined presence of 1A5 and 3A37, which obey different kinetic models, both of which metabolize AFB{sub 1} to the exo-AFBO and to detoxification products aflatoxin M{sub 1} (AFM{sub 1}) and aflatoxin Q{sub 1} (AFQ{sub 1}), respectively, complicates the kinetic analysis of AFB{sub 1} in turkey liver microsomes (TLMs). Antisera directed against 1A5 and 3A37, thereby individually removing the catalytic contribution of these enzymes, were used to identify the P450 responsible for epoxidating AFB{sub 1} in TLMs. In control TLMs, AFB{sub 1} was converted to exo-AFBO in addition to AFM{sub 1} and AFQ{sub 1} confirming the presence of functional 1A5 and 3A37. Pretreatment with anti-1A5 inhibited exo-AFBO formation, especially at low, submicromolar ({approx} 0.1 {mu}M), while anti-3A37, resulted in inhibition of exo-AFBO formation, but at higher (> 50 {mu}M) AFB{sub 1} concentrations. Metabolism in immunoinhibited TLMs resembled that of individual enzymes: 1A5 produced exo-AFBO and AFM{sub 1}, conforming to Michaelis-Menten, while 3A37 produced exo-AFBO and AFQ{sub 1} following the kinetic Hill equation. At 0.1 {mu}M AFB{sub 1}, close to concentrations in livers of exposed animals, 1A5 contributed to 98% of the total exo-AFBO formation. At this concentration, 1A5 accounted for a higher activation:detoxification (50:1, exo-AFBO: AFM{sub 1}) compared to 3A37 (0.15: 1, exo-AFBO: AFQ{sub 1}), suggesting that 1A5 is high, while 3A4 is the low affinity enzyme in turkey liver. The data support the conclusion that P450 1A5 is the dominant enzyme responsible for AFB{sub 1} bioactivation and metabolism at environmentally-relevant AFB{sub 1} concentrations in turkey liver. - Graphical abstract: Display Omitted Highlights: > Efficient bioactivation by P450s 1A5 and 3A4

  13. Histone H3 methylation at lysine 4 on the SLC2A5 gene in intestinal Caco-2 cells is involved in SLC2A5 expression.

    PubMed

    Inamochi, Yuko; Mochizuki, Kazuki; Osaki, Ayumi; Ishii, Takeshi; Nakayama, Tsutomu; Goda, Toshinao

    2010-01-29

    Histone H3 methylation at lysine 4 (K4) is associated with euchromatic regions and is thought to be important for the transcriptional activation of genes during differentiation. In this study, we found that di- and tri-methylation of histone H3 at K4 and acetylation of histones H3 and H4 from the promoter/enhancer to the transcribed region close to the transcription initiation site of the solute carrier family 2, member 5 (SLC2A5) gene, and its expression, were induced by differentiation of intestine-like Caco-2 cells. These effects were accompanied by contact inhibition of cell growth of these cells. Furthermore, these modifications were induced by co-treatment with a synthetic glucocorticoid hormone dexamethasone and a p44/42 mitogen-activated protein kinase inhibitor PD89059. Our results suggest that methylation of histone H3 at K4 and acetylation of histones H3 and H4 are involved in SLC2A5 gene induction associated with intestinal differentiation of Caco-2 cells.

  14. Evaluating a 5 year climate change research teacher professional development program in Southern Nevada

    NASA Astrophysics Data System (ADS)

    Buck, P.; Rudd, L.; McAlister, J.; Bonde, A.

    2013-12-01

    We present results of a 5 yr NSF funded project, part of Nevada ';s Climate Change Research Education and Outreach EPSCoR award. Goals of the K-12 portion of the project included: a replicable professional development model of K-12 climate change science education for Nevada and other institutions; strengthened relationships between secondary school teachers and NSHE climate change researchers; and greater teacher pedagogical content knowledge in climate change science and greater confidence in ability to teach effectively. Two overarching research questions formed the foundation of our teacher professional development program: 1) How will climate change affect Nevada's baseline water resources (groundwater and surface water) and linked ecosystem services? 2) How will climate change affect natural and anthropogenic disturbances (e.g., wildland fires, invasive species, and insect outbreaks)? All teachers participated in at least one (2-week long) summer institute and academic year follow up focused on one of two overarching research questions forming the basis of the award assisted by a disciplinary graduate student . An on-line class (ENV 794) was a 3 credit graduate credit bearing class from UNLV based on the fundamentals of climate change science was available free to participating teachers. A supplemental program in the final award year was added following advisory board recommendations to develop a cohort or "learning community" approach at an interested high school. The 'About Climate Change' Integrated Curriculum spans several subject areas and cuts across national standards for STEM English and Social Studies; a 2-week unit developed by Clark HS teachers for their classes. Our teachers increased their content knowledge about climate change science. This is indicated in student evaluations of the on-line course ENV 794, and in the summer institute post test of content knowledge which included about 25 questions. There was improvement for our one focus

  15. Improved innate immune responses by Frondanol A5, a sea cucumber extract, prevent intestinal tumorigenesis.

    PubMed

    Janakiram, Naveena B; Mohammed, Altaf; Bryant, Taylor; Lightfoot, Stan; Collin, Peter D; Steele, Vernon E; Rao, Chinthalapally V

    2015-04-01

    Sea cucumbers are a source of antibacterial, anti-inflammatory, and anticancer compounds. We show that sea cucumber extract Frondanol A5 is capable of enhancing innate immune responses and inhibiting intestinal tumors in APC(Min/+) mice. APC(Min/+) mice were fed semi-purified diets containing 0, 250, or 500 ppm FrondanolA5 for 14 weeks before we assessed intestinal tumor inhibition. Dietary Frondanol A5 suppressed small intestinal polyp sizes and formation up to 30% (P < 0.02) in males and up to 50% (P < 0.01) in females. Importantly, 250 and 500 ppm Frondanol A5 diet suppressed colon tumor multiplicities by 65% (P < 0.007) and 75% (P < 0.0001), compared with untreated male APC(Min/+) mice. In female APC(Min/+) mice, both dose levels of Frondanol A5 suppressed colon tumor multiplicities up to 80% (P < 0.0001). Isolated peritoneal macrophages from treated mice showed increased phagocytosis efficiency (control 24% vs. treated 50%; P < 0.01) and an increase in GILT mRNA expression, indicating increased innate immune responses by these cells in treated animals. Similarly, we observed an increase in GILT expression in treated tumors, compared with untreated tumors. Furthermore, an increase in G-CSF cytokine, a decrease in inflammatory cytokines and marker 5-LOX, its regulator FLAP, proliferation (PCNA), and angiogenesis (VEGF) markers were observed in treatment groups. These data suggest that Frondanol A5 decreased inflammatory angiogenic molecules and increased GILT expression and macrophage phagocytosis. These decreases may have improved the innate immune systems of the treated mice, thus aiding in inhibition of intestinal tumor formation. These results suggest that Frondanol A5 exhibits significant chemopreventive potential against intestinal tumorigenesis. PMID:25657017

  16. Phenothiazines inhibit S100A4 function by inducing protein oligomerization

    SciTech Connect

    Malashkevich, Vladimir N.; Dulyaninova, Natalya G.; Ramagopal, Udupi A.; Liriano, Melissa A.; Varney, Kristen M.; Knight, David; Brenowitz, Michael; Weber, David J.; Almo, Steven C.; Bresnick, Anne R.

    2010-06-22

    S100A4, a member of the S100 family of Ca{sup 2+}-binding proteins, regulates carcinoma cell motility via interactions with myosin-IIA. Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. Using a unique biosensor-based assay, trifluoperazine (TFP) was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction. To examine the interaction of S100A4 with TFP, we determined the 2.3 {angstrom} crystal structure of human Ca{sup 2+}-S100A4 bound to TFP. Two TFP molecules bind within the hydrophobic target binding pocket of Ca{sup 2+}-S100A4 with no significant conformational changes observed in the protein upon complex formation. NMR chemical shift perturbations are consistent with the crystal structure and demonstrate that TFP binds to the target binding cleft of S100A4 in solution. Remarkably, TFP binding results in the assembly of five Ca{sup 2+}-S100A4/TFP dimers into a tightly packed pentameric ring. Within each pentamer most of the contacts between S100A4 dimers occurs through the TFP moieties. The Ca{sup 2+}-S100A4/prochlorperazine (PCP) complex exhibits a similar pentameric assembly. Equilibrium sedimentation and cross-linking studies demonstrate the cooperative formation of a similarly sized S100A4/TFP oligomer in solution. Assays examining the ability of TFP to block S100A4-mediated disassembly of myosin-IIA filaments demonstrate that significant inhibition of S100A4 function occurs only at TFP concentrations that promote S100A4 oligomerization. Together these studies support a unique mode of inhibition in which phenothiazines disrupt the S100A4/myosin-IIA interaction by sequestering S100A4 via small molecule-induced oligomerization.

  17. Inhibitory Effects of Vegetable Juices on CYP3A4 Activity in Recombinant CYP3A4 and LS180 Cells.

    PubMed

    Tsujimoto, Masayuki; Uchida, Tomoe; Kozakai, Hiroyuki; Yamamoto, Saori; Minegaki, Tetsuya; Nishiguchi, Kohshi

    2016-01-01

    It is thought that eating habits induces individual variation in intestinal absorption and metabolism of drugs. The objective of this research was to clarify the influence of vegetables juices on CYP3A4 activity, which is an important enzyme in intestine. Five vegetables juices (VJ-o, Kagome Original(®); VJ-g, Kagome 30 kinds of vegetables and fruits(®); VJ-p, Kagome Purple vegetables(®); VJ-r, Kagome Sweet Tomato(®); and VJ-y, Kagome Fruity Salada(®); KAGOME Co., Ltd., Aichi, Japan) were centrifuged (1630×g, 10 min) and filtered using filter paper and 0.45-µm membrane filters. In this study, recombinant CYP3A4 and LS180 cells were used for the evaluation of CYP3A4 activity. The metabolisms to 6β-hydroxytestosterone by recombinant CYP3A4 were significantly inhibited by VJ-o, VJ-g, and VJ-y in a preincubation time-dependent manner, and CYP3A4 activity in LS180 cells were significantly inhibited by VJ-o and VJ-y. These results show that the difference in ingestion volume of vegetable juices and vegetables might partially induce individual difference in intestinal drug metabolism.

  18. Inhibitory Effects of Vegetable Juices on CYP3A4 Activity in Recombinant CYP3A4 and LS180 Cells.

    PubMed

    Tsujimoto, Masayuki; Uchida, Tomoe; Kozakai, Hiroyuki; Yamamoto, Saori; Minegaki, Tetsuya; Nishiguchi, Kohshi

    2016-01-01

    It is thought that eating habits induces individual variation in intestinal absorption and metabolism of drugs. The objective of this research was to clarify the influence of vegetables juices on CYP3A4 activity, which is an important enzyme in intestine. Five vegetables juices (VJ-o, Kagome Original(®); VJ-g, Kagome 30 kinds of vegetables and fruits(®); VJ-p, Kagome Purple vegetables(®); VJ-r, Kagome Sweet Tomato(®); and VJ-y, Kagome Fruity Salada(®); KAGOME Co., Ltd., Aichi, Japan) were centrifuged (1630×g, 10 min) and filtered using filter paper and 0.45-µm membrane filters. In this study, recombinant CYP3A4 and LS180 cells were used for the evaluation of CYP3A4 activity. The metabolisms to 6β-hydroxytestosterone by recombinant CYP3A4 were significantly inhibited by VJ-o, VJ-g, and VJ-y in a preincubation time-dependent manner, and CYP3A4 activity in LS180 cells were significantly inhibited by VJ-o and VJ-y. These results show that the difference in ingestion volume of vegetable juices and vegetables might partially induce individual difference in intestinal drug metabolism. PMID:27582329

  19. In vitro inhibition of cytochrome P450 3A4 by Aronia melanocarpa constituents.

    PubMed

    Bräunlich, Marie; Christensen, Hege; Johannesen, Siri; Slimestad, Rune; Wangensteen, Helle; Malterud, Karl E; Barsett, Hilde

    2013-01-01

    Extracts, subfractions, isolated anthocyanins and procyanidins, and two phenolic acids from aronia [Aronia melanocarpa] were investigated for their CYP3A4 inhibitory effects, using midazolam as the probe substrate and recombinant insect cell microsomes expressing CYP3A4 as the enzyme source. Procyanidin B5 was a considerably stronger CYP3A4 inhibitor in vitro than the isomeric procyanidin B2 and comparable to bergamottin, a known CYP3A4 inhibitor from grapefruit juice. The inhibitory activity of proanthocyanidin-containing fractions was correlated to the degree of polymerization. Among the anthocyanins, cyanidin 3-arabinoside showed stronger CYP3A4 inhibition than cyanidin 3-galactoside and cyanidin 3-glucoside. Thus, the ability to inhibit CYP3A4 in vitro seems to be influenced by the sugar unit linked to the anthocyanidin.

  20. Precursor protein of Alzheimer's disease A4 amyloid is encoded by 16 exons

    SciTech Connect

    Lemaire, H.G.; Kang, J.; Mueller-Hill, B. ); Salbaum, J.M.; Multhaup, G.; Beyreuther, K. ); Bayney, R.M.; Unterbeck, A. )

    1989-01-25

    Alzheimer's disease (AD) is characterized by the cerebral deposition of fibrillar aggregates of the amyloid A4 protein. Complementary DNA's coding for the precursor of the amyloid A4 protein have been described. In order to identify the structure of the precursor gene relevant clones from several human genomic libraries were isolated. Sequence analysis of the various clones revealed 16 exons to encode the 695 residue precursor protein (PreA4{sub 695}) of Alzheimer's disease amyloid A4 protein. The DNA sequence coding for the amyloid A4 protein is interrupted by an intron. This finding supports the idea that amyloid A4 protein arises by incomplete proteolysis of a larger precursor, and not by aberrant splicing.

  1. 4-Coumaroyl coenzyme A 3-hydroxylase activity from cell cultures of Lithospermum erythrorhizon and its relationship to polyphenol oxidase.

    PubMed

    Wang, Z X; Li, S M; Löscher, R; Heide, L

    1997-11-15

    A 4-coumaroyl-CoA 3-hydroxylase activity was purified 4600-fold from cell cultures of Lithospermum erythrorhizon. The enzyme showed a molecular mass of 42,400 +/- 1700 Da in gel chromatography and required ascorbate, NADH, or NADPH as cofactors. 4-Coumaroyl-CoA, 4-coumarate, p-cresol, and several other phenolic substances, but not tyrosine, were accepted as substrates for the hydroxylation. Besides hydroxylase activity, the enzyme showed diphenol oxidase activity. Both activities were inhibited by diethyldithiocarbamate or beta-mercaptoethanol, although at different concentrations. The enzyme showed striking similarity to a 4-coumaroyl-glucose 3-hydroxylase from sweet potato (Ipomoe batatas) roots, which has reportedly been purified to homogeneity and identified as a specific enzyme of chlorogenic acid biosynthesis. Close examination and comparison to a commercially available polyphenol oxidase, however, suggest that the enzyme activities purified from both Lithospermum and sweet potato are polyphenol oxidases rather than specific enzymes of secondary metabolism. PMID:9367532

  2. Mutations in ALDH1A3 cause microphthalmia.

    PubMed

    Aldahmesh, M A; Khan, A O; Hijazi, H; Alkuraya, F S

    2013-08-01

    Microphthalmia is an important inborn error of eye development that can be associated with multisystem involvement. Anophthalmia is more severe and rarer. Single mutations in an expanding list of genes are known to cause this spectrum of anomaly. In one branch of a multiplex family with microphthalmia and anophthalmia, autozygome analysis excluded all known microphthalmia genes at the time of doing this study. Exome sequencing and autozygome filtration identified a novel homozygous variant in ALDH1A3. Subsequently, we identified another homozygous variant in 2 of the 10 probands with microphthalmia we specifically screened for mutations in ALDH1A3. Interestingly, the other branch of the original family was found to segregate anophthalmia/syndactyly with a novel homozygous SMOC1 variant. Our data support the very recent and independent identification of ALDH1A3 as a disease gene in microphthalmia. Locus heterogeneity should be considered in consanguineous families even for extremely rare phenotypes.

  3. Water tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A water tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen water, liquid oxygen (LOX) and isopropyl alcohol (IPA) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  4. Liquid oxygen tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A liquid oxygen (LOX) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen LOX, isopropyl alcohol (IPA) and water tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  5. Isopropyl alcohol tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    An isopropyl alcohol (IPA) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen IPA, water and liquid oxygen (LOX) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  6. 26 CFR 1.408A-4 - Converting amounts to Roth IRAs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the valuation methods in § 1.408A-4T (as it appeared in the April 1, 2008, edition of 26 CFR part 1... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Converting amounts to Roth IRAs. 1.408A-4... TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.408A-4...

  7. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., transfers, and buybacks. (10) Vesting. (11) Crediting service. (12) Governmental plans. (13) Employee stock... (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table of contents. This section contains a listing of the major headings of §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. §...

  8. Role of A3 adenosine receptor in diabetic neuropathy.

    PubMed

    Yan, Heng; Zhang, Enshui; Feng, Chang; Zhao, Xin

    2016-10-01

    Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc.

  9. Changes in attack behavior and activity in EphA5 knockout mice.

    PubMed

    Mamiya, Ping Chao; Hennesy, Zach; Zhou, Renping; Wagner, George C

    2008-04-18

    During development, Eph tyrosine kinase receptors and their ephrin ligands function as axon guidance molecules while, in adults, these molecules appear to be involved in the regulation of neural plasticity and emotion. The absence of EphA5 receptor mediated forward signaling may cause alterations in connectivity of neural networks and boundary formation during development, including central monoaminergic systems. In the present studies, we demonstrated altered aggressive responses by animals lacking functional EphA5 receptors. These behavioral changes were accompanied by altered concentrations of serotonin (5-HT) and the metabolite, 5-HIAA, in the hypothalamus. The changes of serotonin activity in hypothalamus also result in increase of body weight in EphA5 knockout mice. Furthermore, EphA5 knockout mice exhibited a significant decrease in activity levels following exposure to naïve intruders in their home cages. We conclude that the EphA5 receptor may be involved in mediation of aggressive behavior regulated, in part, by hypothalamic serotonin. PMID:18353288

  10. Description and Operation of the A3 Subscale Facility

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.; Varner, D. G.; Grover, J. B.

    2010-01-01

    The purpose of this paper is to give an overview of the general design and operation of the A3 Subscale test facility. The goal is to provide the reader with a general understanding of what the major facility systems are, where they are located, and how they are used to meet the objectives supporting the design of the A3 altitude rocket test facility. This paper also provides the reader with the background information prior to reading the subsequent papers detailing the design and test results of the various systems described herein.

  11. Cooperative binding of Annexin A5 to phosphatidylserine on apoptotic cell membranes

    NASA Astrophysics Data System (ADS)

    Janko, Christina; Jeremic, Ivica; Biermann, Mona; Chaurio, Ricardo; Schorn, Christine; Muñoz, Luis E.; Herrmann, Martin

    2013-12-01

    Healthy cells exhibit an asymmetric plasma membrane with phosphatidylserine (PS) located on the cytoplasmic leaflet of the plasma membrane bilayer. Annexin A5-FITC, a PS binding protein, is commonly used to evaluate apoptosis in flow cytometry. PS exposed by apoptotic cells serves as a major ‘eat-me’ signal for phagocytes. Although exposition of PS has been observed after alternative stimuli, no clearance of viable, PS exposing cells has been detected. Thus, besides PS exposure, membranes of viable and apoptotic cells might exhibit specific characteristics. Here, we show that Annexin A5 binds in a cooperative manner to different types of dead cells. Shrunken apoptotic cells thereby showed the highest Hill coefficient values. Contrarily, parafomaldehyde fixation of apoptotic cells completely abrogates the cooperativity effect seen with dead and dying cells. We tend to speculate that the cooperative binding of Annexin A5 to the membranes of apoptotic cells reflects higher fluidity of the exposed membranes facilitating PS clustering.

  12. Ephrin-A5 promotes bovine muscle progenitor cell migration before mitotic activation.

    PubMed

    Li, J; Johnson, S E

    2013-03-01

    Satellite cells are the resident stem cell population of adult skeletal muscle tissue that is responsible for growth and regeneration. The cells typically congregate near the tips of the muscle fibers and in close proximity to the neural muscular junction (NMJ). Ephrin-A5 is a chemotactic molecule that participates in the correct positioning and formation of the NMJ. The objective of the experiment was to examine the effects of ephrin-A5 signaling on bovine satellite cell (BSC) biology. Primary cultures of BSC demonstrate changes in velocity with time in culture that is unique to the Paired box protein 7 (Pax7):Myogenic factor 5 (Myf5) subpopulation. Treatment of the BSC with ephrin-A5 causes a reduction (P < 0.05) in velocity with a concomitant increase (P < 0.05) in directed migration. The chemoattractant properties of ephrin-A5 occur before myogenic differentiation 1 (MyoD) expression in the myogenic precursors and are abrogated after their differentiation to committed myoblasts. Ephrin-A5 induced migration appears to require components of the Ras homolog gene family member A (RhoA) and Rho-associated protein kinase (ROCK) signaling machinery. Supplementation of culture media with a chemical ROCK inhibitor suppressed (P < 0.05) ephrin-A5 initiated BSC migration. These results contrast with treatment of BSC with hepatocyte growth factor (HGF), a key modulator of myogenic and motogenic activity. Treatment of BSC with HGF had no effect on cell motility or migration immediately after culture establishment. Twenty-four hours after culture establishment, BSC demonstrated an increase (P < 0.05) in transwell migration toward HGF. These results document that temporal and spatial gradients of chemokines and growth factors participate in the localization of BSC within the niche.

  13. Evaluation of annexin A5 as a biomarker for Alzheimer's disease and dementia with lewy bodies

    PubMed Central

    Sohma, Hitoshi; Imai, Shin-ichi; Takei, Norio; Honda, Hirohito; Matsumoto, Kyoichi; Utsumi, Kumiko; Matsuki, Kayo; Hashimoto, Eri; Saito, Toshikazu; Kokai, Yasuo

    2013-01-01

    Background: Alzheimer's disease (AD) differs from other forms of dementia in its relation to amyloid beta peptide (Aβ42). Using a cell culture model we previously identified annexin A5, a Ca2+, and phospholipid binding protein, as an AD biomarker. Plasma level of annexin A5 was significantly higher in AD patients compared to that in a control group. On the other hand, AD has been identified to share a number of clinical and pathological features with Dementia with Lewy bodies (DLB). The present study was done to examine whether or not plasma annexin A5 is a specific marker for AD, when being compared with the levels of DLB patients. As Apolipoprotein E (ApoE) gene subtype ε4 (ApoE-ε4) has been noticed as the probable genetic factor for AD, we also examined and compared ApoE genotype in both AD and DLB. Methods: Blood samples were obtained from 150 patients with AD (aged 77.6 ± 6.5 years), 50 patients of DLB (79.4 ± 5.0) and 279 community-dwelling healthy elderly individuals of comparable age and sex (75.6 ± 8.1). All AD patients met NINCDS-ADRDA criteria and all DLB patients were diagnosed as probable DLB according to the latest consensus diagnostic criteria. Quantification was done using the Chemiluminescent Enzyme Immunoassay (CLEIA) Technique (SphereLight assay) using the monoclonal antibodies against annexin A5. DNA genotyping of ApoE was performed by distinguishing unique combinations of Hha1 fragments of PCR-amplified genomic DNA products. Results: The plasma level of annexin A5 was significantly higher in AD patients than in the healthy individuals (control) (P < 0.0001). The plasma annexin A5 level was also significantly higher in DLB patients than in the control group (P < 0.0001). From the ROC curves with plasma annexin A5 concentrations, the mean areas under the curve were 0.863 and 0.838 for the AD/control and DLB/control, respectively. The rate of ApoE4 carrier status and the frequency of the ε4 allele were significantly higher in AD or DLB than

  14. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory

    PubMed Central

    Park, Alan J.; Tolentino, Rosa E.; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Lee, Yool; Hansen, Rolf T.; Guercio, Leonardo A.; Linton, Edward; Neves-Zaph, Susana R.; Meerlo, Peter; Baillie, George S.; Houslay, Miles D.

    2016-01-01

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular

  15. Metastasis-Inducing S100A4 and RANTES Cooperate in Promoting Tumor Progression in Mice

    PubMed Central

    Forst, Birgitte; Hansen, Matilde Thye; Klingelhöfer, Jörg; Møller, Henrik Devitt; Nielsen, Gitte Helle; Grum-Schwensen, Birgitte; Ambartsumian, Noona; Lukanidin, Eugene; Grigorian, Mariam

    2010-01-01

    Background The tumor microenvironment has been described as a critical milieu determining tumor growth and metastases. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. However, the events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved. Methodology/Principal Findings We studied the interplay between the tumor cell-derived cytokine regulated-upon-activation, normal T-cell expressed and secreted (RANTES; CCL5) and S100A4 which were shown to be critical factors in tumor progression. We found that RANTES stimulates the externalization of S100A4 via microparticle shedding from the plasma membrane of tumor and stroma cells. Conversely, the released S100A4 protein induces the upregulation of fibronectin (FN) in fibroblasts and a number of cytokines, including RANTES in tumor cells as well as stimulates cell motility in a wound healing assay. Importantly, using wild type and S100A4-deficient mouse models, we demonstrated a substantial influence of tumor cell-derived RANTES on S100A4 release into blood circulation which ultimately increases the metastatic burden in mice. Conclusions/Significance Altogether, the data presented strongly validate the pro-metastatic function of S100A4 in the tumor microenvironment and define how the tumor cell-derived cytokine RANTES acts as a critical regulator of S100A4-dependent tumor cell dissemination. Additionally, for the first time we demonstrated the mechanism of S100A4 release associated with plasma membrane microparticle shedding from various cells types. PMID:20442771

  16. 29 CFR 1912a.3 - Terms of membership.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for...

  17. 17 CFR 275.203A-3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... adviser: (i) Who has more than five clients who are natural persons (other than excepted persons described in paragraph (a)(3)(i) of this section); and (ii) More than ten percent of whose clients are natural... communicate with clients of the investment adviser; or (ii) Provides only impersonal investment advice....

  18. ALDH1A3 mutations cause recessive anophthalmia and microphthalmia.

    PubMed

    Fares-Taie, Lucas; Gerber, Sylvie; Chassaing, Nicolas; Clayton-Smith, Jill; Hanein, Sylvain; Silva, Eduardo; Serey, Margaux; Serre, Valérie; Gérard, Xavier; Baumann, Clarisse; Plessis, Ghislaine; Demeer, Bénédicte; Brétillon, Lionel; Bole, Christine; Nitschke, Patrick; Munnich, Arnold; Lyonnet, Stanislas; Calvas, Patrick; Kaplan, Josseline; Ragge, Nicola; Rozet, Jean-Michel

    2013-02-01

    Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.

  19. 26 CFR 48.4161(a)-3 - Parts and accessories.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-3 Parts and... the specified article, or be designed to directly improve the performance of the specified article, or... it is neither essential to the use of the rod, nor does it in any way improve its performance...

  20. 26 CFR 48.4161(a)-3 - Parts and accessories.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-3 Parts and... the specified article, or be designed to directly improve the performance of the specified article, or... it is neither essential to the use of the rod, nor does it in any way improve its performance...

  1. 26 CFR 48.4161(a)-3 - Parts and accessories.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-3 Parts and... the specified article, or be designed to directly improve the performance of the specified article, or... it is neither essential to the use of the rod, nor does it in any way improve its performance...

  2. 26 CFR 48.4161(a)-3 - Parts and accessories.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-3 Parts and... the specified article, or be designed to directly improve the performance of the specified article, or... it is neither essential to the use of the rod, nor does it in any way improve its performance...

  3. A 3D Serious City Building Game on Waste Disposal

    ERIC Educational Resources Information Center

    Cuccurullo, Stefania; Francese, Rita; Passero, Ignazio; Tortora, Genoveffa

    2013-01-01

    The environmental priority requires structural interventions that will be effective in the long period only if they are accompanied by modifications of behaviors, orientations and beliefs, specially investing in the new generations. This paper presents a 3D Virtual World serious game named Pappi World, designed according to pedagogical theories…

  4. Development of a 3D digitizer for breast surgery procedures

    NASA Astrophysics Data System (ADS)

    Rodriguez-Larena, Jorge; Canal Bienzobas, Fernando

    1999-03-01

    The planning of a breast reconstruction surgical operation has to resolve the problem of measuring directly on the patient meaningful anthropometric points from which distances, areas and volumes have to be calculated. In this paper, we propose using a 3D optical digitizer to perform this task.

  5. Interferometer using a 3 × 3 coupler and Faraday mirrors

    NASA Astrophysics Data System (ADS)

    Breguet, J.; Gisin, N.

    1995-06-01

    A new interferometric setup using a 3 \\times 3 coupler and two Faraday mirrors is presented. It has the advantages of being built only with passive components, of freedom from the polarization fading problem, and of operation with a LED. It is well suited for sensing time-dependent signals and does not depend on reciprocal or nonreciprocal constant perturbations.

  6. Congenital aganglionosis in a 3-day-old Holstein calf

    PubMed Central

    2005-01-01

    Abstract Necropsy of a 3-day-old Holstein heifer revealed proximal megacolon and distal colorectal hypoplasia. Histologically, the hypoplastic distal colon and rectum lacked submucosal and myenteric ganglia. Clinical history, physical examination, and pathologic findings were consistent with intestinal aganglionosis, a congenital anomaly well documented in humans and foals but not previously reported in cattle. PMID:15943121

  7. Controlled teleportation of a 3-dimensional bipartite quantum state

    NASA Astrophysics Data System (ADS)

    Cao, Hai-Jing; Chen, Zhong-Hua; Song, He-Shan

    2008-07-01

    A controlled teleportation scheme of an unknown 3-dimensional (3D) two-particle quantum state is proposed, where a 3D Bell state and 3D GHZ state function as the quantum channel. This teleportation scheme can be directly generalized to teleport an unknown d-dimensional bipartite quantum state.

  8. Remote sensing for oceanography, hydrology and agriculture; Proceedings of Symposia A5, A3 and A9 of the COSPAR 29th Plenary Meeting, Washington, Aug. 28-Sept. 5, 1992

    NASA Technical Reports Server (NTRS)

    Gower, J. F. R. (Editor); Salomonson, V. V. (Editor); Engman, E. T. (Editor); Ormsby, J. P. (Editor); Gupta, R. K. (Editor)

    1993-01-01

    New results from satellite studies of the ocean and radar mapping of the earth are presented. Atttention is given to data from the ERS-1 satellite. Synthetic aperture radar mapping of land surface features and sea ice, radar backscatter measurements, and orbit altitude measurements are discussed. The use of remote sensing in hydrology, soil moisture determination, precipitation measurement, agricultural meteorology, and crop growth estimation is reviewed.

  9. Sperry versus Hebb: Topographic mapping in Isl2/EphA3 mutant mice

    PubMed Central

    2010-01-01

    Background In wild-type mice, axons of retinal ganglion cells establish topographically precise projection to the superior colliculus of the midbrain. This means that axons of neighboring retinal ganglion cells project to the proximal locations in the target. The precision of topographic projection is a result of combined effects of molecular labels, such as Eph receptors and ephrins, and correlated neural activity. In the Isl2/EphA3 mutant mice the expression levels of molecular labels are changed. As a result the topographic projection is rewired so that the neighborhood relationships between retinal cell axons are disrupted. Results Here we study the computational model for retinocollicular connectivity formation that combines the effects of molecular labels and correlated neural activity. We argue that the effects of correlated activity presenting themselves in the form of Hebbian learning rules can facilitate the restoration of the topographic connectivity even when the molecular labels carry conflicting instructions. This occurs because the correlations in electric activity carry information about retinal cells' origin that is independent on molecular labels. We argue therefore that partial restoration of the topographic property of the retinocollicular projection observed in Isl2/EphA3 heterozygous knockin mice may be explained by the effects of correlated neural activity. We address the maps observed in Isl2/EphA3 knockin/EphA4 knockout mice in which the levels of retinal labels are uniformly reduced. These maps can be explained by either the saturation of EphA receptor mapping leading to the relative signaling model or by the reverse signaling conveyed by ephrin-As expressed by retinal axons. Conclusion According to our model, experiments in Isl2/EphA3 knock-in mice test the interactions between effects of molecular labels and correlated activity during the development of neural connectivity. Correlated activity can partially restore topographic order even

  10. Assessment of Left Ventricular Function in Cardiac MSCT Imaging by a 4D Hierarchical Surface-Volume Matching Process

    PubMed Central

    Simon, Antoine; Boulmier, Dominique; Coatrieux, Jean-Louis; Le Breton, Hervé

    2006-01-01

    Multislice computed tomography (MSCT) scanners offer new perspectives for cardiac kinetics evaluation with 4D dynamic sequences of high contrast and spatiotemporal resolutions. A new method is proposed for cardiac motion extraction in multislice CT. Based on a 4D hierarchical surface-volume matching process, it provides the detection of the heart left cavities along the acquired sequence and the estimation of their 3D surface velocity fields. A Markov random field model is defined to find, according to topological descriptors, the best correspondences between a 3D mesh describing the left endocardium at one time and the 3D acquired volume at the following time. The global optimization of the correspondences is realized with a multiresolution process. Results obtained on simulated and real data show the capabilities to extract clinically relevant global and local motion parameters and highlight new perspectives in cardiac computed tomography imaging. PMID:23165027

  11. Compliance analysis of a 3-DOF spindle head by considering gravitational effects

    NASA Astrophysics Data System (ADS)

    Li, Qi; Wang, Manxin; Huang, Tian; Chetwynd, Derek G.

    2015-01-01

    The compliance modeling is one of the most significant issues in the stage of preliminary design for parallel kinematic machine(PKM). The gravity ignored in traditional compliance analysis has a significant effect on pose accuracy of tool center point(TCP) when a PKM is horizontally placed. By taking gravity into account, this paper presents a semi-analytical approach for compliance analysis of a 3-DOF spindle head named the A3 head. The architecture behind the A3 head is a 3-R PS parallel mechanism having one translational and two rotational movement capabilities, which can be employed to form the main body of a 5-DOF hybrid kinematic machine especially designed for high-speed machining of large aircraft components. The force analysis is carried out by considering both the externally applied wrench imposed upon the platform as well as gravity of all moving components. Then, the deflection analysis is investigated to establish the relationship between the deflection twist and compliances of all joints and links using semi-analytical method. The merits of this approach lie in that platform deflection twist throughout the entire task workspace can be evaluated in a very efficient manner. The effectiveness of the proposed approach is verified by the FEA and experiment at different configurations and the results show that the discrepancy of the compliances is less than 0.04 μm/N-1 and that of the deformations is less than 10μm. The computational and experimental results show that the deflection twist induced by gravity forces of the moving components has significant bearings on pose accuracy of the platform, providing an informative guidance for the improvement of the current design. The proposed approach can be easily applied to the compliance analysis of PKM by considering gravitational effects and to evaluate the deformation caused by gravity throughout the entire workspace.

  12. Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.

    PubMed

    Li, Lei; Jia, Kunzhi; Zhou, Xin; McCallum, Sarah E; Hough, Lindsay B; Ding, Xinxin

    2013-12-01

    Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.

  13. Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.

    PubMed

    Li, Lei; Jia, Kunzhi; Zhou, Xin; McCallum, Sarah E; Hough, Lindsay B; Ding, Xinxin

    2013-12-01

    Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans. PMID:24045421

  14. 26 CFR 31.6011(a)-4 - Returns of income tax withheld.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Returns of income tax withheld. 31.6011(a)-4...) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT... Subtitle F, Internal Revenue Code of 1954) § 31.6011(a)-4 Returns of income tax withheld. (a) Withheld...

  15. 26 CFR 31.6011(a)-4 - Returns of income tax withheld.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Returns of income tax withheld. 31.6011(a)-4...) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT... Subtitle F, Internal Revenue Code of 1954) § 31.6011(a)-4 Returns of income tax withheld. (a) Withheld...

  16. 26 CFR 1.401(a)(4)-7 - Imputation of permitted disparity.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-7... under the plan satisfies the alternative safe harbor for flat benefit plans under § 1.401(a)(4)-3(b)(4... not covered by any of the taxes under section 3111(a), section 3221, or section 1401. (3)...

  17. 26 CFR 1.509(a)-4T - Supporting organizations (temporary).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Supporting organizations (temporary). 1.509(a)-4T... organizations (temporary). (a) through (i)(5)(ii)(A) For further guidance, see § 1.509(a)-4(a) through (i)(5)(ii... of the supporting organization's adjusted net income (as determined by applying the principles...

  18. 26 CFR 1.401(a)(4)-6 - Contributory defined benefit plans.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... § 1.401(a)(4)-6 Contributory defined benefit plans. (a) Introduction. This section provides rules... of § 1.401(a)(4)-1(b)(2). Paragraph (b) of this section provides rules for determining the amount of.... Paragraph (c) of this section provides the exclusive rules for determining whether a contributory DB...

  19. 26 CFR 20.2032A-4 - Method of valuing farm real property.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Method of valuing farm real property. 20.2032A-4 Section 20.2032A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Gross...

  20. 26 CFR 20.2032A-4 - Method of valuing farm real property.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Method of valuing farm real property. 20.2032A-4 Section 20.2032A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Gross Estate §...