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Sample records for a3 a4 a5

  1. Nigellamines A3, A4, A5, and C, new dolabellane-type diterpene alkaloids, with lipid metabolism-promoting activities from the Egyptian medicinal food black cumin.

    PubMed

    Morikawa, Toshio; Xu, Fengming; Ninomiya, Kiyofumi; Matsuda, Hisashi; Yoshikawa, Masayuki

    2004-04-01

    New dolabellane-type diterpene alkaloids, nigellamines A(3), A(4), A(5), and C, were isolated from the methanolic extract of an Egyptian medicinal food, black cumin (the seeds of Nigella sativa). Their absolute configurations were determined on the basis of chemical and physicochemical evidence. Nigellamines were found to lower triglyceride levels in primary cultured mouse hepatocytes, and in particular, the activity of nigellamine A(5) was equivalent to that of the hypolipidemic agent, clofibrate.

  2. The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine.

    PubMed

    Topletz, Ariel R; Dennison, Jennifer B; Barbuch, Robert J; Hadden, Chad E; Hall, Stephen D; Renbarger, Jamie L

    2013-09-01

    Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b5 (CYP3A4+b5) and CYP3A5+b5, the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 μM, respectively, but the Vmax of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b5 and CYP3A5+b5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

  3. Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus

    PubMed Central

    Štabuc-Šilih, Mirna; Ravnik-Glavač, Metka; Glavač, Damjan; Hawlina, Marko

    2009-01-01

    Purpose Alterations in collagen type IV, alpha-3 (COL4A3) and collagen type IV, alpha-4 (COL4A4) genes may be responsible for a decrease in collagen types I and III, a feature often detected in keratoconus (KC). To evaluate the significance of alterations in COL4A3 and COL4A4 genes in KC patients, we screened both genes and estimated the significance of polymorphisms in Slovenian patients with KC. Methods The study included 104 unrelated patients with KC and 157 healthy blood donors. Diagnosis was established by clinical examination, electronic refractometry, and keratometry. DNA was extracted from blood, and gene exons were amplified by PCR. Non-isotopic high-resolution single-stranded conformation analysis (SSCA) was used to screen COL4A3 and COL4A4 genes, and migration shifts detected by SSCA were subsequently sequenced. For statistical evaluation, control blood donors were chosen according to age, sex, and not having blood relationship. Neither patients nor control blood donors chosen for statistical analysis were in blood relationship. We used Fisher’s exact test for statistical evaluation, with p<0.05 considered significant. Results We detected eight polymorphisms in the COL4A3 gene and six in the COL4A4 gene. Allele differences in D326Y in COL4A3 and M1237V and F1644F in COL4A4 are significantly distinctive of KC patients (Fisher’s exact test, p<0.05). When analyzing different genotypes under three models (dominant, recessive, and additive), we established that P141L, D326Y, and G895G in COL4A3 and P482S, M1327V, V1516V, and F1644F in COL4A4 have significant differences in genotype distribution between KC patients and the control group. Conclusions This is the first mutational screening of COL4A3 and COL4A4 genes in KC patients to establish the status of these genes and compare them to a control population. Analysis of COL4A3 and COL4A4 revealed no mutations related to KC patients, but specific genotypes of seven previously described polymorphisms are

  4. SPR and electrochemical analyses of interactions between CYP3A4 or 3A5 and cytochrome b5

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

    The combination of SPR biosensor with electrochemical analysis was used for the study of protein-protein interaction between cytochromes CYP3A4 or 3А5 and cytochromes b5: the microsomal, mitochondrial forms of this protein, and 2 ≪chimeric≫ proteins. Kinetic constants of CYP3A4 and CYP3А5 complex formation with cytochromes b5 were determined by the SPR biosensor. Essential distinction between CYP3A4 and CYP3A5 was observed upon their interactions with mitochondrial cytochrome b5. The electrochemical analysis of CYP3A4, CYP3A5, and cytochromes b5 immobilized on screen printed graphite electrodes modified with membranous matrix revealed that these proteins have very close reduction potentials -0.435 to -0.350 V (vs. Ag/AgCl).

  5. Catalytic function of avian cytochrome P450 1A4 and 1A5 (CYP1A4 and CYP1A5) enzymes heterologously expressed using in vitro yeast system.

    PubMed

    Kubota, Akira; Iwata, Hisato; Kim, Eun-Young

    2008-07-01

    The present study clarifies the enzymatic properties of two avian cytochrome P4501A (CYP1A) paralogs, CYP1A4 and 1A5, using a yeast-based vector system. Recombinant CYP1A4 and 1A5 proteins from common cormorant (Phalacrocorax carbo) were expressed in yeast cells, and showed typical reduced CO-difference spectra with a peak at 446 nm. Kinetic analysis of O-dealkylase of methoxy-, ethoxy-, pentoxy- and benzyloxyresorufin catalyzed by the CYP1A enzymes revealed that Vmax value for ethoxyresorufin-O-deethylase (EROD) activity was much higher than that for the other three O-dealkylase activities for both isozymes. Interestingly, remarkable substrate specificity of the CYP1As was observed for O-dealkylation of benzyloxyresorufin and methoxyresorufin; CYP1A4 was highly specific for catalyzing benzyloxyresorufin-O-debenzylase activity, whereas CYP1A5 was more efficient in catalyzing methoxyresorufin-O-demethylase activity. The present study also measured CYP1A-dependent EROD activity in the presence of 2,3,7,8-tetrachlorodibenzofuran (TCDF) to evaluate the ability of this dioxin-like congener to inhibit the EROD activity. One hundred nanomolar TCDF noncompetitively inhibited CYP1A5-dependent EROD activity, although no inhibitory effect was detected for CYP1A4-dependent EROD activity. These results indicate that the avian CYP1A paralogs have different affinities for substrate and inhibitor, thus suggesting their distinct physiological and toxicological roles.

  6. Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia.

    PubMed

    Singh, Anju; Rahman, Tabassum; Bartiss, Rose; Arabshahi, Alireza; Prasain, Jeevan; Barnes, Stephen; Musteata, Florin Marcel; Sellati, Timothy J

    2017-02-01

    Respiratory infection with Francisella tularensis (Ft) is characterized by a muted, acute host response, followed by sepsis-like syndrome that results in death. Infection with Ft establishes a principally anti-inflammatory environment that subverts host-cell death programs to facilitate pathogen replication. Although the role of cytokines has been explored extensively, the role of eicosanoids in tularemia pathogenesis is not fully understood. Given that lipoxin A4 (LXA4) has anti-inflammatory properties, we investigated whether this lipid mediator affects host responses manifested early during infection. The addition of exogenous LXA4 inhibits PGE2 release by Ft-infected murine monocytes in vitro and diminishes apoptotic cell death. Tularemia pathogenesis was characterized in 5‑lipoxygenase-deficient (Alox5(-/-)) mice that are incapable of generating LXA4 Increased release of proinflammatory cytokines and chemokines, as well as increased apoptosis, was observed in Alox5(-/-) mice as compared with their wild-type counterparts. Alox5(-/-) mice also exhibited elevated recruitment of neutrophils during the early phase of infection and increased resistance to lethal challenge. Conversely, administration of exogenous LXA4 to Alox5(-/-) mice made them more susceptible to infection thus mimicking wild-type animals. Taken together, our results suggest that 5-LO activity is a critical regulator of immunopathology observed during the acute phase of respiratory tularemia, regulating bacterial burden and neutrophil recruitment and production of proinflammatory modulators and increasing morbidity and mortality. These studies identify a detrimental role for the 5-LO-derived lipid mediator LXA4 in Ft-induced immunopathology. Targeting this pathway may have therapeutic benefit as an adjunct to treatment with antibiotics and conventional antimicrobial peptides, which often have limited efficacy against intracellular bacteria. © Society for Leukocyte Biology.

  7. 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.

  8. Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells.

    PubMed

    Defourny, Jean; Poirrier, Anne-Lise; Lallemend, François; Mateo Sánchez, Susana; Neef, Jakob; Vanderhaeghen, Pierre; Soriano, Eduardo; Peuckert, Christiane; Kullander, Klas; Fritzsch, Bernd; Nguyen, Laurent; Moonen, Gustave; Moser, Tobias; Malgrange, Brigitte

    2013-01-01

    Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.

  9. 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

  10. Specificity of the hepatitis C virus NS3 serine protease: effects of substitutions at the 3/4A, 4A/4B, 4B/5A, and 5A/5B cleavage sites on polyprotein processing.

    PubMed Central

    Kolykhalov, A A; Agapov, E V; Rice, C M

    1994-01-01

    Cleavage at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5B) in the hepatitis C virus polyprotein requires a viral serine protease activity residing in the N-terminal one-third of the NS3 protein. Sequence comparison of the residues flanking these cleavage sites reveals conserved features including an acidic residue (Asp or Glu) at the P6 position, a Cys or Thr residue at the P1 position, and a Ser or Ala residue at the P1' position. In this study, we used site-directed mutagenesis to assess the importance of these and other residues for NS3 protease-dependent cleavages. Substitutions at the P7 to P2' positions of the 4A/4B site had varied effects on cleavage efficiency. Only Arg at the P1 position or Pro at P1' substantially blocked processing at this site. Leu was tolerated at the P1 position, whereas five other substitutions allowed various degrees of cleavage. Substitutions with positively charged or other hydrophilic residues at the P7, P3, P2, and P2' positions did not reduce cleavage efficiency. Five substitutions examined at the P6 position allowed complete cleavage, demonstrating that an acidic residue at this position is not essential. Parallel results were obtained with substrates containing an active NS3 protease domain in cis or when the protease domain was supplied in trans. Selected substitutions blocking or inhibiting cleavage at the 4A/4B site were also examined at the 3/4A, 4B/5A, and 5A/5B sites. For a given substitution, a site-dependent gradient in the degree of inhibition was observed, with a 3/4A site being least sensitive to mutagenesis, followed by the 4A/4B, 4B/5A, and 5A/5B sites. In most cases, mutations abolishing cleavage at one site did not affect processing at the other serine protease-dependent sites. However, mutations at the 3/4A site which inhibited cleavage also interfered with processing at the 4B/5A site. Finally, during the course of these studies an additional NS3 protease-dependent cleavage site has been identified in the NS4B

  11. 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.

  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. 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.

  14. 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

  15. Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients.

    PubMed

    Żochowska, Dorota; Wyzgał, Janusz; Pączek, Leszek

    2012-01-01

    Calcineurin inhibitor (cyclosporine, CsA) and mTOR inhibitors (sirolimus, SRL) - immunosuppressants used to prevent allograft rejection after renal transplantation - have a narrow therapeutic index and show considerable inter-individual pharmacokinetic differences. Differences in expression and activity of cytochrome P450 (CYP) 3A4 and 3A5 affect these pharmacokinetics; cytochrome activity differences are associated with CYP genetic polymorphisms. This study evaluated the effects of polymorphisms in CYP3A4 and CYP3A5 on immunosuppressive drug-dose adjusted trough blood concentrations. One hundred renal transplant recipients were genotyped for CYP3A4*1B and CYP3A5*3 using PCR-RFLP. Blood concentrations of CsA and SRL were determined by EMIT and HPLC/UV, respectively. The allelic frequencies of CYP3A4*1B and CYP3A5*3 in the study group were 2.5% and 96.5%, respectively. The mean cyclosporine dose in CYP3A4*1/*1B subjects was 455.04±128.68 mg/day vs. 261.68±64.72 mg/day in CYP3A4*1/*1 subjects (p<0.001). The mean cyclosporine dose-adjusted trough blood concentrations (ng/ml per mg/kg body weight) in CYP3A4*1/*1B subjects were lower than in the CYP3A4*1/*1 group (37.06±10.38 vs. 44.63±13.99; p<0.218). The mean cyclosporine dose in CYP3A5*1/*3 subjects was 400.65±164.97 mg/day vs. 263.52±64.39 mg/day in CYP3A5*3/*3 subjects (p<0.022). No association was detected between sirolimus trough blood concentration (C0) or dose requirement, and CYP3A4 or CYP3A5 genotype. Genetic polymorphisms in CYP3A4 and CYP3A5 may underlie inter-individual differences in cyclosporine pharmacokinetics after renal transplantation. Patients with at least 1 functional CYP3A5*1 or CYP3A4*1B allele require significantly higher doses of cyclosporine to reach target drug levels compared to patients with the CYP3A4*1 or CYP3A5*3 alleles.

  16. Is there a regional difference in morphology interpretation of A3 and A4 fractures among different cultures?

    PubMed

    Schroeder, Gregory D; Kepler, Christopher K; Koerner, John D; Chapman, Jens R; Bellabarba, Carlo; Oner, F Cumhur; Reinhold, Max; Dvorak, Marcel F; Aarabi, Bizhan; Vialle, Luiz; Fehlings, Michael G; Rajasekaran, Shanmuganathan; Kandziora, Frank; Schnake, Klaus J; Vaccaro, Alexander R

    2015-10-09

    OBJECT The aim of this study was to determine if the ability of a surgeon to correctly classify A3 (burst fractures with a single endplate involved) and A4 (burst fractures with both endplates involved) fractures is affected by either the region or the experience of the surgeon. METHODS A survey was sent to 100 AOSpine members from all 6 AO regions of the world (North America, South America, Europe, Africa, Asia, and the Middle East) who had no prior knowledge of the new AOSpine Thoracolumbar Spine Injury Classification System. Respondents were asked to classify 25 cases, including 6 thoracolumbar burst fractures (A3 or A4). This study focuses on the effect of region and experience on surgeons' ability to properly classify these 2 controversial fracture variants. RESULTS All 100 surveyed surgeons completed the survey, and no significant regional (p > 0.50) or experiential (p > 0.21) variability in the ability to correctly classify burst fractures was identified; however, surgeons from all regions and with all levels of experience were more likely to correctly classify A3 fractures than A4 fractures (p < 0.01). Further analysis demonstrated that no region predisposed surgeons to increasing their assessment of severity of burst fractures. CONCLUSIONS A3 and A4 fractures are the most difficult 2 fractures to correctly classify, but this is not affected by the region or experience of the surgeon; therefore, regional variations in the treatment of thoracolumbar burst fractures (A3 and A4) is not due to differing radiographic interpretation of the fractures.

  17. [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.

  18. 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.

  19. Effect of CYP3A4∗1G and CYP3A5∗3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects

    PubMed Central

    Liu, Shuaibing; Shi, Xiangfen; Tian, Xin; Zhang, Xiaojian; Sun, Zhiyong; Miao, Liyan

    2017-01-01

    Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well documented, and CYP3A4∗1G (g.20230G>A, rs2242480) and CYP3A5∗3 (g.6986A>G, rs776746) are the most important single nucleotide polymorphisms in Chinese. Genetic differences in CYP3A4 and CYP3A5 expression in human volunteers and patients might affect the clearance of ticagrelor or AR-C124910XX in vivo resulting in subsequent variable patient response. Thus, this study is designed to explore the effects of CYP3A4∗1G and CYP3A5∗3 polymorphisms on the pharmacokinetics and pharmcodynamics of ticagrelor in healthy Chinese subjects. The results indicated that the CYP3A4∗1G polymorphism significantly influenced the pharmacokinetics of AR-C124910XX, and it may be more important than CYP3A5∗3 with respect to influencing ticagrelor pharmacokinetics by increasing CYP3A4 activity. However, the significant effect of CYP3A4∗1G polymorphism on AR-C124910XX plasma levels did not translate into detectable effect on inhibition of platelet aggregation. Therefore, it seems not necessary to adjust the dosage of ticagrelor according to the CYP3A4 or 3A5 genotype. PMID:28408884

  20. Polymorphism analysis of COL4A3 and COL4A4 genes in Greek patients with keratoconus.

    PubMed

    Kokolakis, Nikolaos S; Gazouli, Maria; Chatziralli, Irini P; Koutsandrea, Chryssanthi; Gatzioufas, Zisis; Peponis, Vasileios G; Droutsas, Konstantinos D; Kalogeropoulos, Christos; Anagnou, Nicholas; Miltsakakis, Dimitrios; Moschos, Marilita M

    2014-12-01

    In this study, we conducted the genotyping of D326Y in COL4A3 and M1327V, as well as F1644F in COL4A4 polymorphisms, in a case-control sample panel of Greek origin population. A case-control panel, with 45 keratoconus (KC) patients and 78 healthy controls, were surveyed. DNA from each individual was tested for the D326Y in COL4A3 and M1327V, as well as F1644F in COL4A4 polymorphisms by direct sequencing. When analyzing the Hardy-Weinberg equilibrium, we observed no significant deviation from expected numbers in both KC patients and controls. The genotype frequencies in the polymorphisms tested were not found to be significantly associated with KC development risk. The M1327V AA and F1644F TT genotypes were significantly over-represented in healthy individuals. We could hypothesize that mutations in COL4A3 and COL4A4 genes are not involved in KC risk in Greek population. Nevertheless, the M1327V AA and F1644F TT genotypes were significantly over-represented in healthy individuals, suggesting a protective role of these genotypes in KC development risk in our population.

  1. Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients

    PubMed Central

    Luo, Xi; Zhu, Li-jun; Cai, Ning-fang; Zheng, Li-yun; Cheng, Ze-neng

    2016-01-01

    Aim: To examine how the endogenous CYP3A4 phenotype and CYP3A5*3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C0/D) and weight-corrected daily dose (D/W) of tacrolimus. Methods: A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone in urine. CYP3A5*3 genotype was determined using PCR-RELP. Results: In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5*3 genotype and post-operative period accounted for 60.1% of the variability in C0/D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5*3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5*3/*3 subjects, a combination of the endogenous CYP3A4 phenotype, post-operative period and age was responsible for 65.3% of the variability in C0/D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range. Conclusion: This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5*3 genotype and other non-genetic variables. PMID:26924289

  2. The expression levels of CYP3A4 and CYP3A5 serve as potential prognostic biomarkers in lung adenocarcinoma.

    PubMed

    Qixing, Mao; Juqing, Xu; Yajing, Wang; Gaochao, Dong; Wenjie, Xia; Run, Shi; Anpeng, Wang; Lin, Xu; Feng, Jiang; Jun, Wang

    2017-04-01

    Lung adenocarcinoma remains to be a high-mortality disease with few effective prognostic biomarkers. Novel biomarkers are urgently demanded to supplement the current prognostic biomarkers. Here, we explored the prognostic value of CYP3A4 and CYP3A5 in lung adenocarcinoma. The tissue microarray was made up of lung adenocarcinoma samples and corresponding normal lung tissues from Nanjing Medical University affiliated Cancer Hospital Tissue Bank. The expression of CYP3A4, together with CYP3A5, was detected by the chip data from Gene Expression Omnibus datasets and immunohistochemistry staining of the tissue microarray. Then, we assessed the relationships between CYP3A4 or CYP3A5 expression level and clinicopathological factors to estimate the clinical significance. Kaplan-Meier curves were applied to analyze the prognosis. Univariate and multivariate Cox analyses were subsequently applied to identify the independent prognostic factors. Immunohistochemistry staining results showed that by comparison with matched normal tissues, CYP3A4 was frequently hyper-expressed in lung adenocarcinoma tissues while CYP3A5 was hypo-expressed, which was consistent with the Gene Expression Omnibus analysis. Kaplan-Meier analysis indicated that high-CYP3A4 or low-CYP3A5 expression level predicted poor survival in lung adenocarcinoma patients. Multivariate Cox analysis found that hypo-expression of CYP3A5 was an independent prognostic factor. Further study revealed that combination of these two markers exhibited a more powerful predictor of poor prognosis, which could target to more accurate survival of lung adenocarcinoma. Our findings indicate that combination of CYP3A4 and CYP3A5 may serve as a novel prognostic biomarker in lung adenocarcinoma, which contribute to the precision of predicting the survival in lung adenocarcinoma.

  3. Cytochrome P450 1A4 and 1A5 in common cormorant (Phalacrocorax carbo): evolutionary relationships and functional implications associated with dioxin and related compounds.

    PubMed

    Kubota, Akira; Iwata, Hisato; Goldstone, Heather M H; Kim, Eun-Young; Stegeman, John J; Tanabe, Shinsuke

    2006-08-01

    The present study characterized cytochrome P4501A (CYP1A) isoforms from common cormorant (Phalacrocorax carbo) with regard to their evolutionary relationships and their roles in disposition of dioxin and related compounds (DRCs). Two clones isolated from a cormorant liver cDNA library were named CYP1A4 and CYP1A5 on the basis of greatest overall amino acid identity shared with chicken (Gallus gallus) CYP1A4 (78%) and CYP1A5 (78%), respectively. Spatial heterogeneity in phylogenetic signal along the sequences strongly indicated that cormorant CYP1A4 and CYP1A5 have undergone partial interparalog gene conversion, similar to chicken and mammalian CYP1As. Phylogenetic analysis of a putatively unconverted region produced a tree topology consistent with the orthology of avian CYP1A5s with mammalian CYP1A2s and avian CYP1A4s with mammalian CYP1A1s. Hepatic CYP1A4 and CYP1A5 mRNA levels in wild cormorants from Lake Biwa, Japan, were quantified to examine the effects of DRCs on isoform-specific expression and to evaluate the toxicokinetics of DRCs in which CYP1A expression is involved. Both CYP1A4 and CYP1A5 mRNA levels were positively correlated with total tetrachlorodibenzo-p-dioxin toxic equivalents and concentrations of each congener in most cases in the liver, suggesting the induction of both enzymes through a shared transcriptional mechanism. The lack of correlation of 2,3,7,8-tetrachlorodibenzofuran and 3,3',4,4'-tetrachlorobiphenyl (PCB77) to CYP1A gene expression is likely due to the rapid metabolism of these two congeners. Liver-to-muscle concentration ratios for most DRC congeners except PCB77 and mono-ortho coplanar polychlorinated biphenyls significantly increased with an elevation of CYP1A4 and CYP1A5 mRNA levels. The present data suggest that hepatic sequestration of some DRCs occurs in cormorant via binding to either CYP1A5 or both CYP1A4 and CYP1A5.

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

    USDA-ARS?s Scientific Manuscript database

    Background: 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...

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

    USDA-ARS?s Scientific Manuscript database

    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...

  6. Association of CYP3A4*18B and CYP3A5*3 polymorphism with cyclosporine-related liver injury in Chinese renal transplant recipients.

    PubMed

    Xin, Hua-wen; Liu, Hui-ming; Li, Yuan-qi; Huang, Hui; Zhang, Li; Yu, Ai-rong; Wu, Xiao-chun

    2014-06-01

    The purpose of this study was to investigate the associations between CYP3A4*18B and CYP3A5*3 polymorphism and cyclosporine-related liver injuries in Chinese renal transplant recipients. We genotyped 339 renal transplant recipients treated with a triple immunosuppressive regimen including cyclosporine for CYP3A4*18B and CYP3A5*3 polymorphism using the polymerase chain reaction restriction fragment length polymorphism assay. The incidence of liver injury in the study population was 36.9% (125/339). At 1 month after transplantation, the trough concentration of cyclosporine (C0) in the group with CYP3A4*1/*1(GG alleles) was significantly higher than in the group with CYP3A4*18B/*1 8B(AA alleles) (p < 0.05). At 3 months after transplantation, the C0 in the group with CYP3A4*1/*1 and group with CYP3A4*1/*18B was markedly higher than in the group with CYP3A4*18B/*18B (p < 0.05). The GG genotypes of CYP3A4*18B were more common in the liver injury group compared with the control group (p < 0.05). Univariate logistic regression analysis showed that subjects carrying the GG genotypes had a 5.136- and 2.528-fold higher risk of developing cyclosporine-related liver injury than those with the AA and GA genotypes. When adjusted for sex, the risk of the CYP3A4*18B genotypes was OR = 4.969 for GG compared to AA (p = 0.030), and OR = 2.634 for GG compared to GA (p = 0.025). However, no association was observed between CYP3A5*3 polymorphisms with cyclosporine-related liver injury. These results suggested that the wild type of CYP3A4*18B is a risk factor for the development of cyclosporine- related liver injuries in Chinese renal transplant recipients.

  7. Functional polymorphisms in the CYP3A4, CYP3A5, and CYP21A2 genes in the risk for hypertension in pregnancy.

    PubMed

    Coto, Eliecer; Tavira, Beatriz; Marín, Rafael; Ortega, Francisco; López-Larrea, Carlos; Ruiz-Ortega, Marta; Ortiz, Alberto; Díaz, Marta; Corao, Ana I; Alonso, Belén; Alvarez, Victoria

    2010-07-02

    An intronic single nucleotide polymorphism (SNP) in the CYP3A5 gene (CYP3A5*3; SNP rs776746) affects RNA splicing and enzymatic activity. The CYP3A5*3 frequency increased with distance from the equator and natural selection has been proposed to explain the worldwide distribution of this allele. CYP3A activity has been related with the risk for hypertension in pregnancy, a major cause of morbidity and mortality among women, and CYP3A5*3 could reduce the risk for this disease in populations from regions with high sodium and water availability. The CYP3A5 genotype was related with blood pressure in the general population, but the effect on the risk for hypertension in pregnancy has not been evaluated.We compared the allele and genotype frequencies of three functional SNPs in the CYP3A5 (rs776746), CYP3A4 (rs2740574), and CYP21A2 (rs6471) genes between pregnant women who developed hypertension (n = 250) or who remained normotensive (control group, n = 250). In addition, we sequenced the full CYP3A5 coding sequence in 40 women from the two groups to determine whether some gene variants could explain the risk for hypertensive pregnancies in our population.Allele and genotype frequencies did not differ between hypertensive and normotensive women for the three CYP variants. We did not find CYP3A5 nucleotide changes that could explain a higher risk for hypertension in pregnancy. Our data suggests that the variation in CYP3A5, CYP3A4, and CYP21A2 did not contribute to the risk for hypertension in pregnancy in our population.

  8. Interactions among cytochromes P450 in microsomal membranes: oligomerization of cytochromes P450 3A4, 3A5, and 2E1 and its functional consequences.

    PubMed

    Davydov, Dmitri R; Davydova, Nadezhda Y; Sineva, Elena V; Halpert, James R

    2015-02-06

    The body of evidence of physiologically relevant P450-P450 interactions in microsomal membranes continues to grow. Here we probe oligomerization of human CYP3A4, CYP3A5, and CYP2E1 in microsomal membranes. Using a technique based on luminescence resonance energy transfer, we demonstrate that all three proteins are subject to a concentration-dependent equilibrium between the monomeric and oligomeric states. We also observed the formation of mixed oligomers in CYP3A4/CYP3A5, CYP3A4/CYP2E1, and CYP3A5/CYP2E1 pairs and demonstrated that the association of either CYP3A4 or CYP3A5 with CYP2E1 causes activation of the latter enzyme. Earlier we hypothesized that the intersubunit interface in CYP3A4 oligomers is similar to that observed in the crystallographic dimers of some microsomal drug-metabolizing cytochromes P450 (Davydov, D. R., Davydova, N. Y., Sineva, E. V., Kufareva, I., and Halpert, J. R. (2013) Pivotal role of P450-P450 interactions in CYP3A4 allostery: the case of α-naphthoflavone. Biochem. J. 453, 219-230). Here we report the results of intermolecular cross-linking of CYP3A4 oligomers with thiol-reactive bifunctional reagents as well as the luminescence resonance energy transfer measurements of interprobe distances in the oligomers of labeled CYP3A4 single-cysteine mutants. The results provide compelling support for the physiological relevance of the dimer-specific peripheral ligand-binding site observed in certain CYP3A4 structures. According to our interpretation, these results reveal an important general mechanism that regulates the activity and substrate specificity of the cytochrome P450 ensemble through interactions between multiple P450 species. As a result of P450-P450 cross-talk, the catalytic properties of the cytochrome P450 ensemble cannot be predicted by simple summation of the properties of the individual P450 species. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. [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.

  10. Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism.

    PubMed

    Sanchez Spitman, A B; Moes, D J A R; Gelderblom, H; Dezentje, V O; Swen, J J; Guchelaar, H J

    2017-08-28

    Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. DNA from 667 women enrolled in the CYPTAM study (NTR1509) was genotyped (CYP2D6, CYP3A4*22, and CYP3A5*3). Tamoxifen and metabolite concentrations were measured in serum, and metabolic ratios were calculated. The effect of the CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes in addition to the CYP2D6 genotypes was examined by multiple linear regression analysis. CYP3A4*22 carriers reached significant higher concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen compared to non-carriers, whereas a tendency toward increased endoxifen levels was observed (p = 0.088). The metabolic ratio tamoxifen/N-desmethyl-tamoxifen was significantly higher in CYP3A4*22 individuals (0.59 vs. 0.52, p < 0.001). At the same time, CYP3A4*22 genotype contributed to improving the inter-variability [R (2) of the (log-transformed) metabolic ratio tamoxifen/N-desmethyl-tamoxifen improved from 21.8 to 23.9%, p < 0.001]. CYP3A5*3 marginally improved the explained variability of the (log transformed) metabolic ratio 4-hydroxy-tamoxifen/endoxifen (from 44.9 to 46.2%, p < 0.038). Our data demonstrate that CYP3A genotype has a minor effect to explaining the variability between patients in tamoxifen metabolism and has no added value in addition to CYP2D6 genotype.

  11. 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.

  12. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients.

    PubMed

    Li, Chuan-Jiang; Li, Liang; Lin, Li; Jiang, Hai-Xia; Zhong, Ze-Yan; Li, Wei-Mo; Zhang, Yan-Jun; Zheng, Ping; Tan, Xu-Hui; Zhou, Lin

    2014-01-01

    Tacrolimus is a widely used immunosuppressive drug for preventing the rejection of solid organ transplants. The efficacy of tacrolimus shows considerable variability, which might be related to genetic variation among recipients. We conducted a retrospective study of 240 Chinese renal transplant recipients receiving tacrolimus as immunosuppressive drug. The retrospective data of all patients were collected for 40 days after transplantation. Seventeen SNPs of CYP3A5, CYP3A4, COMT, IL-10 and POR were identified by the SNaPshot assay. Tacrolimus blood concentrations were obtained on days 1-3, days 6-8 and days 12-14 after transplantation, as well as during the period of the predefined therapeutic concentration range. Kruskal-Wallis test was used to examine the effect of genetic variation on the tacrolimus concentration/dose ratio (C 0/D) at different time points. Chi-square test was used to compare the proportions of patients who achieved the target C 0 range in the different genotypic groups at weeks 1, 2, 3 and 4 after transplantation. After correction for multiple testing, there was a significant association of C 0/D with CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C at different time points after transplantation. The proportion of patients in the IL-10 rs1800871-TT group who achieved the target C 0 range was greater (p = 0.004) compared to the IL-10 rs1800871-CT and IL-10 rs1800871-CC groups at week 3 after transplantation. CYP3A5*3, CYP3A4 *1G, CYP3A4 rs4646437 T>C and IL-10 rs1800871 C>T might be potential polymorphisms affecting the interindividual variability in tacrolimus metabolism among Chinese renal transplant recipients.

  13. Severe Vincristine-induced Neuropathic Pain in a CYP3A5 Nonexpressor With Reduced CYP3A4/5 Activity: Case Study.

    PubMed

    Bosilkovska, Marija; Ing Lorenzini, Kuntheavy; Uppugunduri, Chakradhara Rao S; Desmeules, Jules; Daali, Youssef; Escher, Monica

    2016-01-01

    Peripheral neuropathy is a frequent vincristine-induced adverse effect. Vincristine is a substrate of P-glycoprotein and is metabolized by the cytochrome P-450 (CYP) 3A5 and 3A4 isoforms, with CYP3A5 contributing to 75% of the intrinsic clearance of vincristine. Alterations in the function of these proteins may lead to an increase in vincristine toxicity. CYP3A5 nonexpressor status has been associated with vincristine-induced peripheral neuropathy. The severity of neuropathy has been reported to be inversely correlated to vincristine metabolite concentrations. Recently, the presence of a mutation in the CEP72 gene, which encodes for a protein involved in microtubule formation, has also been associated with vincristine-induced peripheral neuropathy. However, a clear correlation between genetic polymorphisms and vincristine toxicity has not been established. Here we report the case of a 21-year old patient in whom severe neuropathic pain developed after vincristine treatment. The patient was a CYP3A5 nonexpressor and presented with reduced CYP3A4/5 functional activity, a likely reason for the occurrence of the adverse event, as genotyping showed that his status was wild type for the ABCB1 and CEP72 genes. CYP phenotype and genotype may explain the occurrence of severe neuropathy in some patients treated with vincristine. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  14. Polymorphisms in CYP3A5, CYP3A4, and ABCB1 are not associated with cyclosporine pharmacokinetics nor with cyclosporine clinical end points after renal transplantation.

    PubMed

    Bouamar, Rachida; Hesselink, Dennis A; van Schaik, Ron H N; Weimar, Willem; Macphee, Iain A M; de Fijter, Johan W; van Gelder, Teun

    2011-04-01

    The association of CYP3A5, CYP3A4, and ABCB1 single nucleotide polymorphisms (SNPs) with cyclosporine (CsA) pharmacokinetics is controversial. The authors studied the influence of these SNPs on CsA pharmacokinetics as well as on the incidence of biopsy-proven acute rejection (BPAR) and renal function after kidney transplantation. One hundred seventy-one patients participating in an international, randomized controlled trial were genotyped for CYP3A5*3, CYP3A4*1B and the ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T SNPs. The patients were treated with CsA, mycophenolate mofetil, and glucocorticoids. CsA was dosed to reach predose concentrations (C0) or two hours postdose concentrations (C2). Pharmacokinetic parameters were measured on Days 3 and 10 and Months 1, 3, 6, and 12 after transplantation. Renal function was assessed by measuring serum creatinine and calculating the creatinine clearance. The incidence of BPAR and delayed-graft function was recorded. CYP3A5, CYP3A4, and ABCB1 genotype were not associated with dose-adjusted CsA C0 or C2. The incidence of BPAR in this cohort was 16% and was comparable between the different ABCB1 genotype groups. No significant difference in the incidence of BPAR was found between CYP3A5 expressers (10%) and nonexpressers (18%) (P = 0.24) nor was there a difference in the incidence of BPAR between CYP3A4*1 homozygotes (5%) versus CYP3A4*1B carriers (18%) (P = 0.13). There were no differences with regard to creatinine clearance between the different CYP3A and ABCB1 genotype groups. According to the results, determination of CYP3A and ABCB1 SNPs pretransplantation is not helpful in determining the CsA starting dose and does not aid in predicting the risk of BPAR or worse renal function in an individual patient.

  15. 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

  16. 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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  17. Inactivation of cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a thiophene-containing anticancer drug.

    PubMed

    Lin, Hsia-lien; Zhang, Haoming; Medower, Christine; Hollenberg, Paul F; Johnson, William W

    2011-02-01

    An investigational anticancer agent that contains a thiophene moiety, 3-[(quinolin-4-ylmethyl)-amino]-N-[4-trifluoromethox)phenyl] thiophene-2-carboxamide (OSI-930), was tested to investigate its ability to modulate the activities of several cytochrome P450 enzymes. Results showed that OSI-930 inactivated purified, recombinant cytochrome P450 (P450) 3A4 in the reconstituted system in a mechanism-based manner. The inactivation was dependent on cytochrome b(5) and required NADPH. Catalase did not protect against the inactivation. No inactivation was observed in studies with human 2B6, 2D6, or 3A5 either in the presence or in the absence of b(5). The inactivation of 3A4 by OSI-930 was time- and concentration-dependent. The inactivation of the 7-benzyloxy-4-(trifluoromethyl)coumarin catalytic activity of 3A4 was characterized by a K(I) of 24 μM and a k(inact) of 0.04 min(-1). This K(I) is significantly greater than the clinical OSI-930 C(max) of 1.7 μM at the maximum tolerated dose, indicating that clinical drug interactions of OSI-930 via this pathway are not likely. Spectral analysis of the inactivated protein indicated that the decrease in the reduced CO spectrum at 450 nm was comparable to the amount of inactivation, thereby suggesting that the inactivation was primarily due to modification of the heme. High-pressure liquid chromatography (HPLC) analysis with detection at 400 nm showed a loss of heme comparable to the activity loss, but a modified heme was not detected. This result suggests either that the heme must have been modified enough so as not to be observed in a HPLC chromatograph or, possibly, that it was destroyed. The partition ratio for the inactivation of P450 3A4 was approximately 23, suggesting that this P450 3A4-mediated pathway occurs with approximately 4% frequency during the metabolism of OSI-930. Modeling studies on the binding of OSI-930 to the active site of the P450 3A4 indicated that OSI-930 would be oriented properly in the active site

  18. 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.

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-4 Limitations on... and gas through A's ownership interest in Corporation M, A is considered to be selling oil or natural... section 613A(c) would not apply to B because B is selling oil or natural gas to a person given...

  20. Involvement of CYP3A in the metabolism of eplerenone in humans and dogs: differential metabolism by CYP3A4 and CYP3A5.

    PubMed

    Cook, Chyung S; Berry, Loren M; Kim, David H; Burton, Earl G; Hribar, Jeremy D; Zhang, Liming

    2002-12-01

    In vitro studies were conducted to identify the major metabolites of eplerenone (EP) and the cytochrome p450 (p450) isozymes involved in its primary oxidative metabolism in humans and dogs. The major in vitro metabolites were identified as 6 beta-hydroxy EP and 21-hydroxy EP in both humans and dogs. EP was metabolized by cDNA-expressed human CYP3A4 and dog CYP3A12 but only minimally by human CYP3A5. In human microsomes, inhibition of total metabolism by the CYP3A-selective inhibitors ketoconazole, troleandomycin, and 6',7'-dihydroxybergamottin, each at 10 micro M concentration, was 83 to 95%, whereas inhibition with inhibitors selective for other p450 isozymes was minimal. In dog liver microsomes, the percentages of inhibition were 53 to 76% with the CYP3A-selective inhibitors. A monoclonal anti-CYP3A4 antibody inhibited EP metabolism by 84%, whereas other monoclonal antibodies had minimal effects. The formation of 6 beta-hydroxy and 21-hydroxy metabolites in human liver microsomes was best correlated with CYP3A-selective dextromethorphan N-demethylation and testosterone 6 beta-hydroxylation activities. EP moderately inhibited only CYP3A (testosterone 6 beta-hydroxylase) activity in human liver microsomes by 23, 34 and 45% at concentrations of 30, 100, and 300 micro M, respectively. With human microsomes, the V(max) and K(m) for 6 beta-hydroxylation and 21-hydroxylation were 0.973 nmol/min/mg and 217 micro M, and 0.143 nmol/min/mg and 211 micro M, respectively. The human hepatic clearance calculated from total in vitro EP metabolism was 2.30 ml/min/kg, which agrees with in vivo data. In conclusion, 6 beta- and 21-hydroxylation of EP is primarily catalyzed by CYP3A4 in humans and CYP3A12 in dogs. Also, it is unlikely that EP would substantially inhibit the metabolism of other drugs that are metabolized by CYP3A4 or other p450 isoforms.

  1. 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, A2...

  2. 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, A2...

  3. 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, A2...

  4. 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, A2...

  5. 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, A2...

  6. Evidence for the association of the SLC22A4 and SLC22A5 genes with Type 1 Diabetes: a case control study

    PubMed Central

    Santiago, Jose Luis; Martínez, Alfonso; de la Calle, Hermenegildo; Fernández-Arquero, Miguel; Figueredo, M Ángeles; de la Concha, Emilio G; Urcelay, Elena

    2006-01-01

    Background Type 1 diabetes (T1D) is a chronic, autoimmune and multifactorial disease characterized by abnormal metabolism of carbohydrate and fat. Diminished carnitine plasma levels have been previously reported in T1D patients and carnitine increases the sensitivity of the cells to insulin. Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease. For these reasons, we investigated for the first time the association with T1D of six single nucleotide polymorphisms (SNPs) mapping to these candidate genes: slc2F2, slc2F11, T306I, L503F, OCTN2-promoter and OCTN2-intron. Methods A case-control study was performed in the Spanish population with 295 T1D patients and 508 healthy control subjects. Maximum-likelihood haplotype frequencies were estimated by applying the Expectation-Maximization (EM) algorithm implemented by the Arlequin software. Results When independently analyzed, one of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with T1D in our Spanish cohort. The overall comparison of the inferred haplotypes was significantly different between patients and controls (χ2 = 10.43; p = 0.034) with one of the haplotypes showing a protective effect for T1D (rs3792876/rs1050152/rs2631367/rs274559, CCGA: OR = 0.62 (0.41–0.93); p = 0.02). Conclusion The haplotype distribution in the carnitine transporter locus seems to be significantly different between T1D patients and controls; however, additional studies in independent populations would allow to confirm the role of these genes in T1D risk. PMID:16796743

  7. Two novel cultured cell lines, A3/Kawakami and A4/Fukuda, derived from malignant lymphoma of B(non-T)-cell nature of the gastrointestinal tract.

    PubMed

    Hirose, M; Minato, K; Tobinai, K; Shimoyama, M; Watanabe, S; Abe, T; Deura, K

    1983-02-01

    A3/Kawakami was derived from ascitic lymphoma cells of a 68-year-old female patient with malignant lymphoma (non-Hodgkin's lymphoma, diffuse, large cell type) of the stomach and A4/Fukuda was derived from ascitic lymphoma cells of a 52-year-old female patient with double cancer of the colon (well-differentiated papillary adenocarcinoma and non-Hodgkin's lymphoma, diffuse, large cell type). The fresh ascitic lymphoma cells in the case of A3/Kawakami were surface immunoglobulin-positive, but the cultured A3/Kawakami cells no longer expressed any distinct markers. In the case of A4/Fukuda, the fresh ascitic lymphoma cells and cultured cells did not express any specific surface markers. Only 20% of A4/Fukuda cells were reactive with OKI1. However, a small amount of IgM could be detected in the cell extract and concentrated culture supernate of A4/Fukuda. In addition, A4/Fukuda cells heterotransplanted into anti-thymocyte sera-treated newborn hamster or athymic nude mice with a BALB/c genetic background were found to have weak surface immunoglobulin and distinct cytoplasmic immunoglobulin (gamma, mu). These data suggest that A4/Fukuda cells share the characteristics of the late differentiation stage of B-cell lineage (intermediate between mature B-cells and plasma cells). It was found that monoclonal antibodies, OKT4 and anti-Leu 3a, which are known to react specifically with inducer/helper T-cells, reacted to both A3/Kawakami and A4/Fukuda cells. The karyotypes of both A3/Kawakami and A4/Fukuda cells were very complicated but included some marker chromosomes such as 14q+.

  8. No association of SLC6A3 and SLC6A4 gene polymorphisms with schizophrenia in the Han Chinese population.

    PubMed

    Yang, Beimeng; Huang, Xiaoye; Ruan, Liemin; Yu, Tao; Li, Xin; Jesse, Forrest Fabian; Cao, Yanfei; Li, Xingwang; Liu, Baocheng; Yang, Fengping; Lee, Yong-Seok; He, Lin; Li, Weidong; He, Guang

    2014-09-05

    The SLC6A3 and SLC6A4 genes are members of a class of neurotransmitter transporters for the release, re-uptake and recycling of neurotransmitters in synapses. SLC6A3 and SLC6A4 encode a dopamine transporter and serotonin transporter, respectively. Abnormal expression and genetic polymorphism of SLC6A3 and SLC6A4 genes may increase the risk of developing mental illness, such as schizophrenia, bipolar disorder, ADHD, and aggressive behavior in Alzheimer disease, etc. Nevertheless, association between SLC6A3, SLC6A4 genes polymorphism and schizophrenia patients have not been well studied in Han Chinese people. In this study, we examined whether single nucleotide polymorphisms (SNPs) in SLC6A3, SLC6A4 were associated with schizophrenia in Han Chinese people (893 schizophrenia patients and 611 healthy controls). No significant difference in allelic or genotypic frequency was found between schizophrenia patients and healthy controls. No positive linkage disequilibrium (LD) was detected either. No haplotypic distributions were positive. Accordingly, our study suggests that the 10 SNPs within both genes we examined do not play a major role in schizophrenia in the Han Chinese population.

  9. Plexin-A3 and plexin-A4 restrict the migration of sympathetic neurons but not their neural crest precursors.

    PubMed

    Waimey, Kathryn E; Huang, Pei-Hsin; Chen, Maggie; Cheng, Hwai-Jong

    2008-03-15

    During development, the semaphorin family of guidance molecules is required for proper formation of the sympathetic nervous system. Plexins are receptors that mediate semaphorin signaling, but how plexins function during sympathetic development is not fully understood. Using phenotypic analyses of mutant mice in vivo, expression pattern studies, and in vitro assays, we show that plexin-A3 and plexin-A4 are essential for normal sympathetic development. This study confirms our previous in vitro findings that the two plexins differentially regulate the guidance of sympathetic axons. In addition, we find that semaphorin signaling through plexin-A3 and plexin-A4 restricts the migration of sympathetic neurons, but these two plexins function redundantly since migration defects are only observed in plexin-A3/-A4 double mutants. Surprisingly, our analysis also indicates that plexin-A3 and plexin-A4 are not required for guiding neural crest precursors prior to reaching the sympathetic anlagen. Immunoprecipitation studies suggest that these two plexins independently mediate secreted semaphorin signaling. Thus, plexin-A3 and plexin-A4 are expressed in newly-differentiated sympathetic neurons, but not their neural crest precursors. They function cooperatively to regulate the migration of sympathetic neurons and then differentially to guide the sympathetic axons.

  10. 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.

  11. 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

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

    PubMed Central

    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

  13. The mouse Mcmd gene for DNA replication protein P1MCM3 maps to bands A3-A5 on chromosome 1 by fluorescence in situ hybridization

    SciTech Connect

    Yoshida, Ikuya; Kimura, Hiroshi; Takagi, Nobuo

    1996-03-05

    This report describes the localization of the mouse Mcmd gene for DNA replication to mouse chromosome 1, bands A3-A5 using fluorescence in situ hybridization. This finding supports the recent mapping of the human MCM3 gene to human chromosome 6p12, which shows synteny with mouse chromosome 1. The mouse Mcmd gene encodes the protein P1MCM3 which is essential for DNA replication. 13 refs., 1 fig.

  14. Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins.

    PubMed

    Yaron, Avraham; Huang, Pei-Hsin; Cheng, Hwai-Jong; Tessier-Lavigne, Marc

    2005-02-17

    The class 3 Semaphorins Sema3A and Sema3F are potent axonal repellents that cause repulsion by binding Neuropilin-1 and Neuropilin-2, respectively. Plexins are implicated as signaling coreceptors for the Neuropilins, but the identity of the Plexins that transduce Sema3A and Sema3F responses in vivo is uncertain. Here, we show that Plexin-A3 and -A4 are key determinants of these responses, through analysis of a Plexin-A3/Plexin-A4 double mutant mouse. Sensory and sympathetic neurons from the double mutant are insensitive to Sema3A and Sema3F in vitro, and defects in axonal projections in vivo correspond to those seen in Neuropilin-1 and -2 mutants. Interestingly, we found a differential requirement for these two Plexins: signaling via Neuropilin-1 is mediated principally by Plexin-A4, whereas signaling via Neuropilin-2 is mediated principally by Plexin-A3. Thus, Plexin-A3 and -A4 contribute to the specificity of axonal responses to class 3 Semaphorins.

  15. Capable Reader Program: Lesson Plan Guide. Units A1; A2; A3; A4; [and] A5. Pilot Year 1979-1980, Final Edition 1980-1981.

    ERIC Educational Resources Information Center

    Casper, Donna; And Others

    Part of a curriculum series for academically gifted elementary students in the area of reading, the five lesson plan guides are intended to provide teachers with suggested activities stressing high levels of reading comprehension as well as encouraging teachers to use their own ideas. Each guide focuses on one of the following major objectives:…

  16. Capable Reader Program: Lesson Plan Guide. Units A1; A2; A3; A4; [and] A5. Pilot Year 1979-1980, Final Edition 1980-1981.

    ERIC Educational Resources Information Center

    Casper, Donna; And Others

    Part of a curriculum series for academically gifted elementary students in the area of reading, the five lesson plan guides are intended to provide teachers with suggested activities stressing high levels of reading comprehension as well as encouraging teachers to use their own ideas. Each guide focuses on one of the following major objectives:…

  17. In vitro inhibition of UGT1A3, UGT1A4 by ursolic acid and oleanolic acid and drug-drug interaction risk prediction.

    PubMed

    Xie, Hongbo; Wu, Jie; Liu, Dan; Liu, Mingyi; Zhang, Hong; Huang, Shibo; Xiong, Yuqing; Xia, Chunhua

    2017-09-01

    1. Ursolic acid (UA) and oleanolic acid (OA) may have important activity relevant to health and disease prevention. Thus, we studied the activity of UA and OA on UDP-glucuronosyltransferases (UGTs) and used trifluoperazine as a probe substrate to test UGT1A4 activity. Recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as a probe reaction for other UGT isoforms. 2. UA and OA inhibited UGT1A3 and UGT1A4 activity but did not inhibit other tested UGT isoforms. 3. UA-mediated inhibition of UGT1A3 catalyzed 4-MU-β-d-glucuronidation was via competitive inhibition (IC50 0.391 ± 0.013 μM; Ki 0.185 ± 0.015 μM). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 2.651 ± 0.201 μM; Ki 1.334 ± 0.146 μM). 4. OA offered mixed inhibition of UGT1A3-mediated 4-MU-β-d-glucuronidation (IC50 0.336 ± 0.013 μM; Ki 0.176 ± 0.007 μM) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 5.468 ± 0.697 μM; Ki 6.298 ± 0.891 μM). 5. Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.

  18. Human UDP-glucuronosyltransferase (UGT) 2B10 in drug N-glucuronidation: substrate screening and comparison with UGT1A3 and UGT1A4.

    PubMed

    Kato, Yukiko; Izukawa, Takeshi; Oda, Shingo; Fukami, Tatsuki; Finel, Moshe; Yokoi, Tsuyoshi; Nakajima, Miki

    2013-07-01

    Recent observations revealed that human UDP-glucuronosyltransferase (UGT) 2B10 catalyzes N-glucuronidation of amine-containing compounds. Knowledge of the substrate specificity and clinical significance of UGT2B10 is still limited. The purpose of this study was to expand the knowledge of UGT2B10 substrates and to evaluate its significance in drug clearance. Using recombinant UGT2B10, we found that it catalyzes the N-glucuronidation of amitriptyline, imipramine, ketotifen, pizotifen, olanzapine, diphenhydramine, tamoxifen, ketoconazole, and midazolam. These are drugs that were previously reported to be substrates for UGT1A4 or UGT1A3, and that contain in their structure either tertiary aliphatic amines, cyclic amines, or an imidazole group. UGT2B10 was inactive in the glucuronidation of desipramine, nortriptyline, carbamazepine, and afloqualone. This group of drugs contains secondary or primary amines, and these results suggest that UGT2B10 preferably conjugates tertiary amines. This preference is partial because UGT2B10 did not conjugate the tertiary cyclic amine in trifluoperazine. Kinetic analyses revealed that the affinity and clearance of UGT2B10 for amitriptyline, imipramine, and diphenhydramine are significantly higher than the corresponding values of UGT1A4 and UGT1A3, although the Vmax values of UGT1A4 toward these drugs are considerably higher. These findings suggest that UGT2B10 plays a major role in the N-glucuronidation of these drugs at therapeutic concentrations. These results are also supported by inhibition studies with nicotine and hecogenin. In conclusion, this study expands the understanding of the substrate specificity of UGT2B10, highlighting its preference for tertiary amines with higher affinities and clearance values than those of UGT1A4 and UGT1A3.

  19. The radiative lifetimes of O+2(a4[Pi]u, v) and NO+(a3[summation operator]+, v) revisited

    NASA Astrophysics Data System (ADS)

    Marx, R.; Fenistein, S.; Mauclaire, G.; Lemaire, J.; Heninger, M.

    1994-03-01

    The spin-forbidden radiative decays of metastable O+2(a4[Pi]u, v) and NO+(a3[summation operator]+, v) have been reinvestigated using our recently improved tirple cell FT-ICR spectrometer. The monitor ion technique was used to probe the first excited state of O+2(a4[Pi]u) and NO+(a3[summation operator]+). A radiative lifetime of (55 ± 7) ms has been found for O2+(a4[Pi]u) with Ar and CO2 as monitor gases. For NO+(a3[summation operator]+) we found (680+91-87) ms with CO2 (proving v [greater-or-equal, slanted] 0) and (516-62+65) ms with Ar (probing v [greater-or-equal, slanted] 1) respectively as monitor gases. For such long lifetimes it is mandatory to take into account collisional deactivation processes occurring in the relaxation cell even for pressures below 10-8 Torr. In order to correct the observed lifetimes, background gas pressure and rate constants have been carefully determined. For O+2, a double exponential decay due to the metastable state and to high vibrational levels of the ground state has been observed. As a consequence the experimental lifetimes depend on the observation time window explaining most of the differences with the previous published results. For NO+(a3[summation operator]+) the present lifetime is in good agreement with the results of Kuo. [C.H. Kuo, T. Wyttenbach, C.G. Beggs, P.R. Kemper and M.T. Bowers, J. Chem. Phys., 92 (1990) 4849] and with the recent theoretical calculations.

  20. 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

  1. Human UGT1A4 and UGT1A3 conjugate 25-hydroxyvitamin D3: metabolite structure, kinetics, inducibility, and interindividual variability.

    PubMed

    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; Thummel, Kenneth E

    2014-06-01

    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.

  2. Production of novel antioxidative prenyl naphthalen-ols by combinational bioconversion with dioxygenase PhnA1A2A3A4 and prenyltransferase NphB or SCO7190.

    PubMed

    Shindo, Kazutoshi; Tachibana, Ayako; Tanaka, Ayumi; Toba, Shizuka; Yuki, Emi; Ozaki, Taro; Kumano, Takuto; Nishiyama, Makoto; Misawa, Norihiko; Kuzuyama, Tomohisa

    2011-01-01

    We performed combinational bioconversion of substituted naphthalenes with PhnA1A2A3A4 (an aromatic dihydroxylating dioxygenase from marine bacterium Cycloclasticus sp. strain A5) and prenyltransferase NphB (geranyltransferase from Streptomyces sp. strain CL190) or SCO7190 (dimethylallyltransferase from Streptomyces coelicolor A3(2)) to produce prenyl naphthalen-ols. Using 2-methylnaphthalene, 1-methoxynaphthalene, and 1-ethoxynaphthalene as the starting substrates, 10 novel prenyl naphthalen-ols were produced by combinational bioconversion. These novel prenyl naphthalen-ols each showed potent antioxidative activity against a rat brain homogenate model. 2-(2,3-Dihydroxyphenyl)-5,7-dihydroxy-chromen-4-one (2',3'-dihydroxychrysin) generated with another aromatic dihydroxylating dioxygenase and subsequent dehydrogenase was also geranylated at the C-5'-carbon by the action of NphB.

  3. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up.

    PubMed

    Lewis, Joshua R; Calver, Janine; Zhu, Kun; Flicker, Leon; Prince, Richard L

    2011-01-01

    Concern has been expressed that calcium supplementation, a key intervention for preventing osteoporotic fracture in older women, may increase the risk of atherosclerotic vascular disease. To evaluate the risk further, an examination of complete verified atherosclerotic vascular hospitalization and mortality data from a 5-year randomized, controlled trial (RCT) of calcium carbonate and 4.5 years of posttrial follow-up was undertaken. This study used data from a published 5-year randomized, double-blinded, placebo-controlled trial [Calcium Intake Fracture Outcome Study (CAIFOS)]. The participants were 1460 women aged 75.1 ± 2.7 years at baseline (1998) recruited from the general population and randomized to receive 1200 mg of calcium carbonate daily or an identical placebo. All hospital admission and deaths during the 5-year study and the 4.5-year follow-up were derived from the Western Australian Data Linkage Service (WADLS). Hazard ratios (HRs) for the combined endpoint of atherosclerotic vascular mortality or first hospitalization were calculated using prespecified intention-to-treat and per-protocol models. The intervention group that received calcium supplementation did not have a higher risk of death or first-time hospitalization from atherosclerotic vascular disease in either the 5-year RCT [multivariate-adjusted HR = 0.938, 95% confidence interval (CI) 0.690-1.275] or during the 9.5 years of observational study (multivariate-adjusted HR = 0.919, 95% CI 0.737-1.146). Further analysis suggested that calcium supplementation may reduce the risk of hospitalization and mortality in patients with preexisting atherosclerotic cardiovascular disease. This trial provides compelling evidence that calcium supplementation of 1200 mg daily does not significantly increase the risk of atherosclerotic vascular disease in elderly women.

  4. 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.

  5. Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients.

    PubMed

    Kuypers, Dirk R J; de Loor, Henriette; Naesens, Maarten; Coopmans, Tamara; de Jonge, Hylke

    2014-12-01

    In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes. Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3±1.7 vs. 1.34±0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose. Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients.

  6. Effect of CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1 C3435T on the pharmacokinetics of nifedipine in healthy Chinese volunteers.

    PubMed

    Wang, Xiao-Fei; Yan, Liang; Cao, Hui-Min; Wei, Lu-Man; Yang, Wei-Hong; Zhang, Sheng-Jun; Zhang, Li-Rong

    2015-09-01

    Nifedipine is a calcium channel blocker that is widely used in the treatment of cardiovascular disease. However, significant individual variances in the disposition of nifedipine have been reported, and genetic factors are considered to play an important role. The aim of the present study was to investigate the effect of CYP3A4*1G, CYP3A5*3, ABCB1-C3435T, and POR*28 genetic polymorphisms on nifedipine pharmacokinetics in healthy Chinese volunteers. 45 healthy Chinese volunteers enrolled in this study received a single oral dose of 90 mg nifedipine after providing written informed consent. Volunteers were genotyped for CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1-C3435T. The blood concentrations of nifedipine were determined by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method. There were significant differences of AUC00-∞ and AUC0-48h in the different CYP3A5*3 genotype groups (p = 0.043 and p = 0.048, respectively). The CYP3A5*3 GG group and POR*28 CT/TT group were found to have lower AUC00-∞ and Cmax compared with the POR*28 CC group (p = 0.046 and p = 0.002, respectively). In addition, the POR*28 CT/TT group was found to have longer t1/2 but lower Cmax than the CYP3A4*1G GG group (p = 0.032 and p = 0.002, respectively) as well as the CYP3A4*1G GG and the CYP3A5*3 GG group (p = 0.038 and p = 0.036, respectively) compared with the POR*28 CC group. No significant associations were found between CYP3A4*1G/ABCB1-C3435T polymorphism and pharmacokinetics of nifedipine. Both CYP3A5*3 and POR*28 polymorphisms are found to be associated with the difference in disposition of nifedipine; POR*28 is considered to have an impact on CYP3A4 activity.

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

    PubMed

    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.

  8. 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

  9. Alkoxyresorufin (methoxy-, ethoxy-, pentoxy- and benzyloxyresorufin) O-dealkylase activities by in vitro-expressed cytochrome P450 1A4 and 1A5 from common cormorant (Phalacrocorax carbo).

    PubMed

    Kubota, Akira; Kim, Eun-Young; Iwata, Hisato

    2009-05-01

    Here we report the inter-paralog comparison of cytochrome P4501A (CYP1A) catalytic function in common cormorant (Phalacrocorax carbo) using the recombinant proteins synthesized by yeast-based vector system. CYP1A4 and CYP1A5 proteins from common cormorant were heterologously expressed in yeast Saccaromyces cerevisiae. Kinetic analyses revealed that among alkoxyresorufin (methoxy-, ethoxy-, pentoxy- and benzyloxyresorufin) O-dealkylase (AROD) activities V(max) value for ethoxyresorufin O-deethylase (EROD) activity was the highest for both enzymes, reaching 0.91+/-0.034 and 1.8+/-0.043 nmol/min/nmol CYP for CYP1A4 and CYP1A5, respectively. Similar results were obtained for the catalytic efficiencies represented as the ratios of V(max) to K(m) (V(max)/K(m)). Meanwhile, distinct substrate preferences were also observed; CYP1A4 had V(max) and V(max)/K(m) values for benzyloxyresorufin O-debenzylase (BROD) activity 12- and 46-fold greater than CYP1A5, respectively, while CYP1A5 was about 13- and 4.5-fold more efficient in methoxyresorufin O-demethylase (MROD) activity than CYP1A4. The K(m) values showed no significant change among MROD, EROD, pentoxyresorufin O-depenthylase (PROD) and BROD activities for both enzymes, except for significant differences between PROD and other three activities for CYP1A4. Comparing the results in the present study with previous studies addressing chicken and rat CYP1A enzymes, it is also clear that CYP1A orthologs have different catalytic preferences for AROD activities between cormorant and rat and even between cormorant and chicken. Variations in CYP1A catalytic function between cormorant CYP1A paralogs and between CYP1A orthologs from cormorant and other species indicate that enzymatic properties should be characterized on the basis not only of a limited model species such as chicken, but also of multiple species to further understand the mechanism underlying differences in substrate selectivity and the interaction with environmental

  10. 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.

  11. CYP2C19 but not CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1 or P2Y12 genetic polymorphism impacts antiplatelet response after clopidogrel in Koreans.

    PubMed

    Zhang, Hong-Zhe; Kim, Moo Hyun; Guo, Long-Zhe; Serebruany, Victor

    2017-01-01

    Clopidogrel response variability (CRV) is well documented, and may affect clinical outcomes. Impact of genetic polymorphisms is important for assessing and predicting CRV. The extensive evidence indicates the importance of CYP2C19 variants in reducing efficacy of clopidogrel. This study defined the impact of numerous genetic polymorphisms on CRV before and after percutaneous coronary interventions (PCI) exclusively in a Korean cohort assuming less genetic variability noise. One hundred and thirty-six patients of Korean origin undergoing PCI were included. Platelet reactivity was measured by VerifyNow assay before and after PCI. Genetic polymorphism of seven single nucleotides of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ABCB1, PON1, and P2Y12 were evaluated and matched with platelet reactivity. Carriers of at least one CYP2C19*2 or *3 allele uniformly exhibited higher platelet reactivity compared to 0-carrier pre-PCI (odds ratio 3.1, 95% confidence interval 1.4-6.9, P < 0.01) and post-PCI (odds ratio 3.4, 95% confidence interval 1.7-6.8, P < 0.001). The carriers of other gene allele variants lack uniformed impact on CRV. The Korean carriers of CYP2C19*2 or *3 allele are linked to CRV, whereas CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1, and P2Y12 failed to predict CRV. The exact clinical utility of these findings is uncertain, and requires a large randomized national trial for proof of concept.

  12. 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

  13. Association of serotonin transporter (SLC6A4) & receptor (5HTR1A, 5HTR2A) polymorphisms with response to treatment with escitalopram in patients with major depressive disorder: A preliminary study

    PubMed Central

    Basu, Aniruddha; Chadda, R.K.; Sood, Mamta; Kaur, Harpreet; Kukreti, Ritushree

    2015-01-01

    Background & objectives: Genetic factors have potential of predicting response to antidepressants in patients with major depressive disorder (MDD). In this study, an attempt was made to find an association between response to escitalopram in patients with MDD, and serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms. Methods: Fifty five patients diagnosed as suffering from MDD, were selected for the study. The patients were treated with escitalopram over a period of 6-8 wk. Severity of depression, response to treatment and side effects were assessed using standardised instruments. Genetic variations from HTR1A (rs6295), HTR2A (rs6311 and rs6313) and SLC6A4 (44 base-pair insertion/deletion at 5-HTTLPR) were genotyped. The genetic data of the responders and non-responders were compared to assess the role of genetic variants in therapeutic outcome. Results: Thirty six (65.5%) patients responded to treatment, and 19 (34.5%) had complete remission. No association was observed for genotype and allelic frequencies of single nucleotide polymorphisms (SNPs) among remitter/non-remitter and responder/non-responder groups, and six most common side-effects, except memory loss which was significantly associated with rs6311 (P =0.03). Interpretation & conclusions: No significant association was found between the SNPs analysed and response to escitalopram in patients with MDD though a significant association was seen between the side effect of memory loss and rs6311. Studies with larger sample are required to find out genetic basis of antidepressant response in Indian patients. PMID:26261165

  14. 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.

  15. 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

  16. Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)

    PubMed Central

    Weaver, Benjamin P.; Dufner-Beattie, Jodi; Kambe, Taiho; Andrews, Glen K.

    2008-01-01

    Dietary zinc deficiency in mice is accompanied by enhanced expression of the zinc uptake transporter Slc39a4 (Zip4) and repressed expression of Slc39a5 (Zip5) in tissues which regulate zinc homeostasis (intestine, pancreas and visceral yolk sac). Herein, mechanisms controlling this differential expression were investigated. The induction of Zip4 mRNA during zinc deficiency, and its repression in response to zinc repletion were found to reflect changes in Zip4 mRNA stability and not changes in the relative rate of transcription of this gene. During zinc deficiency, ZIP4 protein levels are increased and this protein is localized on the apical membranes. Administration of an oral gavage of zinc caused ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. Similarly, ZIP4 is induced by zinc deficiency in cultured mouse Hepa cells and is rapidly degraded in response to added zinc. Zip5 mRNA abundance does not change in response to zinc, but the translation of this mRNA was found to be zinc-responsive. During zinc deficiency, Zip5 mRNA remains associated with polysomes, while the protein is internalized and degraded in enterocytes, acinar cells and endoderm cells. After zinc-gavage, ZIP5 is rapidly resynthesized and targeted to the basolateral membranes of these cell types. PMID:18020946

  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. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans.

    PubMed

    Dong, C; Wong, M-L; Licinio, J

    2009-12-01

    We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054 + or - 0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and

  19. [Effectiveness of topical acetate tocopherol for the prevention and treatment of skin lesions in newborns: a 5 years experience in a 3rd level Italian Neonatal Intensive Care Unit].

    PubMed

    Manzoni, P; Gomirato, G

    2005-10-01

    Neonates in NICU (especially when premature) are particularly prone to skin damage by action of external aggressive conditions such as chemical, physical, infectious, radiant, mechanical and iatrogenic factors. Strategies for avoiding disruption of the skin barrier are thus highly needed in such patients. We evaluated the effectiveness of a acetate tocopherol (AT) ointment for topical use in 21 neonates admitted to our NICU and affected by neonatal abstinence syndrome with severe diaper exulcerative and erosive erythema with ulcer and granulation tissue at the bottom of the lesion (group A), and compared them to 19 matched neonates affected by the same condition and treated with a commonly used skin ointment (emollient type, water-in-oil category) (group B). For all newborns we calculated: the dermatological severity score (using a clinical score from 0 to 9 points according to the increasing severity of the lesions) at time 0, 4 and 7 days; the mean days for achieving complete recovery; the rate of therapeutical failures. Mean score at day 0 was 7.8 in group A vs 7.9 in group B (P=0.35 NS). At day 4 it was 4.6 in group A vs 6.5 in group B (P=0.03), at day in 7 it was 3.1 in group A vs 5.2 in group B (P=0.04). A complete recovery with restitutio ad integrum occurred after 9.1 mean days in group A vs 12.2 mean days in group B (P=0.04). The rate of therapeutical failures was significantly lower in group A (4.2% vs 30.6%; OR 0.235; P<0.01) than in group B. No adverse effects related to AT use were reported. AT in our experience proved to be safe and more effective than the commonly used skin ointments in the topical treatment of exulcerative skin lesions in NICU neonates.

  20. Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6β-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.

    PubMed

    Chan, S W; Xiao, Y; Hu, M; Yin, O Q P; Chu, T T W; Fok, B S P; Lee, V H L; Tomlinson, B

    2016-10-01

    The oral plasma clearance of midazolam and the ratio of 6β-hydroxycortisol (6β-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6β-OHF/F in healthy Chinese. Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6β-OHF concentrations were measured using UPLC. There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6β-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6β-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6β-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6β-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study. © 2016 John Wiley & Sons Ltd.

  1. HBV subgenotype misclassification expands quasi-subgenotype A3.

    PubMed

    Pourkarim, M R; Amini-Bavil-Olyaee, S; Lemey, P; Maes, P; Van Ranst, M

    2011-06-01

    Recently, we proposed a new classification for 'subgenotype A' of hepatitis B virus (HBV), in which the novel 'quasi-subgenotype A3' group comprising HBV 'subgenotype A3', 'tentative A4', and A5 was introduced. Newly 'Tentative subgenotype A7' strains from Cameroon were introduced by Hubschen et al. However, our meticulous phylogenetic analysis demonstrated that these isolates should also be classified into 'quasi-subgenotype A3'. Such misclassification can be avoided by following established principles for HBV subgenotyping. Moreover, their close evolutionary relationship with A3 highlights our hypothesis that geographical origin may be an important factor in further classification of HBV subgenotypes.

  2. Laser Propagation Research. Volume II. Gaseous and Particulate Characterization of the Atmosphere. App. A-3. Maximum, Mean and Minimum Values of Measured Gas Concentrations at NOP Site. App. A-4. Plots of Nephelometer and Aerosol Mass Monitor Data at Arky Site. App. A-5. Plots of Aerosol Mass Monitor Data at the NOP Site,

    DTIC Science & Technology

    1980-11-01

    The Federal agency responsible for the licensing of radio users and control of the Nation’s airwaves for radio broadcast. Ganmma Rays - See...any two-way system of radio communications may be available and pressed into use in an emergency. Marine , aeronautical, military, broadcast, and...radioiodines decay rather rapidly. If possible, avoid the use of open water sources for drinking water during the first few weeks. Use wells or water

  3. Studies on SF=1902 A2 A5, minor components of SF-1902 (globomycin).

    PubMed

    Omoto, S; Ogino, H; Inouye, S

    1981-11-01

    Four members of globomycin, SF-1902 A2, A3, A4a and A4b were newly isolated from the culture of Streptomyces hygroscopicus SF-1902. These minor components shared four amino acids in common and the fifth was either valine or allo-isoleucine. The fatty acid moiety varied from 3-hydroxy-2-methylheptanoic acid in A2 to 3-hydroxy-2-methylundecanoic acids in A4b. The length of alkyl chain greatly affected the antibacterial activity, and maximum activity was shown by the homologue (A5) possessing the longest alkyl chain.

  4. Synthesis and structural characterization of A3In 2Ge 4 and A5In 3Ge 6 ( A=Ca, Sr, Eu, Yb)—New intermetallic compounds with complex structures, exhibiting Ge-Ge and In-In bonding

    NASA Astrophysics Data System (ADS)

    You, Tae-Soo; Bobev, Svilen

    2010-06-01

    Reported are the synthesis and the structural characterization of four new polar intermetallic phases, which exist only with mixed alkaline-earth and rare-earth metal cations in narrow homogeneity ranges. (Sr 1-xCa x) 5In 3Ge 6 and (Eu 1-xYb x) 5In 3Ge 6 ( x≈0.7) crystallize in the orthorhombic space group Pnma with two formula units per unit cell (own structure type, Pearson symbol oP56). The lattice parameters are as follows: a=13.109(3)-13.266(3) Å, b=4.4089(9)-4.4703(12) Å, and c=23.316(5)-23.557(6) Å. (Sr 1-xCa x) 3In 2Ge 4 and (Sr 1-xYb x) 3In 2Ge 4 ( x≈0.4-0.5) adopt another novel monoclinic structure-type (space group C2 /m, Z=4, Pearson symbol mS36) with lattice parameters in the range a=19.978(2)-20.202(2) Å, b=4.5287(5)-4.5664(5) Å, c=10.3295(12)-10.3447(10) Å, and β=98.214(2)-98.470(2)°, depending on the metal cations and their ratio. The polyanionic sub-structures in both cases are based on chains of InGe 4 corner-shared tetrahedra. The A5In 3Ge 6 structure ( A=Sr/Ca or Sr/Yb) also features Ge 4 tetramers, and isolated In atoms in nearly square-planar environment, while the A3In 2Ge 4 structure ( A=Sr/Ca or Eu/Yb) contains zig-zag chains of In and Ge strings with intricate topology of cis- and trans-bonds. The experimental results have been complemented by tight-binding linear muffin-tin orbital (LMTO) band structure calculations.

  5. A-4 scientific results

    NASA Technical Reports Server (NTRS)

    Matteson, J.

    1979-01-01

    Observations of galactic sources, extragalactic sources and gamma bursts with the A-4 instrument at energy 1 energies of between 0.1 to 10 MeV are discussed. Aximuthal scans are presented. The Crab Nebula and its spectrum and the spectrum of Cygnus Z-1 are described.

  6. A-5A on lakebed.

    NASA Image and Video Library

    1963-10-25

    A North American Aviation A-5A Vigilante (Navy serial number 147858/NASA tail number 858) arrived from the Naval Air Test Center, Patuxent River, MD, on December 19, 1962, at the NASA Flight Research Center (now, Dryden Flight Research Center, Edwards, CA). The Center flew the A-5A in a year-long series of flights in support of the U.S. supersonic transport program. The Center flew the aircraft to determine the let-down and approach conditions of a supersonic transport flying into a dense air traffic network. With the completion of the research flights, the Center sent the A-5A back to the Navy on December 20, 1963.

  7. A-5A on lakebed.

    NASA Image and Video Library

    1963-03-25

    A North American Aviation A-5A Vigilante (Navy serial number 147858/NASA tail number 858) arrived from the Naval Air Test Center, Patuxent River, MD, on December 19, 1962, at the NASA Flight Research Center (now, Dryden Flight Research Center, Edwards, CA). The Center flew the A-5A in a year-long series of flights in support of the U.S. supersonic transport program. The Center flew the aircraft to determine the let-down and approach conditions of a supersonic transport flying into a dense air traffic network. With the completion of the research flights, the Center sent the A-5A back to the Navy on December 20, 1963.

  8. 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.

  9. A-3 Test Stand

    NASA Image and Video Library

    2012-06-08

    A tethered Stennis Space Center employee climbs an A-3 Test Stand ladded June 8, 2012, against the backdrop of the A-2 and B-1/B-2 stands. The new A-3 Test Stand will enable simulated high-altitude testing of next-generation rocket engines.

  10. A-3 Test Stand

    NASA Image and Video Library

    2012-06-08

    A tethered Stennis Space Center employee climbs an A-3 Test Stand ladder June 8, 2012, against the backdrop of the A-2 and B-1/B-2 stands. The new A-3 Test Stand will enable simulated high-altitude testing of next-generation rocket engines.

  11. A-3 Test Stand

    NASA Image and Video Library

    2011-08-19

    The A-3 Test Stand under construction at Stennis Space Center is set for completion and activation in 2013. It will allow operators to conduct simulated high-altitude testing on the next-generation J-2X rocket engine.

  12. A-3 Groundbreaking Ceremony

    NASA Image and Video Library

    2007-08-23

    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.

  13. 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.

  14. A-3 Cleared Site

    NASA Image and Video Library

    2007-06-18

    Work to clear the site for the A-3 Test Stand progresses quickly, as seen in this photo taken June 18 from atop the A-1 Test Stand. The next step in construction at 19-acre site will be the arrival of fill dirt in mid-July, followed by pilings and piling caps.

  15. A-3 Cleared Site

    NASA Technical Reports Server (NTRS)

    2007-01-01

    Work to clear the site for the A-3 Test Stand progresses quickly, as seen in this photo taken June 18 from atop the A-1 Test Stand. The next step in construction at 19-acre site will be the arrival of fill dirt in mid-July, followed by pilings and piling caps.

  16. A-3 Construction

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Workers erect the first beams of structural steel for the 235-foot tall A-3 Test Stand on Oct. 29, 2008. Ground work for the stand was broken in August 2008 and the final structural steel beam was placed on April 9, 2009.

  17. 32 CFR 809a.5 - Barment procedures.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Barment procedures. 809a.5 Section 809a.5 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy § 809a.5...

  18. 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,...

  19. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 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,...

  20. 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 of...

  1. 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 of...

  2. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 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 of...

  3. 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 of...

  4. 32 CFR 352a.5 - Relationships.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 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 of...

  5. 12 CFR 269a.5 - Hearing officer.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Hearing officer. 269a.5 Section 269a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.5 Hearing officer. The term hearing officer means the officer designated by the panel to...

  6. 12 CFR 269a.5 - Hearing officer.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Hearing officer. 269a.5 Section 269a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.5 Hearing officer. The term hearing officer means the officer designated by...

  7. 12 CFR 269a.5 - Hearing officer.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Hearing officer. 269a.5 Section 269a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.5 Hearing officer. The term hearing officer means the officer designated by...

  8. 12 CFR 269a.5 - Hearing officer.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Hearing officer. 269a.5 Section 269a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.5 Hearing officer. The term hearing officer means the officer designated by...

  9. 12 CFR 269a.5 - Hearing officer.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Hearing officer. 269a.5 Section 269a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.5 Hearing officer. The term hearing officer means the officer designated by the panel to...

  10. 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... COVERAGE AND RATES Pt. 61, App. A(5) Appendix A(5) to Part 61 Federal Emergency Management Agency, Federal...

  11. 44 CFR Appendix A(5) to Part 61 - Appendix A(5) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(5) to Part 61 A(5) Appendix A(5) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... COVERAGE AND RATES Pt. 61, App. A(5) Appendix A(5) to Part 61 Federal Emergency Management Agency,...

  12. 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

    ... (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 industrial...

  13. Lessons Learned From a 5-Year Experience With a 4-Week Experiential Quality Improvement Curriculum in a Preventive Medicine Fellowship

    PubMed Central

    Varkey, Prathibha; Karlapudi, Sudhakar Prakash

    2009-01-01

    Background Competency in practice-based learning and improvement (PBLI) and systems-based practice (SBP) empowers learners with the skills to plan, lead, and execute health care systems improvement efforts. Experiences from several graduate medical education programs describe the implementation of PBLI and SBP curricula as challenging because of lack of adequate curricular time and faculty resources, as well as a perception that PBLI and SBP are not relevant to future careers. A dedicated experiential rotation that requires fellow participation in a specialty-specific quality improvement project (QIP) may address some of these challenges. Method We describe a retrospective analysis of our 5-year experience with a dedicated 3-week PBLI-SBP experiential curriculum in a preventive medicine fellowship program at Mayo Clinic, Rochester, Minnesota. Results Between 2004 and 2008, 19 learners including 7 preventive medicine fellows participated in the rotation. Using just-in-time learning, fellows work together on a relatively complex QIP of community or institutional significance. Since 2004, all 19 learners (100%) participating in this rotation have consistently demonstrated statistically significant increase in their quality improvement knowledge application tool (QIKAT) scores at the end of the rotation. At the end of the rotation, all 19 learners stated that they were either confident or very confident of making a change to improve health care in a local setting. Most of the QIPs resulted in sustainable practice improvements, and resultant solutions have been disseminated beyond the location of the original QIP. Conclusion A dedicated experiential rotation that requires learner participation in a QIP is one of the effective methods to address the needs of the SBP and PBLI competencies. PMID:21975713

  14. A 4D spacetime embedded in a 5D pseudo-Euclidean space describing interior of compact stars

    NASA Astrophysics Data System (ADS)

    Singh, Ksh. Newton; Murad, Mohammad Hassan; Pant, Neeraj

    2017-02-01

    The present paper provides a new model of compact stars satisfying the Karmarkar condition. The model is obtained by assuming a new type of metric potential for g_{rr} from the condition of embedding class I. The model parameters are obtained accordingly by employing the metric potentials to Einstein's field equations. Our model is free from geometric singularity and satisfies all the physical conditions. The obtained mass and radius of the compact stars Cen X-3, EXO 1785-248 and SAX 1808.4-3658 obtained from the model are consistent with the observational data of T. Gangopadhyay et al.. Detailed analyses of these neutron stars (Cen X-3, EXO 1785-248 and SAX 1808.4-3658) are also given with the help of graphical representations.

  15. Lessons learned from a 5-year experience with a 4-week experiential quality improvement curriculum in a preventive medicine fellowship.

    PubMed

    Varkey, Prathibha; Karlapudi, Sudhakar Prakash

    2009-09-01

    Competency in practice-based learning and improvement (PBLI) and systems-based practice (SBP) empowers learners with the skills to plan, lead, and execute health care systems improvement efforts. Experiences from several graduate medical education programs describe the implementation of PBLI and SBP curricula as challenging because of lack of adequate curricular time and faculty resources, as well as a perception that PBLI and SBP are not relevant to future careers. A dedicated experiential rotation that requires fellow participation in a specialty-specific quality improvement project (QIP) may address some of these challenges. We describe a retrospective analysis of our 5-year experience with a dedicated 3-week PBLI-SBP experiential curriculum in a preventive medicine fellowship program at Mayo Clinic, Rochester, Minnesota. Between 2004 and 2008, 19 learners including 7 preventive medicine fellows participated in the rotation. Using just-in-time learning, fellows work together on a relatively complex QIP of community or institutional significance. Since 2004, all 19 learners (100%) participating in this rotation have consistently demonstrated statistically significant increase in their quality improvement knowledge application tool (QIKAT) scores at the end of the rotation. At the end of the rotation, all 19 learners stated that they were either confident or very confident of making a change to improve health care in a local setting. Most of the QIPs resulted in sustainable practice improvements, and resultant solutions have been disseminated beyond the location of the original QIP. A dedicated experiential rotation that requires learner participation in a QIP is one of the effective methods to address the needs of the SBP and PBLI competencies.

  16. 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...

  17. 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...

  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

    ... crude oil. (B) Importers of an annual quantity of petroleum products and natural gas liquids that is... natural gas liquids that is equivalent to 25,000 metric tons CO2e or more. Natural gas and natural gas liquids suppliers (subpart NN): (A) All fractionators. (B) Local natural gas distribution companies...

  19. 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... number of graduate and undergraduate students, and physicians and other practitioners in...

  20. 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... number of graduate and undergraduate students, and physicians and other practitioners in...

  1. 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... number of graduate and undergraduate students, and physicians and other practitioners in...

  2. 42 CFR 59a.5 - Awards.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 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... number of graduate and undergraduate students, and physicians and other practitioners in...

  3. 32 CFR 809a.5 - Barment procedures.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Barment procedures. 809a.5 Section 809a.5 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy §...

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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...

  9. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Meetings. 1912a.4 Section 1912a.4 Labor Regulations 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...

  10. 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 to...

  11. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  12. 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 to...

  13. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 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, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  14. 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 to...

  15. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 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, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  16. 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 to...

  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 to...

  18. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  19. 22 CFR 9a.4 - Classification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 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, 1976.... If the officer determines that the information or material warrants classification, he shall assign...

  20. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to...

  1. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to...

  2. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to investigate and...

  3. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to...

  4. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to investigate and...

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

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 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. Air carriers are exempt from the following provisions of Title IV of the Federal Aviation Act of 1958, as...

  6. 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 Technology...

  7. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 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 Technology...

  8. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 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...

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

    USDA-ARS?s Scientific Manuscript database

    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 ...

  10. 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... COVERAGE AND RATES Pt. 61, App. A(4) Appendix A(4) to Part 61 Federal Emergency Management Agency, Federal...

  11. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(4) to Part 61 A(4) Appendix A(4) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... COVERAGE AND RATES Pt. 61, App. A(4) Appendix A(4) to Part 61 Federal Emergency Management Agency,...

  12. View of east elevation of building A5 which is attached ...

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

    View of east elevation of building A5 which is attached to and blocks A3; camera facing west. - Mare Island Naval Shipyard, Shell House No. 1, Railroad Avenue, west side near Maseda Road, Vallejo, Solano County, CA

  13. 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

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

    PubMed

    Aubert, Y; Bourgerie, S; Meunier, L; Mayer, R; Roche, A C; Monsigny, M; Thuong, N T; Asseline, U

    2000-02-01

    A new deprotection procedure enables a medium scale preparation of phosphodiester and phosphor-othioate 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/micromol 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 phosphor-amidite 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 proced-ure 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 oligo-nucleotide; the 5'-dithio-pyridyl group was then -quantitatively reduced to give a free thiol group which was then substituted by reaction with an N alpha-bromoacetyl derivative of a signal peptide containing a KDEL sequence to afford a fluoresceinylated peptide-oligonucleotide conjugate.

  15. Airborne Communications and Electronics Systems AFSC 1A3X1 & Airborne Missions Systems AFSC 1A5X1

    DTIC Science & Technology

    2002-08-01

    and Ms. Dolores Navarro provided administrative support. Major Jose Caussade, Chief, Airman Analysis Section, reviewed and approved this report for...2.00 38 2.16 OFF-DUTY EDU OR TRAINING OPPORTUNITIES 53 2.40 45 2.38 42 2.40 MEDICAL/ DENTAL CARE FOR AD MEMBER 53 2.48 57 2.49 48 2.47 MEDICAL/ DENTAL ...SECURITY JOB SECURITY PAY AND ALLOWANCES PAY AND ALLOWANCES MEDICAL/ DENTAL CARE FOR AD MEMBER MILITARY LIFESTYLE MILITARY LIFESTYLE OFF-DUTY EDU OR

  16. A-3 Test Stand work

    NASA Image and Video Library

    2011-07-29

    Stennis Space Center employees have installed liquid oxygen and liquid hydrogen tanks atop the A-3 Test Stand, raising the structure to its full 300-foot height. The stand is being built to test next-generation rocket engines that could carry humans beyond low-Earth orbit into deep space. The A-3 Test Stand is scheduled for completion and activation in 2013.

  17. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees. (a... at the same cost we charge for duplication of records and/or production of computer output under...

  18. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees. (a... at the same cost we charge for duplication of records and/or production of computer output under...

  19. A-3 Test Stand construction

    NASA Image and Video Library

    2010-09-24

    A 35,000-gallon liquid oxygen tank is placed at the A-3 Test Stand construction site on Sept. 24, 2010. The tank will provide propellant for tests of next-generation rocket engines at the stand. It will be placed upright on top of the stand, helping to increase the overall height to 300 feet. Once completed, the A-3 Test Stand will enable operators to test rocket engines at simulated altitudes of up to 100,000 feet. The A-3 stand is the first large rocket engine test structure to be built at Stennis Space Center since the 1960s.

  20. A-3 Test Stand construction

    NASA Image and Video Library

    2010-10-01

    An 80,000-gallon liquid hydrogen tank is placed at the A-3 Test Stand construction site on Sept. 24, 2010. The tank will provide propellant for tests of next-generation rocket engines at the stand. It will be placed upright on top of the stand, helping to increase the overall height to 300 feet. Once completed, the A-3 Test Stand will enable operators to test rocket engines at simulated altitudes of up to 100,000 feet. The A-3 stand is the first large rocket engine test structure to be built at Stennis Space Center since the 1960s.

  1. 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.

  2. 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.

  3. Paediatric anaphylaxis: a 5 year retrospective review.

    PubMed

    de Silva, I L; Mehr, S S; Tey, D; Tang, M L K

    2008-08-01

    To describe the demographic characteristics, clinical features, causative agents, settings and administered therapy in children presenting with anaphylaxis. This was a retrospective case note study of children presenting with anaphylaxis over a 5-year period to the Emergency Department (ED) at the Royal Children's Hospital, Melbourne. One-hundred and twenty-three cases of anaphylaxis in 117 patients were included. There was one death. The median age of presentation was 2.4 years. Home was the most common setting (48%) and food (85%) the most common trigger. Peanut (18%) and cashew nut (13%) were the most common cause of anaphylaxis. The median time from exposure to anaphylaxis for all identifiable agents was 10 min. The median time from onset to therapy was 40 min. Respiratory features were the principal presenting symptoms (97%). Seventeen per cent of subjects had experienced anaphylaxis previously. This is the largest study of childhood anaphylaxis reported. Major findings are that most children presenting to the ED with anaphylaxis are first-time anaphylactic reactions and the time to administration of therapy is often significantly delayed. Most reactions occurred in the home. Peanut and cashew nut were the most common causes of anaphylaxis in this study population, suggesting that triggers for anaphylaxis in children have not changed significantly over the last decade.

  4. 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.

  5. A-3 First Tree Cutting

    NASA Image and Video Library

    2007-06-13

    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.

  6. 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.

  7. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  8. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  9. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  10. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  11. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  12. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM RULES REGARDING ACCESS... records. We will provide you with copies of the records you request under § 261a.5 of this part at the same cost we charge for duplication of records and/or production of computer output under the Board's...

  13. Ligand Diversity of Human and Chimpanzee CYP3A4: Activation of Human CYP3A4 by Lithocholic Acid Results from Positive SelectionS⃞

    PubMed Central

    Kumar, Santosh; Qiu, Huan; Oezguen, Numan; Herlyn, Holger; Halpert, James R.; Wojnowski, Leszek

    2009-01-01

    For currently unknown reasons, the evolution of CYP3A4 underwent acceleration in the human lineage after the split from chimpanzee. We investigated the significance of this event by comparing Escherichia coli-expressed CYP3A4 from humans, chimpanzee, and their most recent common ancestor. The expression level of chimpanzee CYP3A4 was ∼50% of the human CYP3A4, whereas ancestral CYP3A4 did not express in E. coli. Steady-state kinetic analysis with 7-benzyloxyquinoline, 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC), and testosterone showed no significant differences between human and chimpanzee CYP3A4. Upon addition of α-naphthoflavone (25 μM), human CYP3A4 showed a slightly decreased substrate concentration at which 50% of the maximal rate Vmax is reached for 7-BFC, whereas chimpanzee CYP3A4 showed a >2-fold increase. No significant differences in inhibition/activation were found for a panel of 43 drugs and endogenous compounds, suggesting that the wide substrate spectrum of human CYP3A4 precedes the human-chimpanzee split. A striking exception was the hepatotoxic secondary bile acid lithocholic acid, which at saturation caused a 5-fold increase in 7-BFC debenzylation by human CYP3A4 but not by chimpanzee CYP3A4. Mutagenesis of human CYP3A4 revealed that at least four of the six amino acids positively selected in the human lineage contribute to the activating effect of lithocholic acid. In summary, the wide functional conservation between chimpanzee and human CYP3A4 raises the prospect that phylogenetically more distant primate species such as rhesus and squirrel monkey represent suitable models of the human counterpart. Positive selection on the human CYP3A4 may have been triggered by an increased load of dietary steroids, which led to a novel defense mechanism against cholestasis. PMID:19299527

  14. 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.

  15. A3 TEST STAND CONSTRUCTION

    NASA Technical Reports Server (NTRS)

    2008-01-01

    THIS IMAGE SHOWS THE DEVELOPMENT AND CONSTRUCTION OF THE A3 TEST STAND IN SUPPORT OF THE ARES/CLV UPPER STAGE ENGINE AT STENNIS SPACE CENTER, MISSISSIPPI. THIS IMAGE IS EXTRACTED FROM A HIGH DEFINITION VIDEO FILE AND IS THE HIGHEST RESOLUTION AVAILABLE.

  16. A-3 steel work completed

    NASA Image and Video Library

    2009-04-09

    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. 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.

  18. A-3 Test Stand work

    NASA Image and Video Library

    2011-07-29

    Work continues on the A-3 Test Stand at Stennis Space Center. The new stand will allow operators to test next-generation rocket engines at simulated altitudes up to 100,000 feet. The test stand is scheduled for completion and activation in 2013.

  19. A-3 Test Stand work

    NASA Image and Video Library

    2011-07-29

    Rocket engine propellant tanks and cell dome top the A-3 Test Stand under construction at Stennis Space Center. The stand will test next-generation rocket engines that could carry humans beyond low-Earth orbit into deep space once more.

  20. Vessels installed at A-3

    NASA Image and Video Library

    2009-09-25

    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.

  1. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., 1972, partnership ABC, which makes its returns on the basis of a calendar year, employed WIN employees. Partnership ABC incurred WIN expenses with respect to these employees of $20,000 for the taxable year. Partnership ABC has 10 partners who make their returns on the basis of a calendar year and share...

  2. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., 1972, partnership ABC, which makes its returns on the basis of a calendar year, employed WIN employees. Partnership ABC incurred WIN expenses with respect to these employees of $20,000 for the taxable year. Partnership ABC has 10 partners who make their returns on the basis of a calendar year and share...

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... oil and gas properties in Texas and is also the owner of a service station in Washington, DC, which B... eliminate the effects of: (i) Any depletion with respect to an oil or gas property (other than a gas... royalty or other interest in oil, gas, or other mineral representing any percentage depletion allowance to...

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

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... untenable that the employee is, in effect, compelled by the taxpayer to quit, or if the employee is coerced into quitting, the employee will not be deemed to have voluntarily left the employment of the taxpayer... the employee feels necessitates his quitting work with the taxpayer to remain at home. Any employee...

  5. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... untenable that the employee is, in effect, compelled by the taxpayer to quit, or if the employee is coerced into quitting, the employee will not be deemed to have voluntarily left the employment of the taxpayer... the employee feels necessitates his quitting work with the taxpayer to remain at home. Any employee...

  6. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... untenable that the employee is, in effect, compelled by the taxpayer to quit, or if the employee is coerced into quitting, the employee will not be deemed to have voluntarily left the employment of the taxpayer... the employee feels necessitates his quitting work with the taxpayer to remain at home. Any employee...

  7. Radiative Lifetimes and Kinetic Studies of Metastable NO(+)(a 3 Sigma(+)) and O2(+)(a 4 Pi sub u),

    DTIC Science & Technology

    1985-01-01

    Kimball , "Quantum Chemistry", Wiley, New York, 1944. *44. R. W. Field, J. Mol. Spectros., 47, 194 (1973). 45. P. S. Julienne, private communication. *46. 0...B. Stewart, C. A. McDowell and C. E. Brion, J. Electron Spectrosc. Relat. Phenom., 7, 93 (1975). 51. J. E. Collin, J. Delwiche, and P. Natalis , Int. J...Mass Spec. Ion, Phys., 7, 19 (1971). 52. P. Natalis , J. Deiwiche, J. E. Collin, G. Caprace and M. T. Praet, Chem. Phys. Lett., 49, 177 (1977). 53. 0

  8. Conserved stem-loop structures in the HIV-1 RNA region containing the A3 3' splice site and its cis-regulatory element: possible involvement in RNA splicing.

    PubMed

    Jacquenet, S; Ropers, D; Bilodeau, P S; Damier, L; Mougin, A; Stoltzfus, C M; Branlant, C

    2001-01-15

    The HIV-1 transcript is alternatively spliced to over 30 different mRNAs. Whether RNA secondary structure can influence HIV-1 RNA alternative splicing has not previously been examined. Here we have determined the secondary structure of the HIV-1/BRU RNA segment, containing the alternative A3, A4a, A4b, A4c and A5 3' splice sites. Site A3, required for tat mRNA production, is contained in the terminal loop of a stem-loop structure (SLS2), which is highly conserved in HIV-1 and related SIVcpz strains. The exon splicing silencer (ESS2) acting on site A3 is located in a long irregular stem-loop structure (SLS3). Two SLS3 domains were protected by nuclear components under splicing condition assays. One contains the A4c branch points and a putative SR protein binding site. The other one is adjacent to ESS2. Unexpectedly, only the 3' A residue of ESS2 was protected. The suboptimal A3 polypyrimidine tract (PPT) is base paired. Using site-directed mutagenesis and transfection of a mini-HIV-1 cDNA into HeLa cells, we found that, in a wild-type PPT context, a mutation of the A3 downstream sequence that reinforced SLS2 stability decreased site A3 utilization. This was not the case with an optimized PPT. Hence, sequence and secondary structure of the PPT may cooperate in limiting site A3 utilization.

  9. 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.

  10. An Analog of the Antimicrobial Peptide CopA5 Inhibits Lipopolysaccharide-Induced Macrophage Activation.

    PubMed

    Yoon, I Na; Hong, Ji; Zhang, Peng; Hwang, Jae Sam; Kim, Ho

    2017-02-28

    We previously reported that the CopA3 peptide (LLCIALRKK, D-form) originally isolated from the Korean dung beetle has antimicrobial and immunosuppressive effects. However, the high cost of producing the synthetic peptide, especially the D-form, has limited the development of CopA3 for therapeutic purposes. Here, we investigated whether the CopA3 deletion derivative, CopA5, which is composed of only five amino acids (LLCIA) and has the L-form structure, could inhibit the lipopolysaccharide (LPS)-induced activation of macrophages. Peritoneal exudate macrophages (PEM) were isolated from mice and exposed to LPS in the presence or absence of CopA5, and biomarkers of macrophage activation were measured. Our results revealed that LPS-induced nitric oxide (NO) production, tumor necrosis factor (TNF)-α secretion, and phagocytic activity of PEM were significantly inhibited by CopA5 treatment. Similar to CopA3, the structurally modified CopA5 peptide had no cell toxicity (as assessed by measurement of cell viability loss and apoptosis) in PEM. Moreover, the LPS-induced upregulation of the activating phosphorylation of signal transducer and activator of transcription 1 (STAT1) was markedly inhibited by CopA5 treatment. These results suggest that, similar to CopA3, CopA5 inhibits macrophage activation by inhibiting STAT1 phosphorylation and blocking the release of NO and TNF-α. CopA5 may therefore prove therapeutically useful in the realm of immune suppression.

  11. Identification and characterization of a new human type 9 cGMP-specific phosphodiesterase splice variant (PDE9A5). Differential tissue distribution and subcellular localization of PDE9A variants.

    PubMed

    Wang, Peng; Wu, Ping; Egan, Robert W; Billah, M Motasim

    2003-09-18

    Previously, four splice variants of human cGMP-specific phosphodiesterase (PDE) 9A (PDEs 9A1, 9A2, 9A3 and 9A4) have been identified. In this study, we have cloned a cDNA representing a new human PDE9A variant (PDE9A5). PDE9A5 encodes a protein of 492 amino acids, smaller than PDEs 9A1 and 9A2 but larger than PDEs 9A3 and 9A4. The exon structure of PDE9A5 is different from those of PDEs 9A1, 9A2, 9A3 and 9A4 in that, of the 20 exons of PDE9A gene, it lacks exons 2 and 5. PDE9A5 has been characterized in comparison with PDE9A1, the longest PDE9A variant. PDEs 9A5 and 9A1 have similar enzymatic properties. They both have a high affinity for cGMP with similar Km values (0.39 and 0.25 microM, respectively), although they have slightly different Vmax values (2.55 and 0.96 micromol/min/mg, respectively). They exhibit very similar divalent metal ion dependency and inhibitor sensitivity. Real-time quantitative PCR analysis shows that PDEs 9A5 and 9A1 exhibit differential tissue distribution. They are highly expressed in immune tissues (spleen, lymph node and thymus) and are more abundant in T cells than in B cells, neutrophils and monocytes. When transiently expressed in HEK293 cells, PDEs 9A5 and 9A1 proteins exhibit differential subcellular localization. PDE9A5 localizes exclusively in the cytoplasm, whereas PDE9A1 localizes in the nucleus only. The nuclear localization of PDE9A1 is dependent on a unique pat7 motif. By Western blot analysis, native PDE9A1 is detectable in the nucleus but not in the cytoplasm of T cells. Thus, to our knowledge, PDE9A1 is the only PDE isoform found to localize exclusively in the nucleus. We speculate that the physiological role of the PDE9A diversity may be imparting cGMP-metabolizing ability to specific cellular compartments in appropriate tissues.

  12. X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure

    PubMed Central

    Pierides, A; Voskarides, K; Kkolou, M; Hadjigavriel, M; Deltas, C

    2013-01-01

    Alport syndrome (ATS) results from X-linked, COL4A5 mutations (85%) or from autosomal recessive homozygous or compound heterozygous COL4A3/A4 mutations (15%), associated with alternate thinning and thickening as well as splitting and lamellation of the glomerular basement membranes. In contrast, familial microhematuria with thin basement membranes is thought to result from heterozygous COL4A3/A4 mutations. This absolute separation may not always be true. Renal biopsies and molecular genetics were used to study microhematuric families in the Hellenic population we serve. The COL4A5 gene was studied by PCR and direct re-sequencing for new mutations, while PCR-RFLP was used to identify more carriers of known COL4A5 and COL4A3/A4 mutations. Molecular genetics in two undiagnosed microhematuric Cypriot families, revealed COL4A5 mutation P628L indicating X-linked ATS. Of nine males, seven developed end stage kidney disease (ESKD) between 31 and 56, while two are well at 51 and 57, exhibiting microhematuria and thin basement membrane nephropathy (TBMN). COL4A5 mutation G624D was also identified in six Greek families. Seventy five members had DNA tests and 37 proved positive. Four positive males developed ESKD at 61, 51, 50 and 39 years, while the remaining and all females showed only microhematuria. A literature search revealed eight papers with six similar hypomorphic COL4A5 mutations presenting as phenocopies of TBMN. In conclusion, X-linked COL4A5 ATS mutations produce a phenotypic spectrum with a) classical ATS with early onset ESKD, neurosensory deafness and ocular defects b) males with only ESKD and late deafness and c) males due to missense mutations, such as G624D and P628L that may only exhibit microhematuria, TBMN, mild chronic renal failure (CRF) or late onset ESKD. Consequently when investigating “benign familial hematuria” these and other similar X-linked COL4A5 mutations should also be searched for. PMID:24470729

  13. Charge symmetry breaking in A = 4 hypernuclei

    NASA Astrophysics Data System (ADS)

    Achenbach, P.

    2016-11-01

    Charge symmetry breaking in the A = 4 hypernuclear system is reviewed. The data on binding energies of the mirror nuclei and hypernuclei are examined. At the Mainz Microtron MAMI the high-resolution spectroscopy of decay-pions in strangeness electro-production is used to extract the Λ hyperon ground state binding energy in 4ΛH. This binding energy is used together with the 4ΛHe ground state binding energy from nuclear emulsion experiments and with energy levels of the 1+ excited state for both hypernuclei from γ-ray spectroscopy to address the charge symmetry breaking in the strong interaction. The binding energy difference of the ground states in the mirror pair is reduced from its long accepted value ΔB4Λ(0+g.s.) ≈ 0.35MeV to ≈ 0.24MeV. The energy difference of the excited states becomes ΔB4Λ(1+exc) ≈ -0.08MeV, for the first time with opposite sign. These values were not reproduced by theoretical calculations with the exception of very recent approaches, although with a large systematic dependence. The full understanding of the charge symmetry breaking in the A = 4 hypernuclei still remains one of the open issues of hypernuclear physics.

  14. Allosteric activation of midazolam CYP3A5 hydroxylase activity by icotinib - Enhancement by ketoconazole.

    PubMed

    Zhuang, XiaoMei; Zhang, TianHong; Yue, SiJia; Wang, Juan; Luo, Huan; Zhang, YunXia; Li, Zheng; Che, JinJing; Yang, HaiYing; Li, Hua; Zhu, MingShe; Lu, Chuang

    2016-12-01

    Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4. When co-incubated with selective CYP3A4 inhibitor CYP3cide or monoclonal human CYP3A4 inhibitory antibody in HLM, the activation was extended to ∼60%, suggesting CYP3A5 might be the isozyme involved. Further, the relative activation was enhanced to ∼270% in rhCYP3A5 in the presence of ketoconazole. The activation was substrate and pathway dependent and observed only in the formation of 1'-OH-midazolam, and not 4-OH-midazolam, 6β-OH-testosterone, or oxidized nifedipine. The activation requires the presence of cytochrome b5 and it is only observed in the liver microsomes of dogs, monkeys, and humans, but not in rats and mice. Kinetic analyses of 1'-OH-midazolam formation showed that ICO increased the Vmax values in HLM and rhCYP3A5 with no significant changes in Km values. By adding CYP3cide with ICO to the incubation, the Vmax values increased 2-fold over the CYP3cide control. Addition of ketoconazole with ICO alone or ICO plus CYP3cide resulted in an increase in Vmax values and decrease in Km values compared to their controls. This phenomenon may be attributed to a new mechanism of CYP3A5 heterotropic activation, which warrants further investigation. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Variability in Expression of CYP3A5 in Human Fetal Liver.

    PubMed

    Vyhlidal, Carrie A; Pearce, Robin E; Gaedigk, Roger; Calamia, Justina C; Shuster, Diana L; Thummel, Kenneth E; Leeder, J Steven

    2015-08-01

    Members of the cytochrome P450 3A (CYP3A) subfamily of drug metabolizing enzymes exhibit developmental changes in expression in human liver characterized by a transition between CYP3A7 and CYP3A4 over the first few years of life. In contrast, the developmental expression of CYP3A5 is less well understood due to polymorphic expression of the enzyme in human tissues as a result of the prevalence of the CYP3A5*3 allele, which leads to alternative splicing. We further explored the expression of CYP3A5 and the impact of alternative splicing on the variability of CYP3A5 functional activity in a large bank of human prenatal liver samples (7 to 32 weeks of age postconception). The expression of normally spliced CYP3A5 mRNA in all human fetal liver samples varied 235-fold whereas CYP3A5 SV1 mRNA was only detected in fetal liver samples with at least one CYP3A5*3 allele. Formation of 1'-OH midazolam (MDZ) varied 79-fold, and the ratio of 1'-OH MDZ to 4-OH MDZ varied 8-fold and depended on the presence or absence of the CYP3A5*3 allele. Formation of 4-OH MDZ was significantly associated with 1'-OH MDZ (r(2) = 0.76, P < 0.0001) but varied (36-fold) independently of CYP3A5 genotype or expression. The substantial interindividual variability that remains even after stratification for CYP3A5 genotype suggests that factors such as environmental exposure and epigenetic alterations act in addition to genetic variation to contribute to the variability of CYP3A5 expression in human prenatal liver.

  16. 26 CFR 1.411(a)-5 - Service included in determination of nonforfeitable percentage.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... employee's right to his employer-derived accrued benefit under section 411(a)(2) and § 1.411(a)-3, all of... are not equalled or exceeded by the aggregate number of consecutive 1-year breaks in service occuring... employee has nonforfeitable rights under the predecessor plan, are determined under section 411(a) (5)...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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 general...

  2. 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,...

  3. 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,...

  4. 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,...

  5. 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,...

  6. 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. ...

  7. 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. ...

  8. 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. ...

  9. 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. ...

  10. 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. ...

  11. 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 the...

  12. 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 the...

  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 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 the...

  14. 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 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 the...

  15. 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 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 the...

  16. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  17. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  18. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  19. 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... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...

  20. 22 CFR 3a.5 - Basis for approval or disapproval.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Basis for approval or disapproval. 3a.5 Section 3a.5 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.5 Basis for approval or disapproval. Decisions by the...

  1. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2013-07-01 2013-07-01 false Delegation to the General 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...

  2. 38 CFR 18a.5 - Delegation to the General Counsel.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Delegation to the General 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...

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

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Delegation to the General 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...

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2014-07-01 2014-07-01 false Delegation to the General 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Delegation to the General 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...

  6. Improving Quality and Performance of Leads Loaded with Composition A-5

    DTIC Science & Technology

    1984-03-01

    Composition A-5 sensitivity versus stearic acid and HMX content 8 ř 3 Sieve analysis of the RDX used to produce Composition A-5 9 -A 4 Lot numbers of...cm 3 . The leads were loaded at LSAAP on a 41 station rotary press which is typically used for high volume lead production. Lot numbers assigned to...sample of this lot was made with Class 5 RDX (97% minimum through a No. 325 U.S. Standard Sieve). .9 -’ .’ Table 4. Lot numbers of leads Material: Comp

  7. UNIT 14A.4 Generation of Recombinant Vaccinia Viruses

    PubMed Central

    Earl, Patricia L.; Moss, Bernard; Wyatt, Linda S.

    2016-01-01

    This unit describes how to infect cells with vaccinia virus and then transfect them with a plasmid-transfer vector or PCR fragment to generate a recombinant virus. Selection and screening methods used to isolate recombinant viruses and a method for the amplification of recombinant viruses are described. Finally, a method for live immunostaining that has been used primarily for detection of recombinant modified vaccinia virus Ankara (MVA) is presented. This unit first describes how to infect cells with vaccinia virus and then transfect them with a plasmid-transfer vector or PCR fragment to generate a recombinant virus (see Basic Protocol 1). Also presented are selection and screening methods used to isolate recombinant viruses (see Basic Protocol 2) and a method for the amplification of recombinant viruses (see Basic Protocol 3). Finally, a method for live immunostaining that has been used primarily for detection of recombinant modified vaccinia virus Ankara (MVA) is presented (see Basic Protocol 4). HeLa S3 cells are recommended for large-scale growth of vaccinia virus. BS-C-1 cells may be used for xanthine-guanine phosphoribosyltransferase (XGPRT) and plaque size selection, fluorescent protein screening, transfection and determination of virus titer (UNIT 14A.3). For thymidine kinase (TK) selection, HuTK− 143B cells are used. With MVA, all steps are carried out in CEF or BHK-21 cells (UNIT 14A.3). CAUTION Proceed carefully and follow biosafety level 2 (BL-2) practices when working with standard vaccinia virus (see UNIT 14A.3 for safety precautions). [*Copy Editor: The original CPMB unit referenced CPMB Unit 16.15 for safety. The chapter editor asked that the authors include some of the safety information in the revised units – CPMB 16.16 and 16.17 – which are now CPMC Unit 14A.3 and 14A.4. As a result, the authors changed the safety citation here to “Unit 14A.3”, which doesn’t have nearly as much information as the original CPMB Unit 16.15. Perhaps the

  8. Whole genomic analysis of bovine group A rotavirus strains A5-10 and A5-13 provides evidence for close evolutionary relationship with human rotaviruses.

    PubMed

    Komoto, Satoshi; Pongsuwanna, Yaowapa; Tacharoenmuang, Ratana; Guntapong, Ratigorn; Ide, Tomihiko; Higo-Moriguchi, Kyoko; Tsuji, Takao; Yoshikawa, Tetsushi; Taniguchi, Koki

    2016-11-15

    Bovine group A rotavirus (RVA) is an important cause of acute diarrhea in calves worldwide. In order to obtain precise information on the origin and evolutionary dynamics of bovine RVA strains, we determined and analyzed the complete nucleotide sequences of the whole genomes of six archival bovine RVA strains; four Thai strains (RVA/Cow-tc/THA/A5-10/1988/G8P[1], RVA/Cow-tc/THA/A5-13/1988/G8P[1], RVA/Cow-tc/THA/61A/1989/G10P[5], and RVA/Cow-tc/THA/A44/1989/G10P[11]), one American strain (RVA/Cow-tc/USA/B223/1983/G10P[11]), and one Japanese strain (RVA/Cow-tc/JPN/KK3/1983/G10P[11]). On whole genomic analysis, the 11 gene segments of strains A5-10, A5-13, 61A, A44, B223, and KK3 were found to be considerably genetically diverse, but to share a conserved non-G/P genotype constellation except for the NSP1 gene (I2-R2-C2-M2-(A3/11/13/14)-N2-T6-E2-H3), which is commonly found in RVA strains from artiodactyls such as cattle. Furthermore, phylogenetic analysis revealed that most genes of the six strains were genetically related to bovine and bovine-like strains. Of note is that the VP1, VP3, and NSP2 genes of strains A5-10 and A5-13 exhibited a closer relationship with the cognate genes of human DS-1-like strains than those of other RVA strains. Furthermore, the VP6 genes of strains A5-10 and A5-13 appeared to be equally related to both human DS-1-like and bovine strains. Thus, strains A5-10 and A5-13 were suggested to be derived from the same evolutionary origin as human DS-1-like strains, and were assumed to be examples of bovine RVA strains that provide direct evidence for a close evolutionary relationship between bovine and human DS-1-like strains. Our findings will provide important insights into the origin of bovine RVA strains, and into evolutionary links between bovine and human RVA strains.

  9. COL4A5-associated X-linked Alport syndrome in a female patient with early inner ear deafness due to a mutation in MYH9.

    PubMed

    Strasser, Katja; Hoefele, Julia; Bergmann, Carsten; Büscher, Anja K; Büscher, Rainer; Hoyer, Peter F; Weber, Stefanie

    2012-11-01

    Alport syndrome (ATS) is a type-IV collagen inherited disorder, caused by mutations in COL4A3 and COL4A4 (autosomal recessive) or COL4A5 (X-linked). Clinical symptoms include progressive renal disease, eye abnormalities and high-tone sensorineural deafness. A renal histology very similar to ATS is observed in a subset of patients affected by mutations in MYH9, encoding non-muscle-myosin Type IIa--a cytoskeletal contractile protein. MYH9-associated disorders (May-Hegglin anomaly, Epstein and Fechtner syndrome, and others) are inherited in an autosomal dominant manner and characterized by defects in different organs (including eyes, ears, kidneys and thrombocytes). We describe here a 6-year-old girl with haematuria, proteinuria, and early sensorineural hearing loss. The father of the patient is affected by ATS, the mother by isolated inner ear deafness. Genetic testing revealed a pathogenic mutation in COL4A5 (c.2605G>A) in the girl and her father and a heterozygous mutation in MYH9 (c.4952T>G) in the girl and her mother. The paternal COL4A5 mutation seems to account for the complete phenotype of ATS in the father and the maternal mutation in MYH9 for the inner ear deafness in the mother. It has been discussed that the interaction of both mutations could be responsible for both the unexpected severity of ATS symptoms and the very early onset of inner ear deafness in the girl.

  10. The effects of Bleomycin A5 on infantile maxillofacial haemangioma

    PubMed Central

    2011-01-01

    Objective To examine the effects of bleomycin A5 on infantile maxillofacial haemangiomas. Methods Bleomycin A5 was given by multiple intralesinoal injections and the dosage was given according to the age of the patient and size of the lesion. Parts of patients were accompanied by prednisone treatment(2-5 mg/kg, po, QOD. Results All the haemangiomas involuted completely after treated with bloemycin A5 with better recovery of skin color and less scar forming in small haemangiomas. Conclusion Infantile haemangioma could be effectively treated with bleomycin A5 without serious side effects. PMID:21736714

  11. Topological Quantum Information in a 3D Neutral Atom Array

    DTIC Science & Technology

    2015-01-02

    laser cooling in a 3D large spacing lattice, developing flexible state manipulation techniques, and demonstrating long atomic coherence times...demonstrated the execution of single qubit gates on any arbitrary sequence of individual lattice sites in a 5×5×5 array. This entailed improving laser ... lasers , the development of which is in progress. Theoretical optimization of entangling operations in the presence of experimental noise is critical

  12. 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...

  13. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Request for access to records. 261a.5 Section 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... writing to the Inspector General, Board of Governors of the Federal Reserve System, 20th Street and...

  14. Apolipoprotein A5: Extracellular and Intracellular Roles in Triglyceride Metabolism.

    PubMed

    Forte, Trudy M; Ryan, Robert O

    2015-01-01

    This review addresses two major functions of apolipoprotein (apo) A5 including (1) its role in maintaining normal plasma levels of circulating triglyceride (TG) and (2) its role as a component of hepatic lipid droplets. ApoA5 is synthesized solely in the liver and circulating concentrations are extremely low. In the plasma, ApoA5 associates with TG-rich lipoproteins and enhances TG hydrolysis and remnant lipoprotein clearance. ApoA5 loss-of-function single nucleotide polymorphisms are associated with reduced lipolysis, poor remnant clearance and concomitantly, hypertriglyceridemia. Although there have been substantial breakthroughs in understanding pathophysiology associated with secreted ApoA5, there is a paucity of knowledge on the functionality of intracellular ApoA5. However, recent studies indicate that overexpression of intracellular ApoA5 is positively associated with accumulation of TG-rich lipid droplets in hepatocytes. It is thought that ApoA5 may have a causal role in non-alcoholic fatty liver disease (NAFLD) and thus, may serve as a target for developing therapeutics for NAFLD.

  15. 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...

  16. 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...

  17. 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...

  18. 8 CFR 274a.5 - Use of labor through contract.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Use of labor through contract. 274a.5 Section 274a.5 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF..., 1986 (or, with respect to the Commonwealth of the Northern Mariana Islands, after the...

  19. 26 CFR 1.6038A-5 - Authorization of agent.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Authorization of agent. 1.6038A-5 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6038A-5 Authorization of agent. (a) Failure to... described in paragraph (b) of this section) the reporting corporation to act as its limited agent solely for...

  20. 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... recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority... recommendations any concurring or dissenting views as well as abstentions and absences. Any member may submit...

  1. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 7 2013-07-01 2013-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor... recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority of all Committee members present. The Chairman shall include in any report of such advice or...

  2. 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...

  3. 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...

  4. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 7 2014-07-01 2014-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor... recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority... recommendations any concurring or dissenting views as well as abstentions and absences. Any member may submit...

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

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 7 2012-07-01 2012-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor... recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority... recommendations any concurring or dissenting views as well as abstentions and absences. Any member may submit...

  6. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor... recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority... recommendations any concurring or dissenting views as well as abstentions and absences. Any member may submit...

  7. 26 CFR 1.408A-4 - Converting amounts to Roth IRAs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...,000 exemption under section 469(i) relating to the disallowance of passive activity losses from rental real estate activities. However, as provided in § 1.408A-3 A-5, the taxable conversion amount (and any... section 72(t)(4)(A) has occurred. Distributions from the Roth IRA that are part of the original series of...

  8. Ephrin-A5 Deficiency Alters Sensorimotor and Monoaminergic Development

    PubMed Central

    Sheleg, Michal; Yochum, Carrie L.; Wagner, George C.; Zhou, Renping; Richardson, Jason R.

    2012-01-01

    The Eph receptors and their ligands, the ephrins, play an important role during neural development. In particular, ephrin-A5 is highly expressed in the developing nervous system in several brain regions including the olfactory bulb, frontal cortex, striatum and hypothalamus. Although a number of studies have characterized the expression of ephrin-A5 in these regions, very little is known about the functional consequences that might follow alterations in the expression of this ligand. Previously, we demonstrated that ephrin-A5 acts as a guidance molecule regulating the trajectory of the ascending midbrain dopaminergic pathways. In light of this finding and the critical role of dopamine in modulating a number of behaviors, we sought to determine whether loss of ephrin-A5 altered neurobehavioral development. Our results indicate that ephrin-A5-null mice exhibit delays in reaching developmental milestones and in the maturation of motor skills. In addition, they exhibit increased locomotor activity and reduced levels of brain monoamines. Therefore, we conclude that ephrin-A5 expression appears to be critical for proper development of central monoaminergic pathways and that its loss results in a number of neurodevelopmental abnormalities. Because alterations in monoamine function are associated with a variety of neurodevelopmental disorders, these data suggest that further study on the potential role of ephrin-A5 in such disorders is warranted. PMID:22954718

  9. CYP3A5 Gene Variation Influences Cyclosporine A Metabolite Formation and Renal Cyclosporine Disposition

    PubMed Central

    Zheng, Songmao; Tasnif, Yasar; Hebert, Mary F.; Davis, Connie L.; Shitara, Yoshihisa; Calamia, Justina C.; Lin, Yvonne S.; Shen, Danny D.; Thummel, Kenneth E.

    2013-01-01

    Background Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend upon the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intra-renal CsA accumulation. Methods An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by LC-MS. In vitro incubations of CsA, AM1, AM9 and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. Results The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared to CYP3A5 nonexpressors, the average blood AUC for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P = 0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance, based on a 48-hour collection, was 20.4% lower in CYP3A5 expressors compared to CYP3A5 nonexpressors (4.2 ± 1.0 and 5.3 ± 1.3 mL/min, respectively, P = 0.037), which is suggestive of CYP3A5-dependent intra-renal CsA metabolism. Conclusions At steady-state, intra-renal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to inter-patient variability in the risk of CsA-induced nephrotoxicity. PMID:23354298

  10. 32 CFR 809a.3 - Unauthorized entry.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Unauthorized entry. 809a.3 Section 809a.3 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy § 809a.3...

  11. 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...

  12. 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...

  13. 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 may...

  14. 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 may...

  15. 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 may...

  16. 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 may...

  17. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 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 an...

  18. 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 an...

  19. 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 an...

  20. 12 CFR 269a.3 - Intervenor.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 12 Banks and Banking 4 2012-01-01 2012-01-01 false Intervenor. 269a.3 Section 269a.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.3 Intervenor. The term intervenor means the party in a proceeding whose intervention has...

  1. 12 CFR 269a.3 - Intervenor.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Intervenor. 269a.3 Section 269a.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.3 Intervenor. The term intervenor means the party in a proceeding whose intervention has...

  2. 12 CFR 269a.3 - Intervenor.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Intervenor. 269a.3 Section 269a.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.3 Intervenor. The term intervenor means the party in a proceeding whose intervention has been...

  3. 12 CFR 269a.3 - Intervenor.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 12 Banks and Banking 4 2013-01-01 2013-01-01 false Intervenor. 269a.3 Section 269a.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) DEFINITIONS § 269a.3 Intervenor. The term intervenor means the party in a proceeding whose intervention has...

  4. 12 CFR 269a.3 - Intervenor.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Intervenor. 269a.3 Section 269a.3 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.3 Intervenor. The term intervenor means the party in a proceeding whose intervention has been...

  5. 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 IDENTITY-RESEARCH SUBJECTS § 2a.3 Application; coordination. (a) Any person engaged in (or who intends to...

  6. Bioconversion of the antihistaminc drug loratadine by tobacco cell suspension cultures expressing human cytochrome P450 3A4.

    PubMed

    Warzecha, Heribert; Ferme, Daniela; Peer, Markus; Frank, Andreas; Unger, Matthias

    2010-03-01

    In this study we have expanded the metabolic potential of plant cell suspension cultures by introducing active human cytochrome P450 monooxygenase 3A4 into tobacco cells. Exogenously supplied loratadine was metabolized in a 3A4-specific manner, showing the capacity of this system for the generation of metabolites.

  7. Effect of pyrazole, cobalt and phenobarbital on mouse liver cytochrome P-450 2a-4/5 (Cyp2a-4/5) expression.

    PubMed Central

    Hahnemann, B; Salonpää, P; Pasanen, M; Mäenpää, J; Honkakoski, P; Juvonen, R; Lang, M A; Pelkonen, O; Raunio, H

    1992-01-01

    Pyrazole, cobalt and phenobarbital increase the activity of coumarin 7-hydroxylase (COH) in mouse liver. To study the mechanism of this increase, we measured the expression of the cytochrome P-450 2a-4/5 (Cyp2a-4/5) complex, which mediates testosterone 15 alpha-hydroxylase and COH activities, as a function of dose and time after the treatment of C57BL/6 (B6) and DBA/2 (D2) male mice with the inducers. COH activity and Cyp2a-4/5 steady-state mRNA levels were increased in both strains in response to the inducers. No marked effect occurred with testosterone 15 alpha-hydroxylase or activities associated with Cyp1a-1 or Cyp2e-1. A 2-7-fold increase in response to the inducers was seen in the amount of P-450Coh (cytochrome P-450 isoenzyme catalysing coumarin 7-hydroxylation) protein in Western immunoblots. PCR amplification of a 1 kb region in Cyp2a-4/5-mRNA-derived cDNA, followed by cutting at the diagnostic PstI site, showed that most of the steady-state mRNA consisted of Cyp2a-5, which is also the form most affected by pyrazole. Nuclear run-off analysis revealed no increase in the transcription rate of Cyp2a-4/5 after pyrazole or cobalt treatment, whereas a 2-3-fold increase occurred after phenobarbital pretreatment in B6 mice. Together with previous reports [Aida & Negishi (1991) Biochemistry 30, 8041-8045], the current data suggest that both pyrazole and cobalt increase COH catalytic activity by affecting Cyp2a-5 by post-transcriptional mechanisms in mice. Images Fig. 1. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7. PMID:1520280

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

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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, 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...

  10. 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...

  11. 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...

  12. 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...

  13. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Specifications for Inside Containers, and Linings § 178.33a-5 Material. (a) Uniform quality steel plate such as... plate; or nonferrous metal of uniform drawing quality. (b) Material with seams, cracks, laminations...

  14. A5: Automated Analysis of Adversarial Android Applications

    DTIC Science & Technology

    2014-06-03

    AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Mobile malware is growing ? both in...result there is a pressing need for techniques and tools that provide automated analysis of mobile malware samples. We present A5, an automated system...to process Android malware . A5 is a hybrid system combining static and dynamic malware analysis techniques. Android?s architecture permits many

  15. Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination.

    PubMed

    Miyauchi, Kengo; Tsuchikawa, Takahiro; Wada, Masataka; Abiko, Takehiro; Kyogoku, Noriaki; Shichinohe, Toshiaki; Miyahara, Yoshihiro; Kageyama, Shinichi; Ikeda, Hiroaki; Shiku, Hiroshi; Hirano, Satoshi

    2016-05-01

    To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival. 12 patients who had been injected with 300 μg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed. Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66.7%), compared with six patients (50%) for anti-NY-ESO-1 and five patients (41.7%) for anti-MAGE-A3 after five vaccinations. We identified frequent antigen spreading following MAGE-A4 vaccinations without associations with the clinical response or patient prognosis. Antigen spreading pattern might reflect tumor shrinkage as a response to treatment and treatment history (clinical trial registration number: UMIN000001999).

  16. Human Cytochrome P450 3A4 as a Biocatalyst: Effects of the Engineered Linker in Modulation of Coupling Efficiency in 3A4-BMR Chimeras

    PubMed Central

    Degregorio, Danilo; D'Avino, Serena; Castrignanò, Silvia; Di Nardo, Giovanna; Sadeghi, Sheila J.; Catucci, Gianluca; Gilardi, Gianfranco

    2017-01-01

    Human liver cytochrome P450 3A4 is the main enzyme involved in drug metabolism. This makes it an attractive target for biocatalytic applications, such as the synthesis of pharmaceuticals and drug metabolites. However, its poor solubility, stability and low coupling have limited its application in the biotechnological context. We previously demonstrated that the solubility of P450 3A4 can be increased by creating fusion proteins between the reductase from Bacillus megaterium BM3 (BMR) and the N-terminally modified P450 3A4 (3A4-BMR). In this work, we aim at increasing stability and coupling efficiency by varying the length of the loop connecting the two domains to allow higher inter-domain flexibility, optimizing the interaction between the domains. Starting from the construct 3A4-BMR containing the short linker Pro-Ser-Arg, two constructs were generated by introducing a 3 and 5 glycine hinge (3A4-3GLY-BMR and 3A4-5GLY-BMR). The three fusion proteins show the typical absorbance at 450 nm of the reduced heme-CO adduct as well as the correct incorporation of the FAD and FMN cofactors. Each of the three chimeric proteins were more stable than P450 3A4 alone. Moreover, the 3A4-BMR-3-GLY enzyme showed the highest NADPH oxidation rate in line with the most positive reduction potential. On the other hand, the 3A4-BMR-5-GLY fusion protein showed a Vmax increased by 2-fold as well as a higher coupling efficiency when compared to 3A4-BMR in the hydroxylation of the marker substrate testosterone. This protein also showed the highest rate value of cytochrome c reduction when this external electron acceptor is used to intercept electrons from BMR to P450. The data suggest that the flexibility and the interaction between domains in the chimeric proteins is a key parameter to improve turnover and coupling efficiency. These findings provide important guidelines in engineering catalytically self-sufficient human P450 for applications in biocatalysis. PMID:28377716

  17. Human Cytochrome P450 3A4 as a Biocatalyst: Effects of the Engineered Linker in Modulation of Coupling Efficiency in 3A4-BMR Chimeras.

    PubMed

    Degregorio, Danilo; D'Avino, Serena; Castrignanò, Silvia; Di Nardo, Giovanna; Sadeghi, Sheila J; Catucci, Gianluca; Gilardi, Gianfranco

    2017-01-01

    Human liver cytochrome P450 3A4 is the main enzyme involved in drug metabolism. This makes it an attractive target for biocatalytic applications, such as the synthesis of pharmaceuticals and drug metabolites. However, its poor solubility, stability and low coupling have limited its application in the biotechnological context. We previously demonstrated that the solubility of P450 3A4 can be increased by creating fusion proteins between the reductase from Bacillus megaterium BM3 (BMR) and the N-terminally modified P450 3A4 (3A4-BMR). In this work, we aim at increasing stability and coupling efficiency by varying the length of the loop connecting the two domains to allow higher inter-domain flexibility, optimizing the interaction between the domains. Starting from the construct 3A4-BMR containing the short linker Pro-Ser-Arg, two constructs were generated by introducing a 3 and 5 glycine hinge (3A4-3GLY-BMR and 3A4-5GLY-BMR). The three fusion proteins show the typical absorbance at 450 nm of the reduced heme-CO adduct as well as the correct incorporation of the FAD and FMN cofactors. Each of the three chimeric proteins were more stable than P450 3A4 alone. Moreover, the 3A4-BMR-3-GLY enzyme showed the highest NADPH oxidation rate in line with the most positive reduction potential. On the other hand, the 3A4-BMR-5-GLY fusion protein showed a Vmax increased by 2-fold as well as a higher coupling efficiency when compared to 3A4-BMR in the hydroxylation of the marker substrate testosterone. This protein also showed the highest rate value of cytochrome c reduction when this external electron acceptor is used to intercept electrons from BMR to P450. The data suggest that the flexibility and the interaction between domains in the chimeric proteins is a key parameter to improve turnover and coupling efficiency. These findings provide important guidelines in engineering catalytically self-sufficient human P450 for applications in biocatalysis.

  18. 26 CFR 1.401(a)(4)-12 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... Ancillary benefit. Ancillary benefit is defined in § 1.401(a)(4)-4(e)(2). Average annual compensation. Average annual compensation is defined in § 1.401(a)(4)-3(e)(2). Base benefit percentage. Base benefit... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit...

  19. Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib

    PubMed Central

    Takakusa, Hideo; Wahlin, Michelle D.; Zhao, Chunsheng; Hanson, Kelsey L.; New, Lee Sun; Chan, Eric Chun Yong

    2011-01-01

    Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib. PMID:21363997

  20. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 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.4 How...

  1. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 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.4...

  2. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 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.4...

  3. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 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.4...

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

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 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.4...

  5. 22 CFR 3a.4 - Procedure for requesting approval.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Procedure for requesting approval. 3a.4 Section 3a.4 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.4 Procedure for requesting approval. (a) An applicant must...

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

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

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

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  8. 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 PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  9. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.4 Contents of application; in general. In addition to any other...

  10. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Calculation of time. 260.7a-4 Section 260.7a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-4 Calculation...

  11. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  12. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  13. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  14. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  15. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Good faith defense. 274a.4 Section 274a.4... ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good faith compliance with the employment verification requirements...

  16. CYP3A4/5 polymorphisms affect the blood level of cyclosporine and tacrolimus in Chinese renal transplant recipients.

    PubMed

    Li, Dan-ying; Teng, Rui-chen; Zhu, Huai-jun; Fang, Yun

    2013-06-01

    Both cyclosporine and tacrolimus display a narrow therapeutic index as well as high interindividual pharmacokinetic variability. We approached the effect of the CYP3A4*18B and CYP3A5*3 polymorphisms and haplotypes on the whole blood cyclosporine or tacrolimus concentration in Chinese renal transplant patients during the first month after transplantation. A total of 83 recipients receiving tacrolimus or cyclosporine was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The whole blood concentration was measured by enzyme-multiplied immunoassay technique. Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the tacrolimus dose-adjusted trough concentration (C0/D). The tacrolimus C0/D was higher in carriers of haplotype GG compared with the non-carriers. The cyclosporine dose-adjusted 2-hour post-dose concentrations (C2/D), dose-adjusted C0 + C2 ((C0 + C2)/D) and C2/C0 during Days 15 - 21 displayed significant difference among the three genotypes. Statistical difference was observed between CYP3A4*1/*1 and CYP3A4*18B/*18B groups and between CYP3A4*1/*18B and CYP3A4*18B/*18B groups, but no difference was detected between CYP3A4*1/*1 and CYP3A4*1/*18B groups. No difference was found in C0/D among the three genotypes of CYP3A4*18B polymorphism, and neither CYP3A5*3 polymorphisms nor CYP3A haplotype-derived genotypes affected the cyclosporine dose-adjusted concentration. Genetic polymorphisms of CYP3A5*3 and CYP3A4*18B may be partly responsible in large interindividual variability of cyclosporine and tacrolimus blood levels in Chinese renal transplant patients during the first month after transplantation. A patient carried combined genotype of CYP3A4*1/*1-CYP3A5* 3/*3 might require lower tacrolimus doses to achieve target concentration levels. Genotyping of CYP3A4*18B and CYP3A5*3 before transplantation is of benefit in determining a suitable initial dose for each patient.

  17. 75 FR 6860 - Airworthiness Directives; International Aero Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-12

    ..., V2527M-A5, V2528-D5, V2530-A5, and V2533-A5 Turbofan Engines AGENCY: Federal Aviation Administration (FAA... turbofan engines and certain serial numbers (S/Ns) of IAE V2522-A5, V2524-A5, V2527-A5, V2527E-A5, V2527M-A5, V2530-A5, and V2533-A5 turbofan engines. For certain S/Ns of V2500-A1, V2522-A5, V2524-A5, V2527...

  18. S100A4 protects the myocardium against ischemic stress.

    PubMed

    Doroudgar, Shirin; Quijada, Pearl; Konstandin, Mathias; Ilves, Kelli; Broughton, Kathleen; Khalafalla, Farid G; Casillas, Alexandria; Nguyen, Kristine; Gude, Natalie; Toko, Haruhiro; Ornelas, Luis; Thuerauf, Donna J; Glembotski, Christopher C; Sussman, Mark A; Völkers, Mirko

    2016-11-01

    Myocardial infarction is followed by cardiac dysfunction, cellular death, and ventricular remodeling, including tissue fibrosis. S100A4 protein plays multiple roles in cellular survival, and tissue fibrosis, but the relative role of the S100A4 in the myocardium after myocardial infarction is unknown. This study aims to investigate the role of S100A4 in myocardial remodeling and cardiac function following infarct damage. S100A4 expression is low in the adult myocardium, but significantly increased following myocardial infarction. Deletion of S100A4 increased cardiac damage after myocardial infarction, whereas cardiac myocyte-specific overexpression of S100A4 protected the infarcted myocardium. Decreased cardiac function in S100A4 Knockout mice was accompanied with increased cardiac remodeling, fibrosis, and diminished capillary density in the remote myocardium. Loss of S100A4 caused increased apoptotic cell death both in vitro and in vivo in part mediated by decreased VEGF expression. Conversely, S100A4 overexpression protected cells against apoptosis in vitro and in vivo. Increased pro-survival AKT-signaling explained reduced apoptosis in S100A4 overexpressing cells. S100A4 expression protects cardiac myocytes against myocardial ischemia and is required for stabilization of cardiac function after MI. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Significance of the S100A4 protein in psoriasis.

    PubMed

    Zibert, John R; Skov, Lone; Thyssen, Jacob P; Jacobsen, Grete K; Grigorian, Mariam

    2010-01-01

    The S100A4 protein is reported as a pivotal player in the tumor microenvironment with a metastasis-promoting function. Moreover, the upregulation of S100A4 is found in other non-malignant human disorders as cardiac and pulmonary systems and rheumatoid arthritis. In this study, we investigated the expression and significance of S100A4 in psoriasis. We found significant upregulation of S100A4 in the dermis of psoriatic skin compared with normal skin. This pattern of S100A4 expression differs considerably from that of other S100 proteins, S100A7 and S100A8/9, with predominant expression in the epidermis of psoriasis. Furthermore, we revealed a massive release of the biologically active forms of S100A4 from psoriatic skin. Interestingly, we found stabilization (increase) of p53 in the basal layer of epidermis in close proximity to cells expressing S100A4. To examine the possible implication of S100A4 in the pathogenesis of psoriasis, we analyzed the effect of S100A4 blocking antibodies in a human psoriasis xenograft SCID mouse model and observed a significant reduction of the epidermal thickness and impairment in cell proliferation and dermal vascularization. In conclusion, we showed strong upregulation and release of S100A4 in the upper dermis of psoriatic skin and found evidence indicating that S100A4 might actively contribute to the pathogenesis of psoriasis.

  20. 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

  1. 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...

  2. 46 CFR 147A.3 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 5 2011-10-01 2011-10-01 false Applicability. 147A.3 Section 147A.3 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD... to which 49 CFR parts 171-179 apply under 49 CFR 176.5. ...

  3. 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...

  4. 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...

  5. 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...

  6. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 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 of...

  7. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 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 of...

  8. 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 of...

  9. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 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 of...

  10. 32 CFR 809a.3 - Unauthorized entry.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Unauthorized entry. 809a.3 Section 809a.3 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy §...

  11. 12 CFR 261a.5 - Request for access to record.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... records shall submit a request in writing to the Secretary of the Board, Board of Governors of the Federal... the Division of Human Resources, Board of Governors of the Federal Reserve System, 20th and...

  12. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... Federal Reserve System, 20th Street and Constitution Avenue, NW., Washington, DC 20551. (2) If you request... writing to the Inspector General, Board of Governors of the Federal Reserve System, 20th Street and...

  13. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... Federal Reserve System, 20th Street and Constitution Avenue, NW., Washington, DC 20551. (2) If you request... writing to the Inspector General, Board of Governors of the Federal Reserve System, 20th Street and...

  14. 12 CFR 261a.5 - Request for access to records.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 261a.5 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... Federal Reserve System, 20th Street and Constitution Avenue, NW., Washington, DC 20551. (2) If you request... writing to the Inspector General, Board of Governors of the Federal Reserve System, 20th Street and...

  15. Rhinoscleroma in a 5-year-old Portuguese Child.

    PubMed

    Simão, Inês; Gaspar, Iuri; Faustino, Rosário; Brito, Maria João Rocha

    2014-07-01

    Rhinoscleroma is a chronic granulomatous infectious disease that is rare in Western Europe. We report the case of a 5-year-old Portuguese boy diagnosed with rhinoscleroma in the context of recurrent epistaxis. He had a 6-month course of antibiotic (amoxicillin plus clavulanate) therapy with full recovery.

  16. 32 CFR 383a.5 - Responsibilities and functions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.5 Responsibilities and functions. (a) The Director, Defense Commissary Agency (DeCA), shall: (1) Organize, direct, and manage the DeCA and all... activities assigned to the DeCA. (2) Plan, program, budget, design, manage, and ensure the execution of...

  17. 32 CFR 383a.5 - Responsibilities and functions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.5 Responsibilities and functions. (a) The Director, Defense Commissary Agency (DeCA), shall: (1) Organize, direct, and manage the DeCA and all... activities assigned to the DeCA. (2) Plan, program, budget, design, manage, and ensure the execution of...

  18. 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 law...

  19. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Plexin-A4 negatively regulates T lymphocyte responses.

    PubMed

    Yamamoto, Midori; Suzuki, Kazuhiro; Okuno, Tatsusada; Ogata, Takehiro; Takegahara, Noriko; Takamatsu, Hyota; Mizui, Masayuki; Taniguchi, Masahiko; Chédotal, Alain; Suto, Fumikazu; Fujisawa, Hajime; Kumanogoh, Atsushi; Kikutani, Hitoshi

    2008-03-01

    Semaphorins and their receptors play crucial roles not only in axon guidance during neuronal development but also in the regulation of immune responses. Plexin-A4, a member of the plexin-A subfamily, forms a receptor complex with neuropilins and transduces signals for class III semaphorins in the nervous system. Although plexin-A4 is also expressed in the lymphoid tissues, the involvement of plexin-A4 in immune responses remains unknown. To explore the role of plexin-A4 in the immune system, we analyzed immune responses in plexin-A4-deficient (plexin-A4-/-) mice. Among immune cells, plexin-A4 mRNA was detected in T cells, dendritic cells and macrophages but not in B cells and NK cells. Plexin-A4-/- mice had normal numbers and cell surface markers for each lymphocyte subset, suggesting that plexin-A4 is not essential for lymphocyte development. However, plexin-A4-/- mice exhibited enhanced antigen-specific T cell responses and heightened sensitivity to experimental autoimmune encephalomyelitis. Plexin-A4-/- T cells exhibited hyperproliferative responses to anti-CD3 stimulation and to allogeneic dendritic cells in vitro. Furthermore, this hyperproliferation was also observed in both T cells from neuropilin-1 mutant (npn-1(Sema-)) mice, in which the binding site of class III semaphorins is disrupted, and T cells from Sema3A-deficient (Sema-3A-/-) mice. Collectively, these results suggest that plexin-A4, as a component of the receptor complex for class III semaphorins, negatively regulates T cell-mediated immune responses.

  1. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Lifetime Learning Credit. 1.25A-4 Section 1.25A-4... Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1) Taxable years beginning before January 1, 2003. Subject to the phaseout of the education tax credit described in...

  2. CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing.

    PubMed

    Wang, Danxin; Sadee, Wolfgang

    2016-01-01

    Cytochrome P450 3A4 (CYP3A4) metabolizes 30-50% of clinically used drugs. Large interperson variability in CYP3A4 activity affects response to CYP3A4 substrate drugs. We had demonstrated that an intronic single nucleotide polymorphism rs35599367 (CYP3A4*22, located in intron 6) reduces mRNA/protein expression; however, the underlying mechanism remained unknown. Here we show that CYP3A4*22 is associated with a two-fold or greater increase in formation of a nonfunctional CYP3A4 alternative splice variant with partial intron 6 retention in human liver (P=0.006), but not in small intestines. Consistent with this observation, in-vitro transfection experiments with a CYP3A4 minigene (spanning from intron 5 to intron 7) demonstrated that plasmids carrying the rs35599367 minor T allele caused significantly greater intron 6 retention than the C allele in liver derived HepG2 cells, but not in intestine-derived LS-174T cells. These results indicate that tissue-specific increased formation of nonfunctional alternative splice variant causes reduced CYP3A4 mRNA/protein expression in CYP3A4*22 carriers.

  3. 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.

  4. 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.

  5. Nuclear Data Sheets for A = 3

    SciTech Connect

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

    2015-12-15

    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.

  6. Steel erected at A-3 Test Stand

    NASA Image and Video Library

    2008-10-29

    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.

  7. 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.

  8. A-3 Test Stand work continues

    NASA Image and Video Library

    2011-04-22

    Stennis Space Center employees continue work on the A-3 Test Stand test cell. The stand is being built to test next-generation rocket engines that could carry humans beyond low-Earth orbit into deep space.

  9. Crystal Structure of the Human Ephrin-A5 Ectodomain

    SciTech Connect

    Nikolov,D.; Li, C.; Lackmann, M.; Jeffrey, P.; Himanen, J.

    2007-01-01

    The Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, pathfinding, and mobility in the nervous and cardiovascular systems. Recent structural studies have revealed unique molecular features that explain many of the biochemical and signaling properties of Ephs and ephrins. Nevertheless, open questions remain, including understanding the precise molecular mechanism underlining their binding-partner preferences and subclass specificity. In this study, we have determined and present the crystal structure of the extracellular domain of ephrin-A5--the first structure of an unbound A-class ephrin. The structure, determined at 2.1 Angstroms resolution, is a variation of the Greek key {beta}-barrel folding topology, containing eight {beta}-strands, and stabilized by two disulphide bonds. Overall, ephrin-A5 is structurally very similar to ephrin-B1 and ephrin-B2 but, unlike ephrin-B2, it does not show dimerization either in solution or in the crystals. Comparing free ephrin-A5 to the previously published structure of EphB2-bound ephrin-A5 reveals that significant conformational changes occur only around the G-H ephrin loop that upon binding bends toward the receptor. Interestingly, the G-H loop undergoes a very similar conformational rearrangement in ephrin-B2 upon receptor binding. The results of this study further emphasize the importance of the G-H loop for receptor recognition and selectivity, and could serve as a starting point for the development of structure-based Eph antagonists.

  10. Microbial conversion of milbemycins: hydroxylation of milbemycin A4 and related compounds by Cunninghamella echinulata ATCC 9244.

    PubMed

    Nakagawa, K; Miyakoshi, S; Torikata, A; Sato, K; Tsukamoto, Y

    1991-02-01

    Many strains of zygomycetes and actinomycetes were found to convert milbemycin A4 (1a) to 13 beta-hydroxymilbemycin A4 (1b). Among these strains, Cunninghamella echinulata ATCC 9244 had the most efficient 13 beta-hydroxylation ability on milbemycins. In the conversion of milbemycin A3 (2a), 29-hydroxymilbemycin A4 (4a), and 30-hydroxymilbemycin A4 (5a) with this strain, only 13 beta-hydroxylated products were obtained. On the other hand, starting from milbemycin A4 (1a) and 5-ketomilbemycin A4 5-oxime (6a), 13 beta,24- and 13 beta,30-dihydroxy derivatives were also isolated along with 13 beta-hydroxylated products. Similarly, conversion of milbemycin D (3a) and LL-F28249 alpha (8a) gave 13 beta- and 28-hydroxy derivatives (8b and 8c).

  11. 26 CFR 1.167(a)-4 - Leased property.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 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 or...

  12. 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 INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry Policy...

  13. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Responsibilities and functions. 352a.4 Section...) 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...

  14. 42 CFR 65a.4 - What are the program requirements?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What are the program requirements? 65a.4 Section 65a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  15. 42 CFR 65a.4 - What are the program requirements?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What are the program requirements? 65a.4 Section 65a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  16. 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 Securities...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE Installation Entry...

  2. 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.

  3. Jejunojejunal intussusception secondary to submucosal lipoma resulting in a 5-year history of intermittent abdominal pain.

    PubMed

    Seow-En, Isaac; Foo, Fung Joon; Tang, Choong Leong

    2014-10-29

    Jejunal lipomata are an unusual cause of adult intussusception. We report a case of a 44-year-old Chinese woman who presented with a 3-day history of abdominal pain and nausea; she had a 5-year history of similar episodic symptoms after meals. Contrast-enhanced CT revealed a fat-density lead point in the jejunum resulting in intussusception. Single port laparoscopic surgery was performed with reduction of the intussusception, bowel resection and primary anastamosis. Histology confirmed a benign submucosal lipoma. We discuss the recent published literature on this rare entity and show CT images and intraoperative pictures. 2014 BMJ Publishing Group Ltd.

  4. 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

    2016-02-03

    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.

  5. 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

    ..., and V2533-A5 Turbofan Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule..., V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5, V2530-A5, and V2533-A5 turbofan engines. This AD..., and V2533-A5 turbofan engines. We published the proposed AD in the Federal Register on April 30, 2009...

  6. Enhancement of jump performance after a 5-RM squat is associated with postactivation potentiation.

    PubMed

    Mitchell, Cameron J; Sale, Digby G

    2011-08-01

    Weight lifting exercise may induce postactivation potentiation (PAP), thereby enhancing performance of a subsequent biomechanically similar "explosive" movement. However, it has not been shown that weight lifting induces PAP, indicated as potentiation of muscle twitch force. Therefore, the present study tested whether a five repetition maximum squat (5-RM squat) both induced PAP and increased the height of subsequently performed counter-movement jumps (CMJs). Eleven male athletes completed four laboratory sessions on separate days. Two sessions determined whether the 5-RM squat induced PAP: in one, a quadriceps maximal twitch was evoked immediately before and 8 min after a set of five CMJs (control); in the other, a twitch was evoked before a CMJ set, which was followed by a 4-min rest, a 5-RM squat, a 4-min rest, and a second twitch. Another two sessions tested the effect of the 5-RM squat on jump performance: in one session, two sets of five CMJs were performed with an 8-min rest between the sets (control); in the second, a 5-RM squat was performed 4 min after the first set of CMJs, and then after another 4 min the second set of CMJs was performed. Neither twitch torque nor CMJ height changed in the control sessions (P > 0.05). In contrast, interpolation of the 5-RM squat increased (P < 0.05) both twitch torque (49.5 ± 7.8 to 54.8 ± 11.9 N m; i.e., PAP = 10.7%) and CMJ height (48.1 ± 5.6 to 49.5 ± 5.9 cm; 2.9%). Since PAP was present at the time when CMJ height increased, it was concluded that PAP may have contributed to the increased CMJ height after a 5-RM squat.

  7. 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.

  8. Plasma levels of S100A4 in portopulmonary hypertension.

    PubMed

    Peng, Tien; Zamanian, Roham; Krowka, Michael J; Benza, Raymond L; Roberts, Kari E; Taichman, Darren B; Rybak, Debbie; Trotter, James F; Brown, Robert S; Fallon, Michael B; Kawut, Steven M

    2009-05-01

    We previously showed that a single nucleotide polymorphism in S100A4 was associated with portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case-control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure >25 mmHg, pulmonary vascular resistance >240 dynes s cm(-5) and pulmonary capillary wedge pressure A4. The study sample included 14 cases with PPHTN and 32 controls with liver disease. There was no difference in mean age between cases and controls (p = 0.52). Seventy-nine percent of cases were female compared with 44% of controls (p = 0.03). There was no difference in S100A4 levels between cases and controls (p = 0.58). Both groups had significantly higher S100A4 levels than healthy volunteers (p <0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels.

  9. Plasma Levels of S100A4 in Portopulmonary Hypertension

    PubMed Central

    Peng, Tien; Zamanian, Roham; Krowka, Michael J.; Benza, Raymond L.; Roberts, Kari E.; Taichman, Darren B.; Rybak, Debbie; Trotter, James F.; Brown, Robert S.; Fallon, Michael B.; Kawut, Steven M.

    2010-01-01

    We previously showed that a single nucleotide polymorphism in S100A4 was associated with developing portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case-control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes-sec · cm−5, and pulmonary capillary wedge pressure ≤15 mm Hg. Controls with liver disease had right ventricular systolic pressure < 40 mm Hg and normal right atrial and ventricular morphology by echocardiography. Plasma samples were assayed for S100A4. The study sample included 14 cases with PPHTN and 32 liver disease controls. The mean age for both cases and controls was 52 ± 9 yrs. Eighty percent of cases were female compared to 42% of controls (p = 0.02). There was no difference in S100A4 levels between cases and controls (p = 0.53). Both groups had significantly higher S100A4 levels than healthy volunteers (p < 0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels. PMID:19399660

  10. 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

    ... Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5, V2530... International Aero Engines AG, ``Docket No. FAA-2009-0544'' is corrected to read ``Docket No. FAA- 2009-1100...

  11. Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic

    PubMed Central

    HAAS, David M.; QUINNEY, Sara K.; CLAY, Jayanti M.; RENBARGER, Jamie L.; HEBERT, Mary F.; CLARK, Shannon; UMANS, Jason G.; CARITIS, Steve N.

    2014-01-01

    Objective To characterize the pharmacokinetics and pharmacogenetics of nifedipine in pregnancy. Study Design Pregnant women receiving oral nifedipine underwent steady-state pharmacokinetic testing over one dosing interval. DNA was obtained and genotyped for cytochrome P450 (CYP) 3A5, and CYP3A4*1B. Nifedipine and oxidized nifedipine concentrations were measured in plasma and pharmacokinetic parameters were compared between those women who expressed a CYP3A5*1 allele and those who expressed only variant CYP3A5 alleles (*3,*6, or *7). Results Fourteen women had complete data to analyze. Four women (29%) expressed variant CYP3A5; three of these women were also CYP3A4*1B allele carriers. The mean half-life of nifedipine was 1.68±1.56 hours. AUC0–6 for the women receiving nifedipine every 6 hours was 207±138μg·h/L. Oral clearance was different between high expressers and low expressers (232.0±37.8 μg/mL vs. 85.6±45.0 μg/mL, respectively; p=0.007). Conclusion CYP3A5 genotype influences the oral clearance of nifedipine in pregnant women. PMID:22875663

  12. 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.

  13. Parvoviral myocarditis in a 5-week-old Dachshund.

    PubMed

    Sime, Tara A; Powell, Lisa L; Schildt, Julie C; Olson, Erik J

    2015-01-01

    To describe a case of myocarditis associated with naturally occurring canine parvovirus type 2 (CPV-2). A 5-week-old male intact Dachshund dog presented for acute respiratory distress. Limited diagnostic tests prior to the dog experiencing cardiopulmonary arrest included a lateral thoracic radiograph, which indicated cardiomegaly and diffuse unstructured pulmonary infiltrate. Necropsy was performed and results identified a lymphoplasmacytic myocarditis with positive CPV-2 immunohistochemistry within the myocardium. This report describes the natural occurrence of CPV-2-associated myocarditis. In addition to highlighting this rare form of canine parvovirus, cardiomyopathy in survivors of the acute viral myocarditis phase is reviewed. © Veterinary Emergency and Critical Care Society 2015.

  14. Measuring the Mathematical Attitudes of Elementary Students: The Effects of a 4-Point or 5-Point Likert-Type Scale

    ERIC Educational Resources Information Center

    Adelson, Jill L.; McCoach, D. Betsy

    2010-01-01

    The purpose of this study was to compare how students in Grades 3 to 6 respond to a mathematics attitudes instrument with a 4-point Likert-type scale compared with one with an additional neutral point (a 5-point Likert-type scale). The 606 participating students from six elementary and middle schools randomly received either the 4-point or 5-point…

  15. A-3 Test Stand construction moves forward

    NASA Image and Video Library

    2010-07-13

    Work on the A-3 Test Stand at Stennis Space Center took a step forward in July with delivery of the first-stage steam ejector July 13. Stennis employees are shown preparing the ejector to be lifted into place on the test stand. When activated in 2012, the A-3 Test Stand will allow operators to test rocket engines at simulated altitudes of 100,000 feet, a critical feature for next-generation engines that will take humans beyond low-Earth orbit once more.

  16. 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

  17. Geometrical interpretation of electromagnetism in a 5-dimensional manifold

    NASA Astrophysics Data System (ADS)

    Kim, TaeHun; Kim, Hyunbyuk

    2017-08-01

    In this paper, Kaluza-Klein theory is revisited and its implications are elaborated. We show that electromagnetic 4-potential can be considered as a shearing-like deformation of a 5-dimensional (5D) manifold along the fifth (5th) axis. The charge-to-mass ratio has a physical meaning of the ratio between the movement along the direction of the 5th axis and the movement in the 4D space-time. In order to have a 5D matter which is consistent with the construction of the 5D manifold, a notion of particle-thread is suggested. Examinations on the compatibility of reference frames reveal a covariance breaking of the 5th dimension. The field equations which extend Einstein’s field equations give the total energy-momentum tensor as a sum of that of matter, electromagnetic field, and the interaction between electric current and electromagnetic potential. Finally, the experimental implications are calculated for the weak potential case.

  18. The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients.

    PubMed

    Zhang, Jing-Jing; Liu, Shuai-Bing; Xue, Ling; Ding, Xiao-Liang; Zhang, Hua; Miao, Li-Yan

    2015-09-01

    The aims of this study were to assess the influence of the polymorphism of cytochrome P450 oxidoreductase (POR) as well as other relevant genes (CYP3A4, CYP3A5, ABCB1) on individual variability of tacrolimus pharmacokinetics and perform population pharmacokinetic analysis of tacrolimus in Chinese renal transplant recipients. Tacrolimus trough whole blood concentrations and clinical details were retrospectively collected from 83 renal recipients. CYP3A4*1G, CYP3A5*3, and ABCB1 C3435T were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), POR*28 and CYP3A4*22 were genotyped by sequencing method. Population pharmacokinetic analysis was performed using NONMEM program. The significant influences of CYP3A5*3, CYP3A4*1G, and POR*28 polymorphisms on tacrolimus dose-adjusted trough concentrations (C0/D) were observed in 83 renal recipients. Subgroup analysis showed that POR*28 polymorphisms significantly decreased tacrolimus C0/D by 1.50 - 1.84-fold (p < 0.05) in patients who were CYP3A5 expressers (CYP3A5*1 carriers, n = 46), while similar results could not be obtained from CYP3A5 non-expressers (CYP3A5*3/*3 carriers, n = 37). Additionally, population pharmacokinetic analysis identified that the combined genotype of CYP3A5-POR was the only covariant for the apparent clearance of tacrolimus (CL/F). The study demonstrated that the POR*28 C>T mutation could decrease the C0/D of tacrolimus in renal recipients who were CYP3A5 expressers. The population pharmacokinetic model showed that the combined genotype of CYP3A5-POR was associated with the CL/F of tacrolimus which might provide references for personalized use of tacrolimus in clinic.

  19. The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 enzyme

    PubMed Central

    Murai, Takahiro; Reilly, Christopher R.; Ward, Robert M.; Yost, Garold S.

    2010-01-01

    Inhaled glucocorticoid (GC) therapy is a vital part of the management of chronic asthma. GCs are metabolized by members of the cytochrome P450 3A family in both liver and lung, but the enzymes are differentially expressed. Selective inhibition of one or more P450 3A enzymes could substantially modify target and systemic concentrations of GCs. In this study, we have evaluated the mechanism-based inactivation of P450 3A4, 3A5 and 3A7 enzymes by GCs. Among the five major inhaled GCs approved for clinical use in the United States, fluticasone propionate (FLT) was the most potent mechanism-based inactivator of P450 3A5, the predominant P450 enzyme in the lung. FLT inactivated P450 3A5 in a time- and concentration-dependent manner with KI, kinact and partition ratio of 16 μM, 0.027 min-1 and 3, respectively. In contrast, FLT minimally inactivated P450 3A4 and did not inactivate 3A7, even with a concentration of 100 μM. The inactivation of P450 3A5 by FLT was irreversible because dialysis did not restore enzyme activity. In addition, the exogenous nucleophilic scavenger GSH did not attenuate inactivation. The prosthetic heme of P450 3A5 was not modified by FLT. The loss of P450 3A5 activity in lung cells could substantially decrease the metabolism of FLT, which would increase the effective FLT concentration at its target site, the respiratory epithelium. Also, inactivation of lung P450 3A5 could increase the absorption of inhaled FLT, which could lead to high systemic concentrations and adverse effects, such as life-threatening adrenal crises or cataracts that have been documented in children receiving high doses of inhaled GCs. PMID:20707410

  20. 32 CFR 169a.3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... PROGRAM PROCEDURES General § 169a.3 Definitions. Commercial activity review. The process of evaluating CAs.... A business or other non-Federal activity located in the United States, its territories and... process of developing an estimate of the cost of performance of a CA by DoD employees and comparing it,...

  1. 32 CFR 169a.3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PROGRAM PROCEDURES General § 169a.3 Definitions. Commercial activity review. The process of evaluating CAs.... A business or other non-Federal activity located in the United States, its territories and... process of developing an estimate of the cost of performance of a CA by DoD employees and comparing it,...

  2. 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.

  3. 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.

  4. A3 TEST STAND DEVELOPMENT AND CONSTRUCTION

    NASA Technical Reports Server (NTRS)

    2008-01-01

    THIS IMAGE DOCUMENTS THE DEVELOPMENT AND CONSTRUCTION OF THE A3 TEST STAND IN SUPPORT OF THE ARES/CLV UPPER STAGE ENGINE DEVELOPMENT AT STENNIS SPACE CENTER, MISSIPPI IN SUPPORT OF THE DEVELOPMENT OF THE CONSTELLATION/ARES PROJECT. THIS IMAGE IS EXTRACTED FROM A HIGH DEFINITION VIDEO FILE AND IS THE HIGHEST RESOLUTION AVAILABLE

  5. Steel erected at A-3 Test Stand

    NASA Image and Video Library

    2008-10-24

    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.

  6. 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.

  7. 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…

  8. A-3 Test Stand tops out

    NASA Image and Video Library

    2011-04-13

    A construction 'topping out' milestone was reached April 13 with placement of the test cell dome atop NASA's new A-3 Test Stand at Stennis Space Center. NASA broke ground in 2007 for the new stand, which is being built to provide simulated high-altitude testing for next-generation rocket engines that could carry humans into deep space.

  9. A-3 Test Stand tops out

    NASA Image and Video Library

    2011-04-13

    Stennis Space Center Director Patrick Scheuermann presents center director coins to employees following the 'topping out' of the A-3 Test Stand with placement of test cell dome on April 13. The stand is the first large test structure built at Stennis since the 1960s.

  10. 38 CFR 8a.3 - Effective date.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Section 8a.3 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... insured, or fails to respond within 60 days after the date a final request is made or mailed to the... on or after August 11, 1971, VMLI shall be effective on the date of approval of the grant, if on that...

  11. Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4.

    PubMed

    Chesné, C; Guyomard, C; Guillouzo, A; Schmid, J; Ludwig, E; Sauter, T

    1998-01-01

    1. The metabolism of Meloxicam (ME) and the cytochrome(s) P450 (CYPs) involved were analysed by using primary human hepatocytes, human liver microsomes and microsomes from recombinant human B-lymphoblastoid cell lines. 2. While human hepatocytes were capable of converting ME to a 5-hydroxymethyl metabolite (M7) and then to a 5-carboxyderivative (M5), human liver microsomes formed mostly only the 5-hydroxymethylderivative. The kinetics of the formation of M7 by human liver microsomes were biphasic with Km = 13.6 +/- 9.5 and 381 +/- 55.2 microM respectively. The corresponding Vmax were 33.7 +/- 24.2 and 143 +/- 83.9 pmol/min/mg protein respectively. 3. CYP2C9 and, to a much lesser extent, CYP3A4 were found to convert ME to M7. The involvement of 2C9 was demonstrated by inhibition of tolbutamide hydroxylase activity in the presence of ME, inhibition of ME metabolism by sulphaphenazole, correlation between ME metabolism and tolbutamide hydroxylase activity and active metabolism of ME by recombinant 2C9. The involvement of 3A4 was shown by inhibition of ME metabolism by ketoconazole, correlation between ME metabolism and nifedipine oxidase activity and metabolism of ME by recombinant 3A4. Kinetics of the formation of M7 by the individual enzymes resulted in a Km = 9.6 microM and Vmax = 8.4 pmol/min/mg protein for 2C9 and a Km = 475 microM and Vmax = 23 pmol/min/mg protein for 3A4.

  12. 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.

  13. VizieR Online Data Catalog: CfA4: light curves for 94 type Ia SNe (Hicken+, 2012)

    NASA Astrophysics Data System (ADS)

    Hicken, M.; Challis, P.; Kirshner, R. P.; Rest, A.; Cramer, C. E.; Wood-Vasey, W. M.; Bakos, G.; Berlind, P.; Brown, W. R.; Caldwell, N.; Calkins, M.; Currie, T.; de Kleer, K.; Esquerdo, G.; Everett, M.; Falco, E.; Fernandez, J.; Friedman, A. S.; Groner, T.; Hartman, J.; Holman, M. J.; Hutchins, R.; Keys, S.; Kipping, D.; Latham, D.; Marion, G. H.; Narayan, G.; Pahre, M.; Pal, A.; Peters, W.; Perumpilly, G.; Ripman, B.; Sipocz, B.; Szentgyorgyi, A.; Tang, S.; Torres, M. A. P.; Vaz, A.; Wolk, S.; Zezas, A.

    2012-07-01

    The CfA4 sample consists of 5522 light-curve points. All 94 SNe have BVr'i' measurements, while 14 have U and 12 have u'. The CfA4 data were obtained on the 1.2m telescope at the FLWO using the single-chip, four-amplifier CCD KeplerCam. CfA4 data processing followed the same three steps used for CfA3: reduction, calibration, and host-galaxy subtraction (see Hicken et al. 2009, Cat. J/ApJ/700/331 for a more detailed treatment). (4 data files).

  14. Human Liver Cytochrome P450 3A4 Ubiquitination

    PubMed Central

    Wang, YongQiang; Kim, Sung-Mi; Trnka, Michael J.; Liu, Yi; Burlingame, A. L.; Correia, Maria Almira

    2015-01-01

    CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP)-Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C. We have documented that CYP3A4 Ser/Thr phosphorylation (Ser(P)/Thr(P)) by PKA and/or PKC accelerates/enhances its Lys ubiquitination by either of these E2-E3 systems. Intriguingly, CYP3A4 Ser(P)/Thr(P) and ubiquitinated Lys residues reside within the cytosol-accessible surface loop and/or conformationally assembled acidic Asp/Glu clusters, leading us to propose that such post-translational Ser/Thr protein phosphorylation primes CYP3A4 for ubiquitination. Herein, this possibility was examined through various complementary approaches, including site-directed mutagenesis, chemical cross-linking, peptide mapping, and LC-MS/MS analyses. Our findings reveal that such CYP3A4 Asp/Glu/Ser(P)/Thr(P) surface clusters are indeed important for its intermolecular electrostatic interactions with each of these E2-E3 subcomponents. By imparting additional negative charge to these Asp/Glu clusters, such Ser/Thr phosphorylation would generate P450 phosphodegrons for molecular recognition by the E2-E3 complexes, thereby controlling the timing of CYP3A4 ubiquitination and endoplasmic reticulum-associated degradation. Although the importance of phosphodegrons in the CHIP targeting of its substrates is known, to our knowledge this is the first example of phosphodegron involvement in gp78-substrate

  15. Interactions between CYP3A4 and Dietary Polyphenols

    PubMed Central

    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

  16. 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.

  17. TMS delivered for A-3 Test Stand

    NASA Image and Video Library

    2010-03-17

    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.

  18. Installation Restoration Program. Phase 2. Confirmation/Quantification. Stage 1. Air Force Plant 4, Fort Worth, Texas. Volume 7. Appendices A-3 and A-4.

    DTIC Science & Technology

    1987-12-01

    vI Z z Cr) D Lii jiw E > Q a Im ol L LC v SL CL V 9 C C L -- w...Cu 3a I . U) z cls -0 3 La - DZ CL- GZ 1= I 𔃾 =6 C"~ .i M LLJI- D- 4’ -. 4 0 *- 06 ".. 0 VI In C3 01 Li) LL- 0 .9-W 544 up c 41 W C 0- I- 0 1 65W~CL...SLLU C=0 -A C-> ... -’LU u A.L :ma ru’ =-8 M C-33 CL.GAu 4J a LLE’ ma .O . 6-4 0 ~ LiJ - -a 40 a -~ 10 Ul O -t q . . 0 5- = 2! i - *6n cm ap as. 0 vi

  19. Data Collection Procedures and Descriptive Statistics for the Grade Three Achievement Monitoring Test (A-3 and A-4), Coordinated Study No. 1.

    ERIC Educational Resources Information Center

    Buchanan, Anne E.; Romberg, Thomas A.

    This paper documents the achievement monitoring component of a three-year study on the acquisition of addition-subtraction problem-solving skills by young children. A set of performance objectives contained in or ancillary to ten instructional units on sentence-writing for verbal problems and algorithms specified test content. Tests measuring…

  20. Molecular modeling of cytochrome P450 3A4

    NASA Astrophysics Data System (ADS)

    Szklarz, Grazyna D.; Halpert, James R.

    1997-05-01

    The three-dimensional structure of human cytochrome P450 3A4 was modeled based on crystallographic coordinates of four bacterial P450s: P450 BM-3, P450cam, P450terp, and P450eryF. The P450 3A4 sequence was aligned to those of the known proteins using a structure-based alignment of P450 BM-3, P450cam, P450terp, and P450eryF. The coordinates of the model were then calculated using a consensus strategy, and the final structure was optimized in the presence of water. The P450 3A4 model resembles P450 BM-3 the most, but the B' helix is similar to that of P450eryF, which leads to an enlarged active site when compared with P450 BM-3, P450cam, and P450terp. The 3A4 residues equivalent to known substrate contact residues of the bacterial proteins and key residues of rat P450 2B1 are located in the active site or the substrate access channel. Docking of progesterone into the P450 3A4 model demonstrated that the substrate bound in a 6β-orientation can interact with a number of active site residues, such as 114, 119, 301, 304, 305, 309, 370, 373, and 479, through hydrophobic interactions. The active site of the enzyme can also accommodate erythromycin, which, in addition to the residues listed for progesterone, also contacts residues 101, 104, 105, 214, 215, 217, 218, 374, and 478. The majority of 3A4 residues which interact with progesterone and/or erythromycin possess their equivalents in key residues of P450 2B enzymes, except for residues 297, 480 and 482, which do not contact either substrate in P450 3A4. The results from docking of progesterone and erythromycin into the enzyme model make it possible to pinpoint residues which may be important for 3A4 function and to target them for site-directed mutagenesis.

  1. Identification and characterization of a novel mouse plexin, plexin-A4.

    PubMed

    Suto, Fumikazu; Murakami, Yasunori; Nakamura, Fumio; Goshima, Yoshio; Fujisawa, Hajime

    2003-03-01

    Plexins belonging to the plexin-A subfamily form complexes with neuropilins and propagate signals of class 3 semaphorins into neurons, even though they do not directly bind the semaphorins. In this study, we identified a new member of the plexin-A subfamily in the mice, plexin-A4, and showed that it was expressed in the developing nervous system with a pattern different to that of other members of the plexin-A subfamily (plexin-A1, plexin-A2 and plexin-A3). COS-7 cells coexpressing plexin-A4 with neuropilin-1 were induced to contract by Sema3A, a member of the class 3 semaphorin. Ectopic expression of plexin-A4 in mitral cells that are originally insensitive to Sema3A resulted in the collapse of growth cones in the presence of Sema3A. These results suggest that plexin-A4 plays a role in the propagation of Sema3A activities.

  2. 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.

  3. Manuscript Development and Publishing: A 5-Step Approach.

    PubMed

    Downey, Susan M; Geraci, Stephen A

    2017-02-01

    Publications in peer-reviewed biomedical journals are essential for sharing knowledge and advancing healthcare. This article will articulate a 5-step approach for developing and publishing a manuscript, and provide academic clinicians with an instructional tool they can provide to their protégés and junior faculty. The authors attempt to distill existing advice for preparing manuscripts, which is found in myriad formats, combine these tutorials with their collective experience and present this approach for developing and publishing successfully a manuscript in a peer-reviewed journal. The 5 steps identified instruct would-be authors to (1) know their material and determine their audience; (2) outline their manuscript; (3) be ethically vigilant; (4) develop individual sections and submit their manuscript and (5) respond to reviewers׳ comments. This article describes each of these steps in detail. Rewards of publishing articles include recognition by peers and supervisors, contribution to academic promotion and dissemination of information to the medical community. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  4. 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

  5. Allergy to banana in a 5-month-old infant.

    PubMed

    Moreno-Ancillo, Alvaro; Domínguez-Noche, Carmen; Gil-Adrados, Ana C; Cosmes, Pedro M

    2004-06-01

    Food proteins can sensitize the infants via different sources. A 5-month-old boy suffered three episodes of generalized urticaria 20 min after the ingestion of a fruit purée containing apple, banana and orange. Skin testing showed positive results to banana and chestnut. Other tests were negative. The value of specific immunoglobulin E (Pharmacia CAP-FEIA, Uppsala, Sweden) to banana was 58 KU/l, to orange was 9.7 KU/l, to chestnut was 5.6 KU/l and to latex was 1.6 KU/l. Orange, apple and latex products were well tolerated. He never had eaten chestnut. The parents rejected a banana challenge test. The route of sensitization in our case might be via placenta, breast-milk, and inadvertent oral intake of food or even via inhalation. An early frequent exposure to banana allergens was considered a possibility factor for the development of banana sensitization. We found that the banana consumption during pregnancy and lactation by the mother of our patient was greater than usual. It is not frequent to find so high levels of sensitization to any fruit in first year of life. In our case, latex, chestnut and orange sensitizations did not seem to be clinically relevant. However, latex and foods known to cross-react with banana antigens should be given to banana-sensitive individuals with great caution.

  6. Treatment of anal stenosis: a 5-year review.

    PubMed

    Casadesus, Damian; Villasana, Luis E; Diaz, Hector; Chavez, Mariano; Sanchez, Ines M; Martinez, Pedro P; Diaz, Angelina

    2007-07-01

    Benign anal stenosis is an uncommon, disabling and incapacitating disease, occurring mainly after anorectal surgery. Both non-surgical and surgical treatments have been devised in the treatment of anal stenosis with good results. We described the results of the treatment of this disease in the Coloproctology Department of our institution. A retrospective clinical study was undertaken over a 5-year period for consecutive patients operated on for anal stenosis. Twenty-three patients with benign anal stenosis were treated in our department. Haemorrhoidectomy was the most common cause of anal stenosis (74%). Nineteen patients with moderate to severe symptoms of anal stenosis underwent surgical treatment. Lateral mucosal advancement flap was the most frequently carried out operation (63.1%). Four patients were treated with anal dilatation (17.3%). All patients had remission of the preoperative symptoms. There was no re-operation and only minor complications were present in four patients: three patients with anal pruritus and one patient with temporary incontinence. The easy performance, the absence of major complications and the good results obtained confirm that these methods are effective and safe in the treatment of anal stenosis.

  7. Mandatory influenza vaccination of healthcare workers: a 5-year study.

    PubMed

    Rakita, Robert M; Hagar, Beverly A; Crome, Patricia; Lammert, Joyce K

    2010-09-01

    The rate of influenza vaccination among healthcare workers (HCWs) is low, despite a good rationale and strong recommendations for vaccination from many health organizations. To increase influenza vaccination rates by instituting the first mandatory influenza vaccination program for HCWs. A 5-year study (from 2005 to 2010) at Virginia Mason Medical Center, a tertiary care, multispecialty medical center in Seattle, Washington, with approximately 5,000 employees. All HCWs of the medical center were required to receive influenza vaccination. HCWs who were granted an accommodation for medical or religious reasons were required to wear a mask at work during influenza season. The main outcome measure was rate of influenza vaccination among HCWs. In the first year of the program, there were a total of 4,703 HCWs, of whom 4,588 (97.6%) were vaccinated, and influenza vaccination rates of more than 98% were sustained over the subsequent 4 years of our study. Less than 0.7% of HCWs were granted an accommodation for medical or religious reasons and were required to wear a mask at work during influenza season, and less than 0.2% of HCWs refused vaccination and left Virginia Mason Medical Center. A mandatory influenza vaccination program for HCWs is feasible, results in extremely high vaccination rates, and can be sustained over the course of several years.

  8. 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.

  9. 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

  10. 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.

  11. 26 CFR 1.509(a)-4 - Supporting organizations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... different publicly supported organizations within the class or classes of organizations designated by the... grant made by P to T is specifically earmarked for the training of social workers and teachers... grants to the individual social workers and teachers under section 4945(d)(3) and § 53.4945-4(a)(4...

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

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... any conversion-related economic benefit a director or senior management official will or may receive... information about the communication process with its 90-day notice. (10) A group of members may make a joint... (f)(3) of this section, the credit union will use the group name provided by the group. § 708a.4,...

  13. 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 applications...

  14. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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 other... confidentiality for a research project shall contain: (a) The name and address of the individual primarily...

  15. 26 CFR 1.411(a)-4 - Forfeitures, suspensions, etc.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... benefit plans). (3) Retroactive plan amendment. In the case of a participant's right to his employer...(a)-4 Forfeitures, suspensions, etc. (a) Nonforfeitability. Certain rights in an accrued benefit must... right to an accrued benefit is considered to be nonforfeitable at a particular time if, at that time...

  16. 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 applications...

  17. 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 applications...

  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 applications...

  19. 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 been...

  20. 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 been...

  1. 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 been...

  2. 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 been...

  3. 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 been...

  4. 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...

  5. Severe unilateral buphthalmos in a 4-month-old kitten.

    PubMed

    Finnie, Gillian

    2017-03-01

    A 4-month-old kitten was presented with unilateral buphthalmos. The eye was blind with no menace response, but intraocular pressure was normal. A trans-palpebral enucleation was performed on the affected eye and the globe was submitted for histology. There was a suppurative, lympho-plasmacytic panophthalmitis with inflammatory exudate in the iridocorneal angle.

  6. 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…

  7. 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…

  8. 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.

  9. 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

  10. 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.

  11. Novel mutations in the SLC26A4 gene.

    PubMed

    Busi, Micol; Castiglione, Alessandro; Taddei Masieri, Marina; Ravani, Anna; Guaran, Valeria; Astolfi, Laura; Trevisi, Patrizia; Ferlini, Alessandra; Martini, Alessandro

    2012-09-01

    Mutations in the SLC26A4 gene (7q22.3-7q31.1) are considered one of the most common causes of genetic hearing loss. There are two clinical forms related to these mutations: syndromic and non-syndromic deafness. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Both are transmitted as an autosomal recessive trait, but simple heterozygotes can develop both forms of deafness. Actually it is thought that Pendred Syndrome occurs when both alleles of SLC26A4 gene are mutated; DFNB4 seems due to monoallelic mutations. PS and DFNB4 can be associated with inner ear malformations. In most of the cases (around 80%), these consist in Enlarged Vestibular Aqueduct (EVA). EVA can also be present without SLC26A4 mutations. Understanding the role of new SLC26A4 variants should facilitate clinical assessment, as well as diagnostic and therapeutic approaches. This investigation aims to detect and report genetic causes of two unrelated Italian boys with hearing loss. Patients and family members underwent clinical, audiological and genetic evaluations. To identify genetic mutations, DNA sequencing of SLC26A4 gene (including all 21 exons, exon-intron boundaries and promoter region) was carried out. Both probands were affected by congenital, progressive and fluctuating mixed hearing loss. Temporal bone imaging revealed a bilateral EVA with no other abnormalities in both cases. Probands were heterozygotes for previously undescribed mutations in the SLC26A4 gene: R409H/IVS2+1delG (proband 1) and L236P/K590X (proband 2). No other mutations were detected in GJB2, GJB6 genes or mitochondrial DNA (mit-DNA). The IVS2+1delG and K590X mutations have not yet been described in literature but there is some evidence to suggest that they have a pathological role. The results underlined the importance of considering the complete DNA sequencing of the SLC26A4 gene for differential molecular

  12. Traffic Flow on a 3-LANE Highway

    NASA Astrophysics Data System (ADS)

    Chen, Wen-Yao; Huang, Ding-Wei; Huang, Wei-Neng; Hwang, Wen-Liang

    The traffic flow on a 3-lane highway is investigated using a cellular automaton method. Two different kinds of vehicles, cars and trucks, with different driving behaviors are presented on the highway. It is found that in the high density region, a control scheme requiring passing from the inner lane will enhance the traffic flow; while restricting the trucks to the outer lane will enhance the flow in the low density region and also has the benefit of suppressing the unnecessary lane-changing rate.

  13. A-3 Test Stand construction update

    NASA Technical Reports Server (NTRS)

    2007-01-01

    The concrete foundation placed Dec. 18 (foreground) for Stennis Space Center's future A-3 Test Stand has almost completely cured by early January, according to Bo Clarke, NASA's contracting officer technical representative for the foundation contract. By late December, construction on foundations for many of the test stand's support structures - diffuser, liquid oxygen, isopropyl alcohol and water tanks and gaseous nitrogen bottle battery - had begun with the installation of (background) `mud slabs.' The slabs provide a working surface for the reinforcing steel and foundation forms.

  14. A-3 Test Stand construction update

    NASA Image and Video Library

    2007-12-18

    The concrete foundation placed Dec. 18 (foreground) for Stennis Space Center's future A-3 Test Stand has almost completely cured by early January, according to Bo Clarke, NASA's contracting officer technical representative for the foundation contract. By late December, construction on foundations for many of the test stand's support structures - diffuser, liquid oxygen, isopropyl alcohol and water tanks and gaseous nitrogen bottle battery - had begun with the installation of (background) `mud slabs.' The slabs provide a working surface for the reinforcing steel and foundation forms.

  15. A-3 Test Stand construction update

    NASA Technical Reports Server (NTRS)

    2007-01-01

    The concrete foundation placed Dec. 18 (foreground) for Stennis Space Center's future A-3 Test Stand has almost completely cured by early January, according to Bo Clarke, NASA's contracting officer technical representative for the foundation contract. By late December, construction on foundations for many of the test stand's support structures - diffuser, liquid oxygen, isopropyl alcohol and water tanks and gaseous nitrogen bottle battery - had begun with the installation of (background) `mud slabs.' The slabs provide a working surface for the reinforcing steel and foundation forms.

  16. Interaction between CFTR and prestin (SLC26A5).

    PubMed

    Homma, Kazuaki; Miller, Katharine K; Anderson, Charles T; Sengupta, Soma; Du, Guo-Guang; Aguiñaga, Salvador; Cheatham, Maryann; Dallos, Peter; Zheng, Jing

    2010-06-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel that is present in a variety of epithelial cell types, and usually expressed in the luminal membrane. In contrast, prestin (SLC26A5) is a voltage-dependent motor protein, which is present in the basolateral membrane of cochlear outer hair cells (OHCs), and plays an important role in the frequency selectivity and sensitivity of mammalian hearing. By using in situ hybridization and immunofluorescence, we found that both mRNA and protein of CFTR are present in OHCs, and that CFTR localizes in both the apical and the lateral membranes. CFTR was not detected in the lateral membrane of inner hair cells (IHCs) or in that of OHCs derived from prestin-knockout mice, i.e., in instances where prestin is not expressed. These results suggest that prestin may interact physically with CFTR in the lateral membrane of OHCs. Immunoprecipitation experiments confirmed a prestin-CFTR interaction. Because chloride is important for prestin function and for the efferent-mediated inhibition of cochlear output, the prestin-directed localization of CFTR to the lateral membrane of OHCs has a potential physiological significance. Aside from its role as a chloride channel, CFTR is known as a regulator of multiple protein functions, including those of the solute carrier family 26 (SLC26). Because prestin is in the SLC26 family, several members of which interact with CFTR, we explored the potential modulatory relationship associated with a direct, physical interaction between prestin and CFTR. Electrophysiological experiments demonstrated that cAMP-activated CFTR is capable of enhancing voltage-dependent charge displacement, a signature of OHC motility, whereas prestin does not affect the chloride conductance of CFTR.

  17. Effect of alpha lipoic acid on leukotriene A4 hydrolase.

    PubMed

    Torres, María José; Fierro, Angélica; Pessoa-Mahana, C David; Romero-Parra, Javier; Cabrera, Gonzalo; Faúndez, Mario

    2017-03-15

    Leukotriene A4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4 to leukotriene B4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A4 Hydrolase. Alpha lipoic acid inhibited both activities of the enzyme at concentrations lower than 10μM. The 5-lipoxygenase inhibitor zileuton, or the 5-lipoxygenase activating protein inhibitor MK-886, were unable to inhibit the activity of the enzyme. Acute promyelocytic leukaemia HL-60 cells were differentiated to leukotriene A4 hydrolase expressing neutrophil-like cells. Alpha lipoic acid inhibited the aminopeptidase activity of the cytosolic fraction from neutrophil-like cells but had no effect on the cytosolic fraction from undifferentiated cells. Docking and molecular dynamic approximations revealed that alpha lipoic acid participates in electrostatic interactions with K-565 and R-563, which are key residues for the carboxylate group recognition of endogenous substrates by the enzyme. Alpha lipoic acid is a compound widely used in clinical practice, most of its therapeutic effects are associated with its antioxidants properties, however, antioxidant effect alone is unable to explain all clinical effects observed with alpha lipoic acid. Our results invite to evaluate the significance of the inhibitory effect of alpha lipoic acid on the catalytic activity of leukotriene A4 hydrolase using in vivo models.

  18. Helicopter Scene Response for Stroke Patients: A 5-Year Experience.

    PubMed

    Hawk, Andrew; Marco, Catherine; Huang, Matt; Chow, Bonnie

    The purpose of this study was to examine the usefulness of an emergency medical service (EMS)-requested air medical helicopter response directly to the scene for a patient with clinical evidence of an ischemic cerebrovascular accident (CVA) and transport to a regional comprehensive CVA center. CareFlight, an air medical critical care transportation service, is based in Dayton, OH. The 3 CareFlight helicopters are geographically located and provided transport to all CVA scene patients in this study. A retrospective chart review was completed for all CareFlight CVA scene flights for 5 years (2011-2015). A total of 136 adult patients were transported. EMS criteria included CVA symptom presence for less than 3 hours or awoke abnormal, nonhypoglycemia, and a significantly positive Cincinnati Prehospital Stroke Scale. The majority of patients (75%) met all 3 EMS CVA scene criteria; 27.5% of these patients received peripheral tissue plasminogen activator, and 9.8% underwent a neurointerventional procedure. Using a 3-step EMS triage for acute CVA, air medical transport from the scene to a comprehensive stroke center allowed for the timely administration of tissue plasminogen activator and/or a neurointerventional procedure in a substantive percentage of patients. Further investigation into air medical scene response for acute stroke is warranted. Copyright © 2016 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

  19. 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.

  20. Management of an Anterior Cruciate Ligament Tear in a 5 Year-Old Boy.

    PubMed

    Masaracchio, Michael; Comet, Sheryl; Godwin, Ellen

    2015-01-01

    The purpose of this retrospective case report was to describe clinical decision making during the examination and treatment of a 5-year-old boy with an anterior cruciate ligament (ACL) tear. A paucity of research exists for the management of ACL tears in children. A combination of manual therapy interventions initially, followed by a unique and comprehensive therapeutic exercise program, was implemented during the course of a 3-month treatment period. Improvements in range of motion, quadriceps strength, single-leg stance time, and the Knee Injury and Osteoarthritis Outcome Score were noted. At discharge, the patient safely returned to unrestricted home and school activities. This case demonstrates successful management of a child after an ACL injury. Clinicians are encouraged to implement sound clinical reasoning in the absence of well-established evidence when treating similar patients in their clinical practice.

  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. [Significance and progress of DIAN/A4/API].

    PubMed

    Shimada, Hiroyuki

    2016-03-01

    The DIAN observational study compared the pathophysiological markers between mutation carriers and non-carriers for autosomal dominant Alzheimer's disease. It has revealed the biomarker changes in the mutation carrier's brain started as early as 20, even 25 years prior to symptoms. The researchers of DIAN started the prevention trial(DIAN-TU) with two monoclonal antibodies. The API study is the clinical trial of the anti-amyloid monoclonal antibody therapy to the kindred of early onset familial AD (EOAD) who carry the PSEN1 E280A mutation. This study has also shown the same biomarker changes that were reported in the DIAN study. Anti-Amyloid Treatment in Asymptomatic AD (A4) is a prevention trial aimed at treating cognitive normal older individuals at risk of developing Alzheimer's disease dementia on the basis of having biomarker evidence of amyloid (pre-clinical AD). Solanezumab was selected for the anti-amyloid treatment for A4.

  3. Rotordynamic and Leakage Characteristics of a 4-Stage Brush Seal

    DTIC Science & Technology

    1992-12-01

    AD-A266 012 WL-TR-92-2125 .AP ROTORDYNAMIC AND LEAKAGE CHARACTERISTICS OF A 4-STAGE BRUSH SEAL K. J. CONNER D. W. CHILDS TURBOMACHINERY LABORATORIES...pre-rotation, and seal spacing. Direct damping is shown to increase with running speed; otherwise, the rotordynamic coefficients are relatively...test results for the 4-stage brush seal with an 8-cavity labyrinth showed superior rotordynamics performance for the brush seal; viz., larger values for

  4. A 4 K FTS demonstrator for future cooled space telescopes

    NASA Astrophysics Data System (ADS)

    Naylor, David; Veenendaal, Ian; Gom, Brad; Ade, Peter

    2016-07-01

    A commercial Fourier transform spectrometer scanning mechanism has been modified for operation at cryogenic temperatures. When installed in a 4 K cryostat with a multiple component blackbody calibration source and sensitive sub-Kelvin detector, the spectrometer will allow the evaluation of different scanning methods, metrology options and data compression techniques. It will also enable the study of the performance of critical optical components such as beam splitters and filters at their intended operating temperatures.

  5. 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∘.

  6. Solution structure of leptospiral LigA4 Big domain

    SciTech Connect

    Mei, Song; Zhang, Jiahai; Zhang, Xuecheng; Tu, Xiaoming

    2015-11-13

    Pathogenic Leptospiraspecies express immunoglobulin-like proteins which serve as adhesins to bind to the extracellular matrices of host cells. Leptospiral immunoglobulin-like protein A (LigA), a surface exposed protein containing tandem repeats of bacterial immunoglobulin-like (Big) domains, has been proved to be involved in the interaction of pathogenic Leptospira with mammalian host. In this study, the solution structure of the fourth Big domain of LigA (LigA4 Big domain) from Leptospira interrogans was solved by nuclear magnetic resonance (NMR). The structure of LigA4 Big domain displays a similar bacterial immunoglobulin-like fold compared with other Big domains, implying some common structural aspects of Big domain family. On the other hand, it displays some structural characteristics significantly different from classic Ig-like domain. Furthermore, Stains-all assay and NMR chemical shift perturbation revealed the Ca{sup 2+} binding property of LigA4 Big domain. - Highlights: • Determining the solution structure of a bacterial immunoglobulin-like domain from a surface protein of Leptospira. • The solution structure shows some structural characteristics significantly different from the classic Ig-like domains. • A potential Ca{sup 2+}-binding site was identified by strains-all and NMR chemical shift perturbation.

  7. Solution structure of leptospiral LigA4 Big domain.

    PubMed

    Mei, Song; Zhang, Jiahai; Zhang, Xuecheng; Tu, Xiaoming

    2015-11-13

    Pathogenic Leptospiraspecies express immunoglobulin-like proteins which serve as adhesins to bind to the extracellular matrices of host cells. Leptospiral immunoglobulin-like protein A (LigA), a surface exposed protein containing tandem repeats of bacterial immunoglobulin-like (Big) domains, has been proved to be involved in the interaction of pathogenic Leptospira with mammalian host. In this study, the solution structure of the fourth Big domain of LigA (LigA4 Big domain) from Leptospira interrogans was solved by nuclear magnetic resonance (NMR). The structure of LigA4 Big domain displays a similar bacterial immunoglobulin-like fold compared with other Big domains, implying some common structural aspects of Big domain family. On the other hand, it displays some structural characteristics significantly different from classic Ig-like domain. Furthermore, Stains-all assay and NMR chemical shift perturbation revealed the Ca(2+) binding property of LigA4 Big domain. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. 26 CFR 1.6038A-4 - Monetary penalty.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... period. Any uncompleted fraction of a 30-day period shall count as a 30-day period for purposes of this... information, documents, or records, kept outside the United States under the requirements of § 1.6038A-3(f... first 30-day period following the expiration of the 90-day period, and $10,000 for the fraction of the...

  9. 26 CFR 1.509(a)-4 - Supporting organizations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... control among the governing bodies of all organizations involved, such as the presence of common directors... supporting organization are appointed or elected by the governing body, members of the governing body... supported organizations within the meaning of section 509(a)(3)(B) even though its governing body is not...

  10. The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically-based pharmacokinetic model.

    PubMed

    Emoto, Chie; Fukuda, Tsuyoshi; Venkatasubramanian, Raja; Vinks, Alexander A

    2015-12-01

    Sirolimus is an mTOR inhibitor metabolized by CYP3A4 and CYP3A5. Reported effects of CYP3A5 polymorphisms on sirolimus pharmacokinetics (PK) have shown unexplained discrepancies across studies. We quantitatively assessed the effect of CYP3A5*3 status on sirolimus PK by in vitro assessment and simulation using a physiologically-based PK (PBPK) model. In addition, we explored designs for an adequately powered pharmacogenetic association study. In vitro metabolism studies were conducted to confirm individual CYP contribution to sirolimus metabolism. PK profiles were simulated in CYP3A5 expressers and non-expressers with a PBPK model. The pre-dose concentration predictions were used as the outcome parameter to estimate the required sample size for a pharmacogenetic association study. Sirolimus metabolism was inhibited by over 90% by ketoconazole, a CYP3A specific inhibitor. The PBPK model developed based on CL(int) of recombinant CYP3A4, CYP3A5 and CYP2C8 predicted a small CYP3A5*3 effect on simulated sirolimus PK profiles. A subsequent power analysis based on these findings indicated that at least 80 subjects in an enrichment design, 40 CYP3A5 expressers and 40 non-expressers, would be required to detect a significant difference in the predicted trough concentrations at 1 month of therapy (P < 0.05, 80% power). This study suggests that CYP3A5 contribution to sirolimus metabolism is much smaller than that of CYP3A4. Observed discrepancies across studies could be explained as the result of inadequate sample size. PBPK model simulations allowed mechanism-based evaluation of the effects of CYP3A5 genotype on sirolimus PK and provided preliminary data for the design of a future prospective study. © 2015 The British Pharmacological Society.

  11. [Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study].

    PubMed

    Moreno, Iván; Quiñones, Luis; Catalán, Johanna; Miranda, Carla; Roco, Ángela; Sasso, Jaime; Tamayo, Evelyn; Cáceres, Dante; Tchernitchin, Andrei N; Gaete, Leonardo; Saavedra, Iván

    2012-01-01

    Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteers.

  12. Annexin A3 Knockdown Suppresses Lung Adenocarcinoma

    PubMed Central

    Liu, Qing-Qing; Zhang, Yue-Hua; Qiu, Jing-Hua

    2016-01-01

    Our previous study identified an elevated abundance of annexin A3 (Anxa3) as a novel prognostic biomarker of lung adenocarcinoma (LADC) through quantitative proteomics analysis. However, the biological functions of Anxa3 in LADC are not fully clear. In this study, in vitro and in vivo assays were performed to investigate the effects of Anxa3 downregulation on the growth, migration, invasion, metastasis, and signaling pathway activation of LADC cells. After Anxa3 downregulation, the growth of A549 and LTEP-a2 LADC cells was slowed and they showed decreased migration and invasion in vitro. Anxa3 knockdown significantly inhibited tumor formation by A549 cells in vivo; while many metastases were formed by control A549 cells, there were obvious reductions in the numbers of lung, liver, and brain metastases formed by Anxa3 knockdown in A549 cells. Furthermore, Anxa3 knockdown significantly decreased MMP-2 and N-cadherin expression and increased E-cadherin expression both in cell lines in vitro and in tumor nodules examined during in vivo tumorigenesis assays. Interestingly, Anxa3 downregulation reduced the phosphorylated levels of MEK and ERK. In summary, Anxa3 knockdown inhibited the growth, migration, invasion, and metastasis of LADC, decreased the activation of the MEK/ERK signaling pathway, and modulated the expression of MMP-2, E-cadherin, and N-cadherin. PMID:27995049

  13. A 4-meter wide field coronagraph space telescope for general astrophysics and exoplanet observations

    NASA Astrophysics Data System (ADS)

    Tenerelli, Domenick; Angel, Roger; Burge, Jim; Guyon, Olivier; Zabludoff, Ann; Belikov, Ruslan; Pluzhnik, Eugene; Egerman, Robert

    2010-07-01

    The Wide Field Coronagraph Telescope (WFCT) is a 4-meter space telescope for general astrophysics and exoplanet observations that meets the 2000 Decadal Committee requirements. This paper presents a design for a 4-m diameter, off-axis space telescope that offers high performance in both wide field and coronagraphic imaging modes. A 3.8 x 3.3-m unobstructed elliptical pupil is provided for direct coronagraphic imaging of exoplanets and a 4-m diameter pupil for wide-field imaging from far-ultraviolet (UV) to near-infrared (IR). The off-axis wide-field optics are all reflective and designed to deliver an average of 12 nm wavefront aberrations over a 6 x 24 arcminute field of view (FOV), therefore providing diffraction-limited images down to 300 nm wavelength and 15 mas images down to a wavelength limit set only by the mirror coatings. The coronagraph with phase-induced amplitude apodization (PIAA) provides diffraction suppression around a 360-degree field with high Strehl and sensitivity at the 1e-10 level to an inner working angle of 2 λ/D (or 50 mas at 500 nm wavelength). This paper focuses on the optical design that allows the above imaging features to be combined in single telescope, and gives a preliminary spacecraft design and costing, assuming a distant trailing orbit.

  14. Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma.

    PubMed

    Darwish, Mohamad H; Farah, Roula A; Farhat, Ghada N; Torbey, Paul-Henri N; Ghandour, Fatima A; Bejjani-Doueihy, Noha A; Dhaini, Hassan R

    2015-02-01

    Neuroblastoma (NB) is a rare pediatric disease in Lebanon for which poor prognosis remains a major challenge. Genetic polymorphism of genes coding for drug‑metabolizing enzymes may influence the response of a patient to chemotherapy. This study investigates a possible association between CYP3A4/5 polymorphism and expression levels and survival in NB patients. All patients with stage III and IV NB diagnosed between 1993 and 2012 in three major hospitals in Beirut were included (n=27). Demographic information and survival time were obtained from medical records. CYP3A4 and CYP3A5 genotypes and expression levels were determined in archival tumors by polymerase chain reaction (PCR) and restriction fragment length polymorphism and quantitative PCR, respectively. Additionally, MYCN amplification was assessed. A Cox proportional hazards model was used to evaluate potential associations, adjusting for MYCN amplification. A statistically significant increase in the risk of mortality was observed in patients with MYCN amplification [hazard ratio (HR) 4.11, 95% confidence interval (CI) 1.14‑14.80]. Patients with CYP3A5 expression levels above the median had a lower risk of mortality (HR 0.61, 95% CI 0.21‑1.74) and patients with CYP3A4 expression levels above the median had a higher risk of mortality (HR 2.00, 95% CI 0.67‑5.90). CYP3A5*3/*3 homozygote mutants had a 4.3‑fold increase in the risk of mortality compared with that of homozygote wild‑type or heterozygote mutants (HR 4.30, 95% CI 0.56‑33.30). Carriers of the CYP3A4*1B mutant allele had a 52% lower risk of mortality compared with that of non‑carriers (HR 0.48, 95% CI 0.06‑3.76). Although the results of the present study did not achieve statistical significance, associations were observed, which indicates that CYP3A4 and CYP3A5 may modulate the clinical outcome of NB. Further studies with larger sample sizes are required to characterize the effects of the polymorphism and expression

  15. A human-mouse chimera of the alpha3alpha4alpha5(IV) collagen protomer rescues the renal phenotype in Col4a3-/- Alport mice.

    PubMed

    Heidet, Laurence; Borza, Dorin-Bogdan; Jouin, Mélanie; Sich, Mireille; Mattei, Marie-Geneviève; Sado, Yoshikazu; Hudson, Billy G; Hastie, Nicholas; Antignac, Corinne; Gubler, Marie-Claire

    2003-10-01

    Collagen IV is a major structural component of basement membranes. In the glomerular basement membrane (GBM) of the kidney, the alpha3, alpha4, and alpha5(IV) collagen chains form a distinct network that is essential for the long-term stability of the glomerular filtration barrier, and is absent in most patients affected with Alport syndrome, a progressive inherited nephropathy associated with mutation in COL4A3, COL4A4, or COL4A5 genes. To investigate, in vivo, the regulation of the expression, assembly, and function of the alpha3alpha4alpha5(IV) protomer, we have generated a yeast artificial chromosome transgenic line of mice carrying the human COL4A3-COL4A4 locus. Transgenic mice expressed the human alpha3 and alpha4(IV) chains in a tissue-specific manner. In the kidney, when expressed onto a Col4a3(-/-) background, the human alpha3(IV) chain restored the expression of and co-assembled with the mouse alpha4 and alpha5(IV) chains specifically at sites where the human alpha3(IV) was expressed, demonstrating that the expression of all three chains is required for network assembly. The co-assembly of the human and mouse chains into a hybrid network in the GBM restores a functional GBM and rescues the Alport phenotype, providing further evidence that defective assembly of the alpha3-alpha4-alpha5(IV) protomer, caused by mutations in any of the three chains, is the pathogenic mechanism responsible for the disease. This line of mice, humanized for the alpha3(IV) collagen chain, will also provide a valuable model for studying the pathogenesis of Goodpasture syndrome, an autoimmune disease caused by antibodies against this chain.

  16. Short-term effects of amelogenin gene splice products A+4 and A-4 implanted in the exposed rat molar pulp

    PubMed Central

    Jegat, Nadège; Septier, Dominique; Veis, Arthur; Poliard, Anne; Goldberg, Michel

    2007-01-01

    In order to study the short-time effects of two bioactive low-molecular amelogenins A+4 and A-4, half-moon cavities were prepared in the mesial aspect of the first maxillary molars, and after pulp exposure, agarose beads alone (controls) or beads soaked in A+4 or A-4 (experimental) were implanted into the pulp. After 1, 3 or 7 days, the rats were killed and the teeth studied by immunohistochemistry. Cell proliferation was studied by PCNA labeling, positive at 3 days, but decreasing at day 7 for A+4, whilst constantly high between 3 and 7 days for A-4. The differentiation toward the osteo/odontoblast lineage shown by RP59 labeling was more apparent for A-4 compared with A+4. Osteopontin-positive cells were alike at days 3 and 7 for A-4. In contrast, for A+4, the weak labeling detected at day 3 became stronger at day 7. Dentin sialoprotein (DSP), an in vivo odontoblast marker, was not detectable until day 7 where a few cells became DSP positive after A-4 stimulation, but not for A+4. These results suggest that A +/- 4 promote the proliferation of some pulp cells. Some of them further differentiate into osteoblast-like progenitors, the effects being more precocious for A-4 (day 3) compared with A+4 (day 7). The present data suggest that A +/- 4 promote early recruitment of osteogenic progenitors, and evidence functional differences between A+4 and A-4. PMID:18154672

  17. Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus

    PubMed Central

    Dostalek, Miroslav; Court, Michael H; Yan, Bingfang; Akhlaghi, Fatemeh

    2011-01-01

    BACKGROUND AND PURPOSE Patients with diabetes mellitus require pharmacotherapy with numerous medications. However, the effect of diabetes on drug biotransformation is not well understood. Our goal was to investigate the effect of diabetes on liver cytochrome P450 3As, the most abundant phase I drug-metabolizing enzymes in humans. EXPERIMENTAL APPROACH Human liver microsomal fractions (HLMs) were prepared from diabetic (n = 12) and demographically matched nondiabetic (n = 12) donors, genotyped for CYP3A4*1B and CYP3A5*3 polymorphisms. Cytochrome P450 3A4, 3A5 and 2E1 mRNA expression, protein level and enzymatic activity were compared between the two groups. KEY RESULTS Midazolam 1′- or 4-hydroxylation and testosterone 6β-hydroxylation, catalyzed by P450 3A, were markedly reduced in diabetic HLMs, irrespective of genotype. Significantly lower P450 3A4 protein and comparable mRNA levels were observed in diabetic HLMs. In contrast, neither P450 3A5 protein level nor mRNA expression differed significantly between the two groups. Concurrently, we have observed increased P450 2E1 protein level and higher chlorzoxazone 6-hydroxylation activity in diabetic HLMs. CONCLUSIONS AND IMPLICATIONS These studies indicate that diabetes is associated with a significant decrease in hepatic P450 3A4 enzymatic activity and protein level. This finding could be clinically relevant for diabetic patients who have additional comorbidities and are receiving multiple medications. To further characterize the effect of diabetes on P450 3A4 activity, a well-controlled clinical study in diabetic patients is warranted. PMID:21323901

  18. Experimental validation of a 4D elastic registration algorithm.

    PubMed

    Leung, Corina; Hashtrudi-Zaad, Keyvan; Foroughi, Pezhman; Abolmaesumi, Purang

    2008-01-01

    This paper presents an extensive validation study of an elastic registration algorithm for dynamic 3D ultrasound images (also known as a 4D image). The registration algorithm uses attribute vectors from both a fixed and previous moving images to perform feature-based alignment of a series of images. The 4D method reduces computational requirements and increases the effective search space for the location of corresponding features, resulting in enhanced registration speed when compared to a static 3D registration technique. Experimental analysis revealed up to 32% improvement in speed when using the 4D method, which makes the algorithm attractive for real-time applications.

  19. A 4D representation of DNA sequences and its application

    NASA Astrophysics Data System (ADS)

    Liao, Bo; Tan, Mingshu; Ding, Kequan

    2005-02-01

    A 4D representation of DNA sequences has been derived for mathematical denotation of DNA sequence. The 4D representation also avoids loss of information accompanying alternative 2D and 3D representation. The geometrical centers of the 4D graph of DNA sequences indicate the distribution of base frequencies. A interesting phenomenon is observed for Goat and Gallus β-globin genomes with high G + C content. The examination of similarities/dissimilarities among the coding sequences of the first exon of β-globin gene of different species illustrates the utility of the approach.

  20. Cytochrome P450 3A4 activity after surgical stress.

    PubMed

    Haas, Curtis E; Kaufman, David C; Jones, Carolyn E; Burstein, Aaron H; Reiss, William

    2003-05-01

    To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. Prospective, open-label study with each patient serving as his or her own control. University-affiliated, acute care, general hospital. A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5). Cytochrome P450 3A4 activity was estimated using the carbon-14 [14C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p =.06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r(s) = -.541, p =.03) and log interleukin-6 area under the curve from 0 to 72 hrs (r(s) = -.597, p =.014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% +/- 5.2% vs. 74.7% +/- 5.1%, p <.001). Acute inflammation after

  1. A 4MM-Wave composite mode multimode conical feedhorn

    NASA Astrophysics Data System (ADS)

    Lin, Zhisheng; Du, Zhengmi; Chen, Shener

    1996-10-01

    A 4MM-Wave composite mode multimode conical feedhorn has been developed. Its mode-ratios are calculated and its formulas of the radiation patterns are derived. The measurement results of one and two dimension radiation patterns, measured by the automatic measurement system which we had researched, and the properties of band width and sidelobe are given. Theoretical analyses and measurements show that at the centre frequency 69.1GHZ, down to -23dB, the radiation pattern is rotationally symmetric, in this range there is not any sidelobe existing, the band width is 4.5 GHZ. The multimode feedhorn is thus of certain practical using value.

  2. 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.

  3. Effects of metronidazole on hepatic CYP3A4 activity.

    PubMed

    Haas, C E; Kaufman, D C; DiCenzo, R C

    2001-10-01

    To evaluate the effect of a short course of oral metronidazole, commonly used for bowel-preparation regimens, on hepatic cytochrome P450 (CYP) 3A4 activity, as measured by the [14C N-methyl]-erythromycin breath test (ERMBT) in healthy volunteers. Prospective, nonrandomized, interventional study University-affiliated, community, teaching hospital. Five healthy male volunteers. Subjects underwent a baseline ERMBT in the morning before receiving three oral doses of metronidazole 500 mg administered at 3 P.M., 7 P.M., and 11 P.M. Repeat ERMBTs were performed at 24, 72, and 96 hours after the initial ERMBT. Changes in ERMBT values were compared with baseline results using Freidman's repeated-measures analysis of variance on ranks. The ERMBT values did not change significantly compared with baseline (p=0.82). Median (range) ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively A short course of oral metronidazole does not result in a significant change in hepatic CYP3A4 activity as measured by the ERMBT.

  4. 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.

  5. The Clamp Loader Assembles the β Clamp onto Either a 3′ or 5′ Primer Terminus

    PubMed Central

    Park, Mee Sook; O'Donnell, Mike

    2009-01-01

    Clamp loaders assemble sliding clamps onto 3′ primed sites for DNA polymerases. Clamp loaders are thought to be specific for a 3′ primed site, and unable to bind a 5′ site. We demonstrate here that the Escherichia coli γ complex clamp loader can load the β clamp onto a 5′ primed site, although with at least 20-fold reduced efficiency relative to loading at a 3′ primed site. Preferential clamp loading at a 3′ site does not appear to be due to DNA binding, as the clamp loader forms an avid complex with β at a 5′ site. Preferential loading at a 3′ versus a 5′ site occurs at the ATP hydrolysis step, needed to close the ring around DNA. We also address DNA structural features that are recognized for preferential loading at a 3′ site. Although the single-stranded template strand extends in opposite directions from 3′ and 5′ primed sites, thus making it a favorite candidate for distinguishing between 3′ and 5′ sites, the single-strand polarity at a primed template junction does not determine 3′ site selection for clamp loading. Instead, we find that clamp loader recognition of a 3′ site lies in the duplex portion of the primed site, not the single-strand portion. We present evidence that the β clamp facilitates its own loading specificity for a 3′ primed site. Implications to eukaryotic clamp loader complexes are proposed. PMID:19759020

  6. A 3-D shape model of Interamnia

    NASA Astrophysics Data System (ADS)

    Sato, Isao

    2015-08-01

    A 3-D shape model of the sixth largest of the main belt asteroids, (704) Interamnia, is presented. The model is reproduced from its two stellar occultation observations and six lightcurves between 1969 and 2011. The first stellar occultation was the occultation of TYC 234500183 on 1996 December 17 observed from 13 sites in the USA. An elliptical cross section of (344.6±9.6km)×(306.2±9.1km), for position angle P=73.4±12.5 was fitted. The lightcurve around the occultation shows that the peak-to-peak amplitude was 0.04 mag. and the occultation phase was just before the minimum. The second stellar occultation was the occultation of HIP 036189 on 2003 March 23 observed from 39 sites in Japan and Hawaii. An elliptical cross section of (349.8±0.9km)×(303.7±1.7km), for position angle P=86.0±1.1 was fitted. A companion of 8.5 mag. of the occulted star was discovered whose separation is 12±2 mas (milli-arcseconds), P=148±11 . A combined analysis of rotational lightcurves and occultation chords can return more information than can be obtained with either technique alone. From follow-up photometric observations of the asteroid between 2003 and 2011, its rotation period is determined to be 8.728967167±0.00000007 hours, which is accurate enough to fix the rotation phases at other occultation events. The derived north pole is λ2000=259±8, β2000=-50±5 (retrograde rotation); the lengths of the three principal axes are 2a=361.8±2.8km, 2b=324.4±5.0km, 2c=297.3±3.5km, and the mean diameter is D=326.8±3.0km. Supposing the mass of Interamnia as (3.5±0.9)×10-11 solar masses, the density is then ρ=3.8±1.0 g cm-3.

  7. Role of CYP2A5 in the clearance of nicotine and cotinine: insights from studies on a Cyp2a5-null mouse model.

    PubMed

    Zhou, Xin; Zhuo, Xiaoliang; Xie, Fang; Kluetzman, Kerri; Shu, Yue-Zhong; Humphreys, W Griffith; Ding, Xinxin

    2010-02-01

    CYP2A5, a mouse cytochrome P450 monooxygenase that shows high similarities to human CYP2A6 and CYP2A13 in protein sequence and substrate specificity, is expressed in multiple tissues, including the liver, kidney, lung, and nasal mucosa. Heterologously expressed CYP2A5 is active in the metabolism of both endogenous substrates, such as testosterone, and xenobiotic compounds, such as nicotine and cotinine. To determine the biological and pharmacological functions of CYP2A5 in vivo, we have generated a Cyp2a5-null mouse. Homozygous Cyp2a5-null mice are viable and fertile; they show no evidence of embryonic lethality or developmental deficits; and they have normal circulating levels of testosterone and progesterone. The Cyp2a5-null mouse and wild-type mouse were then used for determination of the roles of CYP2A5 in the metabolism of nicotine and its major circulating metabolite, cotinine. The results indicated that the Cyp2a5-null mouse has lower hepatic nicotine 5'-hydroxylation activity in vitro, and slower systemic clearance of both nicotine and cotinine in vivo. For both compounds, a substantially longer plasma half-life and a greater area under the concentration-time curve were observed for the Cyp2a5-null mice, compared with wild-type mice. Further pharmacokinetics analysis confirmed that the brain levels of nicotine and cotinine are also influenced by the Cyp2a5 deletion. These findings provide direct evidence that CYP2A5 is the major nicotine and cotinine oxidase in mouse liver. The Cyp2a5-null mouse will be valuable for in vivo studies on the role of CYP2A5 in drug metabolism and chemical toxicity, and for future production of CYP2A6- and CYP2A13-humanized mouse models.

  8. Role of CYP2A5 in the Clearance of Nicotine and Cotinine: Insights from Studies on a Cyp2a5-null Mouse ModelS⃞

    PubMed Central

    Zhou, Xin; Zhuo, Xiaoliang; Xie, Fang; Kluetzman, Kerri; Shu, Yue-Zhong; Humphreys, W. Griffith

    2010-01-01

    CYP2A5, a mouse cytochrome P450 monooxygenase that shows high similarities to human CYP2A6 and CYP2A13 in protein sequence and substrate specificity, is expressed in multiple tissues, including the liver, kidney, lung, and nasal mucosa. Heterologously expressed CYP2A5 is active in the metabolism of both endogenous substrates, such as testosterone, and xenobiotic compounds, such as nicotine and cotinine. To determine the biological and pharmacological functions of CYP2A5 in vivo, we have generated a Cyp2a5-null mouse. Homozygous Cyp2a5-null mice are viable and fertile; they show no evidence of embryonic lethality or developmental deficits; and they have normal circulating levels of testosterone and progesterone. The Cyp2a5-null mouse and wild-type mouse were then used for determination of the roles of CYP2A5 in the metabolism of nicotine and its major circulating metabolite, cotinine. The results indicated that the Cyp2a5-null mouse has lower hepatic nicotine 5′-hydroxylation activity in vitro, and slower systemic clearance of both nicotine and cotinine in vivo. For both compounds, a substantially longer plasma half-life and a greater area under the concentration-time curve were observed for the Cyp2a5-null mice, compared with wild-type mice. Further pharmacokinetics analysis confirmed that the brain levels of nicotine and cotinine are also influenced by the Cyp2a5 deletion. These findings provide direct evidence that CYP2A5 is the major nicotine and cotinine oxidase in mouse liver. The Cyp2a5-null mouse will be valuable for in vivo studies on the role of CYP2A5 in drug metabolism and chemical toxicity, and for future production of CYP2A6- and CYP2A13-humanized mouse models. PMID:19923441

  9. 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.

  10. Lyapunov exponent diagrams of a 4-dimensional Chua system.

    PubMed

    Stegemann, Cristiane; Albuquerque, Holokx A; Rubinger, Rero M; Rech, Paulo C

    2011-09-01

    We report numerical results on the existence of periodic structures embedded in chaotic and hyperchaotic regions on the Lyapunov exponent diagrams of a 4-dimensional Chua system. The model was obtained from the 3-dimensional Chua system by the introduction of a feedback controller. Both the largest and the second largest Lyapunov exponents were considered in our colorful Lyapunov exponent diagrams, and allowed us to characterize periodic structures and regions of chaos and hyperchaos. The shrimp-shaped periodic structures appear to be malformed on some of Lyapunov exponent diagrams, and they present two different bifurcation scenarios to chaos when passing the boundaries of itself, namely via period-doubling and crisis. Hyperchaos-chaos transition can also be observed on the Lyapunov exponent diagrams for the second largest exponent.

  11. 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

  12. Efficient helium recondensing using a 4 K pulse tube cryocooler

    NASA Astrophysics Data System (ADS)

    Wang, Chao

    2005-12-01

    This paper introduces helium recondensing in a 4000 l dewar using a 4 K pulse tube cryocooler at Amundsen-Scott research station at the South Pole. The helium dewar has a normal boil-off rate of 14 l/day. Two features of cooling the dewar neck by helium vapor and precooling helium gas to be liquefied ensured high efficiency of the pulse tube recondenser in this application. The liquefier/recondenser has being successfully operating in the dewar at South Pole station since February 2005. It not only maintains zero boil-off of the dewar, but also liquefies helium gas supplied from outside of the dewar with a rate around 2.7 l/day.

  13. 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. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Pneumococcal sacroiliitis in a 4-year-old boy.

    PubMed

    Perez, A; Padilla, E; Marco, A; De Otero, J; Bandiera, D; Marimón, I

    2008-01-01

    Pyogenic sacroiliitis is an extremely rare manifestation of invasive pneumococcal disease in childhood as only four cases have been described to date. We report and comment on a case of pneumococcal sacroiliitis in a 4-year-old boy. This patient was diagnosed promptly on account of the symptom triad of fever, buttock pain, and limping gait, along with characteristic findings in magnetic resonance imaging (MRI) and bone scans, and recovered fully after 6 weeks of antimicrobial therapy. Pyogenic sacroiliitis is an uncommon disease in which the diagnosis is often delayed because of nonspecific clinical presentation. The key to successful management is early diagnosis in which MRI and bone scan findings play a crucial role. If the diagnosis is established promptly, most patients can be managed successfully following the therapeutic principles used in other osteoarticular infections.

  15. 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.

  16. Spontaneous Mutation at a 5-Methylcytosine Hotspot Is Prevented by Very Short Patch (Vsp) Mismatch Repair

    PubMed Central

    Lieb, M.

    1991-01-01

    In many strains of Escherichia coli, the product of gene dcm methylates the internal cytosines in the sequence 5'CC(A or T)GG. Spontaneous deamination of 5-methylcytosine produces thymine which, if not corrected, can result in a transition mutation. 5-Methylcytosines in the lacI gene are hotspots for spontaneous C to T mutations. dcm is linked to vsr, a gene required for very short patch (VSP) repair. VSP repair corrects T.G mispairs in the following contexts: (GGTCC)(CTAGG), (GGACC)(CTTGG), (GTCC)(TAGG) and (GGTC)(CTAG). I have investigated the relationships between cytosine methylation, mutation, and VSP repair. Spontaneous mutations in the repressor (cI) gene of lambda prophage were isolated in wild-type and mutant lysogens. A hotspot for spontaneous mutation that corresponds with a 5-methylcytosine was observed in wild-type lysogens but was not present in bacteria lacking both methylase and VSP repair activity. Introduction of a plasmid containing dcm(+) and vsr(+) restored the mutation hotspot. If the added plasmid carried only dcm(+), the frequency of spontaneous mutations at the 5-methylcytosine was over 10-fold higher than in Dcm(+)Vsr(+) lysogens. The addition of vsr on a plasmid to a wild-type lysogen resulted in a 4-fold reduction in mutation at the hotspot. These findings support the previously untested hypothesis that VSP repair prevents mutations resulting from deamination of 5-methylcytosine. PMID:1829427

  17. The effect of a 5-day space flight on the immature rat spine.

    PubMed

    Sinha, Raj K; Shah, Suken A; Hume, Eric L; Tuan, Rocky S

    2002-01-01

    Spaceflight has many reported effects upon the musculoskeletal system structure and function. This study was designed to determine the effect of a 5-day flight on the rat spine. In September 1991, 8 neonatal rats were flown aboard the Space Shuttle Columbia flight STS-48 during a 5-day mission. Upon return to earth, the spines were dissected, frozen and shipped to our laboratory. Matched ground-based rats were used as controls. The spines were radiographed and then slowly thawed. Individual vertebrae were subjected to compressive biomechanical testing using an Instron tester (Instron Corp, Canton, MA, USA) and then processed for determination of calcium and phosphorus content. The intervertebral discs were placed in physiological saline and the stress-relaxation characteristics measured. The discs were then lyophilized and assayed for collagen and proteoglycan content. Disc height on radiographs was measured by image analysis. After space flight, the heights of the discs were found to be 150 to 200 microns greater, although the values were not statistically significant. There was no difference in the resiliency of the thoracic discs as determined by stress-relaxation. However, in the lumbar discs, space flight increased the resiliency (p<.01). There was no difference in water content. In both the thoracic and lumbar discs there was a 3.3-fold increase in hydroxyproline-proteoglycan ratio after space flight. However, because of the small sample size, these values were not statistically significant. In the vertebrae, there was no difference in calcium-phosphate ratio or compressive strength. These data suggest that even after a short 5-day flight, the spine begins to undergo biomechanical and biochemical changes. In addition, the weightless environment in space may provide a good model to study the effects of immobilization on earth.

  18. 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

  19. Induction of human sulfotransferase 1A3 (SULT1A3) by glucocorticoids.

    PubMed

    Bian, Hao Sheng; Ngo, Sherry Yan Yan; Tan, Weiqi; Wong, Chang Hua; Boelsterli, Urs A; Tan, Theresa May Chin

    2007-12-14

    Sulfotransferases (SULTs) play an important role in the detoxification and bioactivation of endogenous compounds and xenobiotics. Studies on rat sulfotransferases had shown that SULT genes, like cytochrome P450 genes, can be regulated by ligands that bind nuclear receptors. For human SULT genes, the regulation of human SULT2A1 expression is currently the best characterized. In this study, we systematically examined the regulation of human SULT1A genes by glucocorticoids. Treatment of the human hepatocellular carcinoma derived HepG2 cells with 10(-7) M dexamethasone did not affect the SULT1A1 activity toward p-nitrophenol. In contrast, SULT1A3 activity toward dopamine was significantly induced. Transient transfection of the SULT1A3 5'-flanking region/luciferase reporter construct showed that SULT1A3 was responsive to dexamethasone and prednisolone in a concentration-dependent manner with maximal induction at 10(-7) M dexamethasone or 1 microM prednisolone. In addition, induction by dexamethasone was dependent on the level of expression of the glucocorticoid receptor. Analysis of the 5'-flanking region led to the identification of a putative glucocorticoid response element at position (-1211 to -1193) upstream of the transcription start site and deletion or mutation of this element resulted in a loss of response. In summary, the data from this study shows that the human SULT1A3 gene is inducible by glucocorticoids through a glucocorticoid receptor-mediated mechanism and the glucocorticoid response element at position (-1211 to -1193) is necessary for this induction.

  20. 106-17 Telemetry Standards. Annex A.4. Asynchronous Recorder Multiplexer Output Re-Constructor (ARMOR)

    DTIC Science & Technology

    2017-07-01

    Telemetry Standards, RCC Standard 106-17 Annex A.4, July 2017 ANNEX A.4 Asynchronous Recorder Multiplexer Output Re-Constructor (ARMOR...A.4-10 Telemetry Standards, RCC Standard 106-17 Annex A.4, July 2017 A.4-ii This page...intentionally left blank. Telemetry Standards, RCC Standard 106-17 Annex A.4, July 2017 A.4-iii Acronyms ARMOR Asynchronous Recorder

  1. Can a $4 drug stop vertical HIV transmission?

    PubMed

    1999-11-01

    Researchers have determined that a $4 dose of Nevirapine, which is 70 times cheaper than a short course of AZT therapy, is more effective than the AZT treatment in reducing the transmission of HIV from mother to baby. About 1,800 infants are born each day with HIV infection, and an estimated 45 percent of pregnant women in South Africa will be infected by the end of the year. The Nevirapine therapy still remains too expensive for much of the world, and there are still many women who are not tested during pregnancy and do not know they are at risk of transmitting the disease. Because of the stigma, many African women decline testing even when it is free and treatment is available. A study in Uganda found that Nevirapine lowers the risk of HIV transmission by breast feeding by nearly 50 percent during a baby's first four months. Vertical transmission remains a difficult issue, especially where contaminated water supplies could put an infant at risk for other infections when they are fed formula mixed with contaminated water.

  2. 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.

  3. 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

  4. Rotordynamic and leakage characteristics of a 4-stage brush seal

    NASA Astrophysics Data System (ADS)

    Conner, K. J.; Childs, D. W.

    1992-12-01

    Experimental results are presented for the direct and cross-coupled stiffness and damping coefficients as well as the leakage performance for a 4-stage brush seal. Variable test parameters include the inlet pressure, pressure ratio, shaft speed, fluid prerotation, and seal spacing. Direct damping is shown to increase with running speed; otherwise, the rotordynamic coefficients are relatively insensitive to changes in the test parameters. Cross-coupled stiffness is generally unchanged by increasing the inlet tangential velocity to the seals, suggesting that the brush seal is not affected by inlet swirl. Direct stiffness is shown to increase with frequency; however, the magnitudes of direct stiffness are always positive. Cross-coupled stiffness increases slightly with frequency; yet not as drastically as direct stiffness. Comparisons of test results for the 4-stage brush seal with an 8-cavity labyrinth showed superior rotordynamics performance for the brush seal; viz., large values for direct stiffness and lower values for the (destabilizing) cross-coupled stiffness coefficient. The damping for brush seals is smaller, but comparable to labyrinth seals. The whirl-frequency ratio is always smaller for the brush seal.

  5. Combretastatin A4 disodium phosphate-induced myocardial injury

    PubMed Central

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

    2016-01-01

    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

  6. Combination of vascular targeting PDT with combretastatin A4 phosphate

    NASA Astrophysics Data System (ADS)

    He, Chong; Fateye, Babasola; Chen, Bin

    2009-06-01

    Tumor vasculature is an attractive target for cancer therapy due to its accessibility to blood-borne therapeutic agents and the dependence of tumor cells on a functional blood supply for survival and growth. Vascular targeting photodynamic therapy (vPDT) is a novel modality based on the selective laser light activation of photosensitizers localized inside tumor vasculature to shutdown tumor vascular function. Although this vascular targeting therapy is showing great promise for cancer treatment, tumor recurrence has been observed in both preclinical and clinical studies. In this study, we intend to enhance the therapeutic outcome of vascular targeting PDT by combining it with combretastatin A4 phosphate (CA4P), a blood flow inhibitor. We found that the combination of CA4P and vPDT significantly increased endothelial cell apoptosis than each single therapy. Western blot analysis suggests that myosin light chain kinase (MLCK) is a common target of CA4P and vPDT. In a PC-3 prostate tumor model, we found that CA4P was able to greatly enhance tumor response to vPDT. These results demonstrate that CA4P and vPDT can be combined to enhance the therapeutic effect.

  7. Comparison of the In Vivo Distribution of Four Different Annexin A5 Adducts in Rhesus Monkeys

    PubMed Central

    McQuade, Paul; Belanger, Marie-Jose; Meng, Xiangjun; Guenther, Ilonka; Krause, Stephen; Gonzalez Trotter, Dinko; Reutelingsperger, Chris; Hostetler, Eric; Klimas, Michael; Mehmet, Huseyin; Cook, Jacquelynn

    2011-01-01

    Annexin A5 has been used for the detection of apoptotic cells, due to its ability to bind to phosphatidylserine (PS). Four different labeled Annexin A5 adducts were evaluated in rhesus monkey, with radiolabeling achieved via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Of these adducts differing conjugation methods were employed which resulted in nonspecific radiolabeling (AxA5-I), or site-specific radiolabeling (AxA5-II). A nonbinding variant of Annexin A5 was also evaluated (AxA5-IINBV), conjugation here was site specific. The fourth adduct examined had both specific and nonspecific conjugation techniques employed (AxA5-IImDOTA). Blood clearance for each adduct was comparable, while appreciable uptake was observed in kidney, liver, and spleen. Significant differences in uptake of AxA5-I and AxA5-II were observed, as well as between AxA5-II and AxA5-IINBV. No difference between AxA5-II and AxA5-IImDOTA was observed, suggesting that conjugating DOTA nonspecifically did not affect the in vivo biodistribution of Annexin A5. PMID:21629847

  8. Comparison of the in vivo distribution of four different annexin a5 adducts in rhesus monkeys.

    PubMed

    McQuade, Paul; Belanger, Marie-Jose; Meng, Xiangjun; Guenther, Ilonka; Krause, Stephen; Gonzalez Trotter, Dinko; Reutelingsperger, Chris; Hostetler, Eric; Klimas, Michael; Mehmet, Huseyin; Cook, Jacquelynn

    2011-01-01

    Annexin A5 has been used for the detection of apoptotic cells, due to its ability to bind to phosphatidylserine (PS). Four different labeled Annexin A5 adducts were evaluated in rhesus monkey, with radiolabeling achieved via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Of these adducts differing conjugation methods were employed which resulted in nonspecific radiolabeling (AxA5-I), or site-specific radiolabeling (AxA5-II). A nonbinding variant of Annexin A5 was also evaluated (AxA5-II(NBV)), conjugation here was site specific. The fourth adduct examined had both specific and nonspecific conjugation techniques employed (AxA5-II(mDOTA)). Blood clearance for each adduct was comparable, while appreciable uptake was observed in kidney, liver, and spleen. Significant differences in uptake of AxA5-I and AxA5-II were observed, as well as between AxA5-II and AxA5-II(NBV). No difference between AxA5-II and AxA5-II(mDOTA) was observed, suggesting that conjugating DOTA nonspecifically did not affect the in vivo biodistribution of Annexin A5.

  9. 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.

  10. Experimental validation of a 4D dose calculation routine for pencil beam scanning proton therapy.

    PubMed

    Pfeiler, T; Bäumer, C; Engwall, E; Geismar, D; Spaan, B; Timmermann, B

    2017-08-23

    Respiratory induced organ motion poses a major challenge for high-precision radiotherapy such as pencil beam scanning proton therapy (PBS). In order to employ PBS for target regions affected by respiratory motion, the implementation of dedicated motion mitigation techniques should be considered and residual uncertainties need to be assessed. For the latter purpose, a routine simulating the delivery of a scanned proton beam to a moving target was developed and implemented in the commercial treatment planning system RayStation. The time structure of the beam delivery was extracted from electronic irradiation protocols of the delivery system. Alternatively to electronic irradiation protocols, an empirical time model of the beam delivery was created to allow for prospective estimations of interplay effects between target motion and pencil beam scanning. The experimental validation of the routine was performed using a two-dimensional ionization chamber array and a dynamic phantom. A 4D CT data set, including 10 respiratory phases, provided the spatial temporal information about the phantom motion. The dosimetric comparison of the measured and the calculated dose distribution yielded gamma pass rates above 96% using a 3% dose difference and a 3mm distance to agreement criterion. Thus, a tool for the evaluation of interplay effects is available in a clinical software environment and patient-specific quality assurance can be extended to dynamic treatment scenarios. Copyright © 2017. Published by Elsevier GmbH.

  11. Availability of a 5% lidocaine patch used prophylactically for venipuncture- or injection-related pain in children.

    PubMed

    Kim, Cheul-Hong; Yoon, Ji-Uk; Lee, Hyeon-Jung; Shin, Sang-Wook; Yoon, Ji-Young; Byeon, Gyeong-Jo

    2012-08-01

    Venipuncture- or injection-related pain is still major problem during anesthetic induction in children. This study was designed to determine the availability of a 5% lidocaine patch used prophylactically for venipuncture- or injection-related pain during the induction of anesthesia. In a randomized, double-blind study, 72 pediatric patients were allocated to one of two groups: pretreatment with a 5% lidocaine patch (Lidoderm(®), Endo Pharmaceuticals, Chadds Ford, PA, USA) (group A) or pretreatment with a placebo patch (group B). Pain severity was evaluated on the Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) during venipuncture, and a 4-point scale during the injection of rocuronium. The FLACC score during venipuncture was significantly lower for group A than group B (p < 0.001). There was no significant difference in the grades of the 4-point scale observed during the injection of rocuronium between groups A and B. No significant adverse effect was noted for the groups. Although pretreatment with a 5% lidocaine patch was found to be a safe, effective, and simple method of preventing venipuncture pain in children, this method did not reduce drug injection pain during the induction of anesthesia.

  12. A5 segment aneurysm of the anterior cerebral artery, imbedded into the body of the corpus callosum: A case report

    PubMed Central

    Sharafeddin, Fransua; Hafez, Ahmad; Lehecka, Martin; Raj, Rahul; Colasanti, Roberto; Rafiei, Ahmadreza; Choque, Joham; Jahromi, Behnam R.; Niemelä, Mika; Hernesniemi, Juha

    2017-01-01

    Background: The A5 segment aneurysms of the anterior cerebral artery are rare, approximately 0.5% of all intracranial aneurysms. They are small with a wide base located in the midline, with the domes mostly projecting upward or backward. Case Description: The authors describe a unique case of A5 segment aneurysm, with the dome embedded into the body of the corpus callosum. This 41-year-old female was admitted to the neurology department for possible multiple sclerosis investigation. Computed tomography angiogram (CTA) revealed a 4-mm right-sided pericallosal artery aneurysm, with rare configuration, which was caudally projected, embedded into the body of the corpus callosum. Considering the family history, patient underwent a prophylactic ligation surgery. The postoperative CT and CTA showed no complication and successful occlusion of the aneurysm with no ischemia or hemorrhage in the corpus callosum. Conclusion: To the best of our knowledge, this is the first case of an aneurysm with this configuration. Our rare case of A5 segment aneurysm demonstrates the importance of planning of the surgery, choosing the appropriate approach, and knowing the detailed anatomy of the region, as well as the necessity of microsurgical clipping of small unruptured AdistAs. PMID:28217397

  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. 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  15. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  16. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  17. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  18. 42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 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 AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.5 Contents of...

  19. 8 CFR 213a.5 - Relationship of this part to other affidavits of support.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Relationship of this part to other affidavits of support. 213a.5 Section 213a.5 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.5 Relationship of this part...

  20. 8 CFR 213a.5 - Relationship of this part to other affidavits of support.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Relationship of this part to other affidavits of support. 213a.5 Section 213a.5 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.5 Relationship of this part...

  1. 8 CFR 213a.5 - Relationship of this part to other affidavits of support.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Relationship of this part to other affidavits of support. 213a.5 Section 213a.5 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.5 Relationship of this part...

  2. 8 CFR 213a.5 - Relationship of this part to other affidavits of support.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Relationship of this part to other affidavits of support. 213a.5 Section 213a.5 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.5 Relationship of this part...

  3. 8 CFR 213a.5 - Relationship of this part to other affidavits of support.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Relationship of this part to other affidavits of support. 213a.5 Section 213a.5 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS AFFIDAVITS OF SUPPORT ON BEHALF OF IMMIGRANTS § 213a.5 Relationship of this part...

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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...

  9. Orthologs of the class A4 heat shock transcription factor HsfA4a confer cadmium tolerance in wheat and rice.

    PubMed

    Shim, Donghwan; Hwang, Jae-Ung; Lee, Joohyun; Lee, Sichul; Choi, Yunjung; An, Gynheung; Martinoia, Enrico; Lee, Youngsook

    2009-12-01

    Cadmium (Cd) is a widespread soil pollutant; thus, the underlying molecular controls of plant Cd tolerance are of substantial interest. A screen for wheat (Triticum aestivum) genes that confer Cd tolerance to a Cd hypersensitive yeast strain identified Heat shock transcription factor A4a (HsfA4a). Ta HsfA4a is most similar to the class A4 Hsfs from monocots. The most closely related rice (Oryza sativa) homolog, Os HsfA4a, conferred Cd tolerance in yeast, as did Ta HsfA4a, but the second most closely related rice homolog, Os HsfA4d, did not. Cd tolerance was enhanced in rice plants expressing Ta HsfA4a and decreased in rice plants with knocked-down expression of Os HsfA4a. An analysis of the functional domain using chimeric proteins constructed from Ta HsfA4a and Os HsfA4d revealed that the DNA binding domain (DBD) of HsfA4a is critical for Cd tolerance, and within the DBD, Ala-31 and Leu-42 are important for Cd tolerance. Moreover, Ta HsfA4a-mediated Cd resistance in yeast requires metallothionein (MT). In the roots of wheat and rice, Cd stress caused increases in HsfA4a expression, together the MT genes. Our findings thus suggest that HsfA4a of wheat and rice confers Cd tolerance by upregulating MT gene expression in planta.

  10. [A 4-week oral toxicity study of prulifloxacin (NM441) in rats followed by a 4-week recovery test].

    PubMed

    Nishimura, N; Fukuda, K; Yamazaki, S; Tamura, K; Shindo, Y; Iwakura, K; Sumi, N

    1996-06-01

    A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Male and female rats were given the test material orally for 4 weeks at doses of 0 (control), 30, 300 and 3000 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted. There was one case of death in the 3000 mg/kg group. Grayish green and soft feces, unkempt fur, transient deep respiration and decreased body weight gain were observed in the 3000 mg/kg group. Decreased food consumption and increased water intake were seen in the 300 and 3000 mg/kg groups. Ophthalmoscopic examination failed to show any abnormalities related to the treatment. In urinalysis, crystalline substance in the urinary sediments, cloudy urine and decreased Na+ excretion were observed in the 300 and 3000 mg/kg groups. Increased urine volume, lowered urine specific gravity and decreased K+ and Cl- excretions were seen in the 3000 mg/kg group. Hematologic examination showed decreased Hb, Ht, MCV and MCH and increased WBC in the 3000 mg/kg group. Blood chemical examination revealed increased BUN and decreased K+ and Cl- in the 3000 mg/kg group, and decreased K+ and gamma-globulin in the 300 mg/kg group. Pathological changes caused by the treatment were as follows. Cecal weight was increased in all dose groups. Cecal distention and swelling of its absorptive cells were seen in the 300 and 3000 mg/kg groups. In kidney, tubular nephrosis with crystalline substance was observed in the 300 and 3000 mg/kg groups, and its organ weight was increased in the 3000 mg/kg group. The above-mentioned changes were reversible except for decreased gamma-globulin, increased BUN and urine volume, and lowered urine specific gravity. Ulcer and small cavities associated with proliferation of fibrous tissue in the femoral articular cartilage were observed in the 3000 mg/kg group at the end of recovery period of 4 weeks. Plasma levels and urinary concentrations of active

  11. Preparation and identification of Per a 5 as a novel American cockroach allergen.

    PubMed

    Wei, Ji-Fu; Yang, Haiwei; Li, Dongning; Gao, Peisong; He, Shaoheng

    2014-01-01

    Glutathione S-transferase (GST) from various arthropods can elicit allergic reactions. In the present study, Per a 5, a GST, was cloned from American cockroach (CR) and expressed in both baculovirus-infected insect cell (iPer a 5) and E. coli expression (bPer a 5) systems. The secondary structures were predicted to be 45.93 and 8.69% of α-helix β-sheets in iPer a 5 and 42.54 and 8.49% of α-helix and β-sheets in bPer a 5, respectively. It is found that 4 out of 16 (25%) sera from American CR allergy patients reacted to both bPer a 9 and iPer a 9 as assessed by ELISA and Western blotting analysis, confirming that Per a 5 is not a major allergen of American CR. Induction of upregulated expression of CD63 and CCR3 on passively sensitized human basophils (sera from American CR allergy patients) by approximately up to 4.5- and 3.2-fold indicates that iPer a 5 and bPer a 5 are functionally active. Recombinant Per a 5 (rPer a 5) should be a useful tool for studying and understanding the role of Per a 5 in CR allergy.

  12. Metformin ameliorates obesity-associated hypertriglyceridemia in mice partly through the apolipoprotein A5 pathway.

    PubMed

    Li, Rong; Chen, Lu-Zhu; Zhao, Wang; Zhao, Shui-Ping; Huang, Xian-Sheng

    2016-09-23

    Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotriglyceridemic actions. Two obese mouse models, including high-fat diet-induced obese mice and ob/ob obese mice, were adopted. The effects of low- and high-dose metformin were determined on plasma and hepatic TG and apoA5 of these obese mice. Besides, the effects of metformin on TG and apoA5 were also detected in mouse and human hepatocytes in vitro. (1) Plasma apoA5 levels in the obese mice were markedly elevated and positively correlated with TG. Hepatic TG contents and apoA5 expressions were also remarkably increased in the obese mice. (2) Metformin dose-dependently decreased hepatic and plasma TG and apoA5 in the obese mice. Similarly, metformin dose-dependently reduced cellular TG contents and apoA5 expressions in hepatocytes in vitro. Compared to APOA5 knock-down (KD), metformin plus APOA5 KD resulted in more TG reduction of hepatocytes. Increased hepatic and plasma apoA5 could be a result of obesity-associated hypertriglyceridemia, and metformin displays hypotriglyceridemic effects on obese mice partly via the apoA5 pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 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....

  14. 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 of...

  15. 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 of...

  16. 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 of...

  17. 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 PROVISIONS RURAL PHYSICIAN TRAINING GRANT PROGRAM § 5a.3 Definition of Underserved Rural Community...

  18. 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 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN TRAINING GRANT PROGRAM § 5a.3 Definition of Underserved Rural Community...

  19. 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 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 Estate § 20.2056A-3 QDOT election...

  20. 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 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 Estate § 20.2056A-3 QDOT election...