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Sample records for a3 a4 a5

  1. CYP3A4 and CYP3A5 genotyping by Pyrosequencing

    PubMed Central

    Garsa, Adam A; McLeod, Howard L; Marsh, Sharon

    2005-01-01

    Background Human cytochrome P450 3A enzymes, particularly CYP3A4 and CYP3A5, play an important role in drug metabolism. CYP3A expression exhibits substantial interindividual variation, much of which may result from genetic variation. This study describes Pyrosequencing assays for key SNPs in CYP3A4 (CYP3A4*1B, CYP3A4*2, and CYP3A4*3) and CYP3A5 (CYP3A5*3C and CYP3A5*6). Methods Genotyping of 95 healthy European and 95 healthy African volunteers was performed using Pyrosequencing. Linkage disequilibrium, haplotype inference, Hardy-Weinberg equilibrium, and tag SNPs were also determined for these samples. Results CYP3A4*1B allele frequencies were 4% in Europeans and 82% in Africans. The CYP3A4*2 allele was found in neither population sample. CYP3A4*3 had an allele frequency of 2% in Europeans and 0% in Africans. The frequency of CYP3A5*3C was 94% in Europeans and 12% in Africans. No CYP3A5*6 variants were found in the European samples, but this allele had a frequency of 16% in the African samples. Allele frequencies and haplotypes show interethnic variation, highlighting the need to analyze clinically relevant SNPs and haplotypes in a variety of ethnic groups. Conclusion Pyrosequencing is a versatile technique that could improve the efficiency of SNP analysis for pharmacogenomic research with the ultimate goal of pre-screening patients for individual therapy selection. PMID:15882469

  2. Catalytic Properties of Botulinum Neurotoxins Subtypes A3 and A4

    PubMed Central

    Henkel, James S.; Jacobson, Mark; Tepp, William; Pier, Christina; Johnson, Eric A.; Barbieri, Joseph T.

    2009-01-01

    Botulinum toxins (BoNT) are zinc proteases (serotypes A-G) which cause flaccid paralysis through the cleavage of SNARE proteins within motor neurons. BoNT/A was originally organized into two subtypes: BoNT/A1 and BoNT/A2, which are ~ 95 % homologous and possess similar catalytic activities. Subsequently, two additional subtypes were identified; BoNT/A3 (Loch Maree), and BoNT/A4 (657Ba), which have 81 and 88% homology with BoNT/A1, respectively. Alignment studies predicted that BoNT/A3 and BoNT/A4 were sufficiently different to BoNT/A1 to affect SNAP25 binding and cleavage. Recombinant Light Chain (LC) of BoNT/A3 (LC/A3) and BoNT/A4 (LC/A4) were subjected to biochemical analysis. LC/A3 cleaved SNAP25 at 50% the rate of LC/A1, but cleaved SNAPtide® at a faster rate than LC/A1, while LC/A4 cleaved SNAP25 and SNAPtide® at slower rates than LC/A1. LC/A3 and LC/A4 had similar Kms for SNAP25 relative to LC/A1, while the kcat for LC/A4 was 10- fold slower than LC/A1, suggesting a defect in substrate cleavage. Neither LC/A3 nor LC/A4 possessed autocatalytic activity, a property of LC/A1 and LC/A2. Thus, the four subtypes of BoNT/A bind SNAP25 with similar affinity but have different catalytic capacities for SNAP25 cleavage, SNAPtide® cleavage, and autocatalysis. The catalytic properties identified among the subtypes of LC/A may influence strategies for the development of small molecule- or peptide- inhibitors as therapies against botulism. PMID:19256469

  3. 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).

  4. 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 A 4 (LXA 4 ) has anti-inflammatory properties, we investigated whether this lipid mediator affects host responses manifested early during infection. The addition of exogenous LXA 4 inhibits PGE 2 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 LXA 4 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 LXA 4 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 LXA 4 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.

  5. Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.

    PubMed

    Fukushima-Uesaka, Hiromi; Saito, Yoshiro; Watanabe, Hidemi; Shiseki, Kisho; Saeki, Mayumi; Nakamura, Takahiro; Kurose, Kouichi; Sai, Kimie; Komamura, Kazuo; Ueno, Kazuyuki; Kamakura, Shiro; Kitakaze, Masafumi; Hanai, Sotaro; Nakajima, Toshiharu; Matsumoto, Kenji; Saito, Hirohisa; Goto, Yu-ichi; Kimura, Hideo; Katoh, Masaaki; Sugai, Kenji; Minami, Narihiro; Shirao, Kuniaki; Tamura, Tomohide; Yamamoto, Noboru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Kitamura, Yutaka; Kamatani, Naoyuki; Ozawa, Shogo; Sawada, Jun-ichi

    2004-01-01

    In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations. Copyright 2003 Wiley-Liss, Inc.

  6. Microneurosurgical management of aneurysms at A4 and A5 segments and distal cortical branches of anterior cerebral artery.

    PubMed

    Lehecka, Martin; Dashti, Reza; Hernesniemi, Juha; Niemelä, Mika; Koivisto, Timo; Ronkainen, Antti; Rinne, Jaakko; Jääskeläinen, Juha

    2008-10-01

    Aneurysms originating distal to the A3 segment of the ACA, located on the A4 and the A5 segments or the distal cortical branches of the ACA (AdistAs) are rare, forming about 0.5% of all IAs. There are only few reports on management of AdistAs. In this article, we review the practical anatomy, preoperative planning, and avoidance of complications in the microsurgical dissection and clipping of AdistAs. This review, and the whole series on IAs, is mainly based on the personal microneurosurgical experience of the senior author (J. H.) in 2 Finnish centers (Helsinki and Kuopio), which serve without patient selection the catchment area in Southern and Eastern Finland. These 2 centers have treated more than 10000 patients with IAs since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients and 4253 IAs, there were 26 patients carrying 26 AdistAs, forming 0.9% of all patients with IAs, 0.6% of all IAs, and 2% of all ACA aneurysms. A total of 10 (38%) patients presented with ruptured AdistAs, with ICH in 4 (40%) and IVH in 2 (20%); 16 patients (62%) had multiple aneurysms. AdistAs are small, even when ruptured, with relatively wide base, and they are frequently associated with ICHs. Our data suggest that AdistAs rupture at smaller size than IAs in general. The challenge is to locate the aneurysm inside the interhemispheric fissure and to clip the neck adequately without obstructing branching arteries at the base. Unruptured AdistAs also need microneurosurgical clipping even when they are small.

  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.

    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 datamore » 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.« less

  8. Differential Regulation of CYP3A4 and CYP3A5 and Its Implication in Drug Discovery

    PubMed Central

    Lolodi, Ogheneochukome; Wang, Yue-Ming; Wright, William C.; Chen, Taosheng

    2017-01-01

    Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them. PMID:28558634

  9. 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.

  10. 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

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

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and A4. 80.1093 Section 80.1093 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety...

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

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and A4. 80.1093 Section 80.1093 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety...

  13. 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 A4. 80.1093 Section 80.1093 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety...

  14. 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 A4. 80.1093 Section 80.1093 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety...

  15. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.

    PubMed

    Talmud, Philippa J; Hawe, Emma; Martin, Steve; Olivier, Michael; Miller, George J; Rubin, Edward M; Pennacchio, Len A; Humphries, Steve E

    2002-11-15

    Since triglycerides (TG) are a major independent risk factor for coronary heart disease, understanding their genetic and environmental determinants is of major importance. Mouse models indicate an inverse relationship between levels of the newly identified apolipoprotein AV (APOAV) and TG concentrations. We have examined the relative influence of human APOA5 variants on plasma lipids, compared to the impact of variation in APOC3 and APOA4 which lie in the same cluster. Single nucleotide polymorphisms (SNPs) in APOA5 (S19W, -1131T>C) and APOA4 (T347S, Q360H) and an APOA4/A5 intergenic T>C SNP were examined in a large study of healthy middle-aged men (n=2808). APOA5 19WW and -1131CC men had 52% and 40% higher TG (P<0.003) compared to common allele homozygotes, respectively, effects which were independent and additive. APOA4 347SS men had 23% lower TG compared to TT men (P<0.002). Haplotype analysis was carried out to identify TG-raising alleles and included, in addition, four previously genotyped APOC3 SNPs (-2845T>G, -482C>T, 1100C>T, and 3238C>G). The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T. This suggests that the TG-lowering effect of APOA4 S347 might merely reflect the strong negative linkage disequilibrium with the common alleles of these variants. Thus variation in APOA5 is associated with differences in TGs in healthy men, independent of those previously reported for APOC3, while association between APOA4 and TG reflects linkage disequilibrium with these sites. The molecular mechanisms for these effects remain to be determined.

  16. 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...

  17. COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome.

    PubMed

    Storey, Helen; Savige, Judy; Sivakumar, Vanessa; Abbs, Stephen; Flinter, Frances A

    2013-12-01

    Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6-54 years). The median age at end stage renal failure was 22.5 years (range, 10-38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C>G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome.

  18. COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

    PubMed Central

    Savige, Judy; Sivakumar, Vanessa; Abbs, Stephen; Flinter, Frances A.

    2013-01-01

    Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6–54 years). The median age at end stage renal failure was 22.5 years (range, 10–38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C>G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome. PMID:24052634

  19. CYP3A4 and CYP3A5 catalyse the conversion of the N-methyl-D-aspartate (NMDA) antagonist CJ-036878 to two novel dimers.

    PubMed

    Emoto, C; Nishida, H; Hirai, H; Iwasaki, K

    2007-12-01

    CJ-036878, N-(3-phenethoxybenzyl)-4-hydroxybenzamide, was developed as an antagonist of the N-methyl-D-aspartate receptor NR2B subunit. Two dimeric metabolites, CJ-047710 and CJ-047713, were identified from the incubation mixture with CJ-036878 in human liver microsomes (HLM). The identification of the enzymes involved in the formation of these dimeric metabolites was investigated in the current study. Inhibition of the formation of CJ-047710 and CJ-047713 in pooled HLM by 1-aminobenztriazole, SKF-525A, and ketoconazole were observed. Ketoconazole played a significant role in inhibiting formation of these two metabolites in a concentration-dependent manner. Recombinant CYP3A4 and CYP3A5 exhibited a markedly high activity toward the formation of CJ-047710 and CJ-047713 from CJ-036878, but the contribution of other CYP enzymes to these formations was at a very low level or negligible. The formation of CJ-047710 and CJ-047713 in pooled HLM, CYP3A4, and CYP3A5 showed sigmoid characteristics. S50 values for CJ-047710 and CJ-047713 formation in HLM were almost equivalent with those for CYP3A4 and CYP3A5. For the CYP3A enzymes, maximal clearance due to auto-activation values for CJ-047710 and CJ-047713 formation catalysed by CYP3A5 were 3.6- and 3.1-fold higher than those catalysed by CYP3A4. This is the first report that shows both CYP3A4 and CYP3A5 simultaneously contribute to dimerization through oxidative C-C and C-O coupling reactions.

  20. CYP3A4 and CYP3A5 polymorphisms and blood pressure response to amlodipine among African-American men and women with early hypertensive renal disease.

    PubMed

    Bhatnagar, Vibha; Garcia, Erin P; O'Connor, Daniel T; Brophy, Victoria H; Alcaraz, John; Richard, Erin; Bakris, George L; Middleton, John P; Norris, Keith C; Wright, Jackson; Hiremath, Leena; Contreras, Gabriel; Appel, Lawrence J; Lipkowitz, Michael S

    2010-01-01

    To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164). Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of < or =107 mm Hg by CYP3A4 (A-392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response. Women randomized to a usual MAP goal with an A allele at CYP3A4 A-392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20-9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17-3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response. Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study. Copyright (c) 2009 S. Karger AG, Basel.

  1. CYP3A4 and CYP3A5 Polymorphisms and Blood Pressure Response to Amlodipine among African-American Men and Women with Early Hypertensive Renal Disease

    PubMed Central

    Bhatnagar, Vibha; Garcia, Erin P.; O’Connor, Daniel T.; Brophy, Victoria H.; Alcaraz, John; Richard, Erin; Bakris, George L.; Middleton, John P.; Norris, Keith C.; Wright, Jackson; Hiremath, Leena; Contreras, Gabriel; Appel, Lawrence J.; Lipkowitz, Michael S.

    2010-01-01

    Purpose To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164). Methods Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of ≤107 mm Hg by CYP3A4 (A–392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response. Results Women randomized to a usual MAP goal with an A allele at CYP3A4 A–392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20–9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17–3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response. Conclusions Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study. PMID:19907160

  2. Analysis of single-nucleotide polymorphisms (SNPs) in human CYP3A4 and CYP3A5 genes: potential implications for the metabolism of HIV drugs

    PubMed Central

    2014-01-01

    Background Drug metabolism via the cytochrome P450 (CYP450) system has emerged as an important determinant in the occurrence of several drug interactions (adverse drug reactions, reduced pharmacological effect, drug toxicities). In particular, CYP3A4 and CYP3A5 (interacting with more than 60% of licensed drugs) exhibit the most individual variations of gene expression, mostly caused by single nucleotide polymorphisms (SNPs) within the regulatory region of the CYP3A4 and CYP3A5 genes which might affect the level of enzyme production. In this study, we sought to improve the performance of sensitive screening for CYP3A polymorphism detection in twenty HIV-1 infected patients undergoing lopinavir/ritonavir (LPV/r) monotherapy. Methods The study was performed by an effective, easy and inexpensive home-made Polymerase Chain Reaction Direct Sequencing approach for analyzing CYP3A4 and CYP3A5 genes which can detect both reported and unreported genetic variants potentially associated with altered or decreased functions of CYP3A4 and CYP3A5 proteins. Proportions and tests of association were used. Results Among the genetic variants considered, CYP3A4*1B (expression of altered function) was only found in 3 patients (15%) and CYP3A5*3 (expression of splicing defect) in 3 other patients (15%). CYP3A5*3 did not appear to be associated with decreased efficacy of LPV/r in any patient, since none of the patients carrying this variant showed virological rebound during LPV/r treatment or low levels of TDM. In contrast, low-level virological rebound was observed in one patient and a low TDM level was found in another; both were carrying CYP3A4*1B. Conclusions Our method exhibited an overall efficiency of 100% (DNA amplification and sequencing in our group of patients). This may contribute to producing innovative results for better understanding the inter-genotypic variability in gene coding for CYP3A, and investigating SNPs as biological markers of individual response to drugs

  3. A new donors' CYP3A5 and recipients' CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients.

    PubMed

    Liu, Yuan; Zhang, Tao; Zhang, Xiaoqing; Ye, Ling; Gu, Haitao; Zhong, Lin; Sun, Hongcheng; Song, Chenlong; Peng, Zhihai; Fan, Junwei

    2017-09-19

    The purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors. In this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included. Both donors' CYP3A5 *3 and recipients' CYP3A4 *1G had a correlation with Tac pharmacokinetics at four weeks (all P <0.05), except recipients' CYP3A4 *1G nearly had an association at week 2 ( P =0.055). The model of donors' CYP3A5 *3, recipients' CYP3A4*1G , and total bilirubin (TBL), for the prediction of Tac disposition, was better than donors' CYP3A5 *3 only at week 1, 2, and 3 ( P =0.010, P =0.007, and P =0.010, respectively), but not apparent at week 4 ( P =0.297). Besides, when the P value was greater than or equal to 0.6685 after considering the false-positive rate R=10%, the patients were considered to have a faster metabolism, according to the mentioned model. Interestingly, we found that if more than or equal to two alleles A were present in the combination of donors' CYP3A5 *3 and recipients' CYP3A4 *1G genotype, there was a lower Tac C/D ration at week 1, 2, and 3 ( P <0.001, P =0.001, and P <0.001), except at week 4 ( P =0.082), and the probability of new-onset hypertension was lesser ( P <0.001). These data provided a potential basis for a comprehensive approach to predicting the Tac dose requirement in individual patients and provided a strategy for the effective prevention, early diagnosis of new-onset hypertension in Chinese LT recipients.

  4. 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.

  5. Inactivation of Cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a Thiophene-Containing Anticancer DrugS⃞

    PubMed Central

    Lin, Hsia-lien; Zhang, Haoming; Medower, Christine; Johnson, William W.

    2011-01-01

    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 b5 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 b5. 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 KI of 24 μM and a kinact of 0.04 min−1. This KI is significantly greater than the clinical OSI-930 Cmax 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 for oxidation

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... paragraph (a) of § 1.50A-3 if it is determined by the appropriate State administrative agency or State court... compensation), he could reasonably have been found by such administrative agency or court to have been... comparable wages to such employee (within the meaning of paragraph (a)(2) of § 1.50A-3), then paragraph (a)(3...

  7. Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes

    PubMed Central

    Weiss, Robert B.; Bolt, Daniel; von Niederhausern, Andrew; Fiore, Michael C.; Dunn, Diane M.; Piper, Megan E.; Matsunami, Nori; Smith, Stevens S.; Coon, Hilary; McMahon, William M.; Scholand, Mary B.; Singh, Nanda; Hoidal, John R.; Kim, Su-Young; Leppert, Mark F.; Cannon, Dale S.

    2009-01-01

    Introduction: Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerström Test for Nicotine Dependence among individuals reporting daily smoking by age 17. The present study used subsamples of participants from that study to investigate associations between the CHRNA5-A3-B4 haplotypes and an array of phenotypes not analyzed previously (i.e., withdrawal severity, ability to stop smoking, and specific scales on the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) that reflect loss of control, strong craving, and heavy smoking. Methods: Two cohorts of current or former smokers (N = 886) provided both self-report data and DNA samples. One sample (Wisconsin) comprised smokers making a quit smoking attempt, which permitted the assessment of withdrawal and relapse during the attempt. The other sample (Utah) comprised participants studied for risk factors for nicotine dependence and chronic obstructive pulmonary disease and included individuals originally recruited in the Lung Health Study. Results: The CHRNA5-A3-B4 haplotypes were significantly associated with the targeted WISDM-68 scales (Tolerance, Craving, Loss of Control) in both samples of participants but only among individuals who began smoking early in life. The haplotypes were significantly associated with relapse likelihood and withdrawal severity, but these associations showed no evidence of an interaction with age at daily smoking. Discussion: The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking. PMID:19436041

  8. Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients.

    PubMed

    Debette-Gratien, Marilyne; Woillard, Jean-Baptiste; Picard, Nicolas; Sebagh, Mylène; Loustaud-Ratti, Véronique; Sautereau, Denis; Samuel, Didier; Marquet, Pierre

    2016-10-01

    This study investigated the influence of the CYP3A4*22, CYP3A5*3, and ABCB1 exons 12, 21, and 26 polymorphisms in donors and recipients on clinical outcomes and renal function in 170 liver transplant patients on cyclosporin A (CsA) or tacrolimus (Tac). Allelic discrimination assays were used for genotyping. Multivariate time-dependent Cox proportional hazard models, multiple linear regression using the generalized estimating equation and linear mixed-effect models were used for statistical analysis. Expression of CYP3A5 by either or both the donor and the recipient was significantly associated with lower Tac, but not CsA, dose-normalized trough levels. In the whole population, graft loss was only significantly associated with longer exposure to high calcineurin inhibitor (CNI) concentrations (hazard ratio, 6.93; 95% confidence interval, 2.13-22.55), P = 0.00129), whereas in the Tac subgroup, the risk of graft loss was significantly higher in recipient CYP3A5*1 expressers (hazard ratio, 3.39; 95% confidence interval, 1.52-7.58; P = 0.0028). Renal function was significantly associated with: (1) baseline modification of diet in renal disease (β = 0.51 ± 0.05; P < 0.0001); (2) duration of patient follow-up (per visit, β = -0.98 ± 0.22; P < 0.0001); and (3) CNI exposure (per quantile increase, β = -2.42 ± 0.59; P < 0.0001). No genetic factor was associated with patient survival, acute rejection, liver function test results, recurrence of viral or other initial liver disease, or renal function. This study confirms the effect of CYP3A5*3 on tacrolimus dose requirement in liver transplantation and shows unexpected associations between the type of, and exposure to, CNI and either chronic rejection or graft loss. None of the genetic polymorphisms studied had a noticeable impact on renal function degradation at 10 years.

  9. 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...

  10. Genetic engineering of Streptomyces bingchenggensis to produce milbemycins A3/A4 as main components and eliminate the biosynthesis of nanchangmycin.

    PubMed

    Zhang, Ji; An, Jing; Wang, Ji-Jia; Yan, Yi-Jun; He, Hai-Rong; Wang, Xiang-Jing; Xiang, Wen-Sheng

    2013-12-01

    Milbemycins A3/A4 are important 16-membered macrolides which have been commercialized and widely used as pesticide and veterinary medicine. However, similar to other milbemycin producers, the production of milbemycins A3/A4 in Streptomyces bingchenggensis is usually accompanied with undesired by-products such as C5-O - methylmilbemycins B2/B3 (α-class) and β1/β2 (β-class) together with nanchangmycin. In order to obtain high yield milbemycins A3/A4-producing strains that produce milbemycins A3/A4 as main components, milD, a putative C5-O-methyltransferase gene of S. bingchenggensis , was biofunctionally investigated by heterologous expression in Escherichia coli . Enzymatic analysis indicated that MilD can catalyze both α-class (A3/A4) and β-class milbemycins (β11) into C5-O-methylmilbemycins B2/B3 and β1, respectively, suggesting little effect of furan ring formed between C6 and C8a on the C5-O-methylation catalyzed by MilD. Deletion of milD gene resulted in the elimination of C5-Omethylmilbemycins B2/B3 and β1/β2 together with an increased yield of milbemycins A3/A4 in disruption strain BCJ13. Further disruption of the gene nanLD encoding loading module of polyketide synthase responsible for the biosynthesis of nanchangmycin led to strain BCJ36 that abolished the production of nanchangmycin. Importantly, mutant strain BCJ36 (ΔmilDΔnanLD) produced milbemycins A3/A4 as main secondary metabolites with a yield of 2312 ± 47 μg/ml, which was approximately 74 % higher than that of the initial strain S. bingchenggensis BC-109-6 (1326 ± 37 μg/ml).

  11. 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

    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 withmore » 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.« less

  12. Altered expression of miR-181a-5p and miR-23a-3p is associated with obesity and TNFα-induced insulin resistance.

    PubMed

    Lozano-Bartolomé, Javier; Llauradó, Gemma; Otin, Manel Portero; Altuna-Coy, Antonio; Rojo-Martínez, Gemma; Vendrell, Joan; Jorba, Rosa; Rodríguez-Gallego, Esther; Chacón, Matilde R

    2018-02-01

    The proinflammatory cytokine TNFα is a key player in insulin resistance (IR). While several miRNAs are believed to be involved in the development of adipose tissue (AT) IR, the role of miRNAs in the association between inflammation and IR is poorly understood. To investigate the expression profile of miR-181a-5p and miR-23a-3p in obesity and to study their role in TNFα-induced IR in adipocytes. Two separate cohorts were employed. Cohort 1 was used for AT expression studies and included 28 subjects with BMI<30 and 30 subjects with BMI≥30. Cohort 2 was used for circulating serum miRNA studies and included 101 subjects with 4-years follow-up (48 cases and 53 controls). miR-181a-5p and miR-23a-3p expression was assessed in subcutaneous (SAT) and visceral (VAT) AT. Functional analysis was performed in adipocytes utilizing miRNA mimics and inhibitors. Key molecules of the insulin pathway, AKT, PTEN, AS160 and S6K, were analyzed. Expression of miR-181a-5p and miR-23a-3p was reduced in AT from obese and diabetic subjects and was inversely correlated to adiposity and HOMA-IR. Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin-stimulated AKT activation and reduced TNFα-induced IR, regulating PTEN and S6K expression. Serum levels of miR-181a-5p were reduced in cases vs controls at baseline, pointing towards its prognostic value. Variable importance in projection scores revealed miR-181a-5p had more impact in the model than insulin or glucose at 120 minutes. miR-181a-5p and miR-23a-3p may prevent TNFα-induced IR in adipocytes through modulation of PTEN and S6K expression. Copyright © 2018 Endocrine Society

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

    PubMed

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

    2016-06-01

    Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found. © 2016 British Society for Immunology.

  14. Mutation analysis of COL4A3 and COL4A4 genes in a Chinese autosomal-dominant Alport syndrome family.

    PubMed

    Guo, Liwei; Li, Duan; Dong, Shuangshuang; Wan, Donghao; Yang, Baosheng; Huang, Yanmei

    2017-06-01

    Autosomal dominant Alport syndrome (ADAS) accounts for 5% of all cases of Alport syndrome (AS), a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family.Mutations in COL4A3 and COL4A4 genes were reported to be associated with ADAS. In this study, clinical data in a large consanguineous family with seven affected members were reviewed, and genomic DNA was extracted. For mutation screening, all exons of COL4A3 and COL4A4 genes were polymerase chain reaction-amplified and direct sequenced from genomic DNA, and the mutations were analyzed by comparing with members in this family, 100 ethnicitymatched controls and the sequence of COL4A3 and COL4A4 genes from GenBank. A novel mutation determining a nucleotide change was found, i.e. c.4195 A>T (p.Met1399Leu) at 44th exon of COL4A4 gene, and this mutation showed heterozygous in all patients of this family. Also a novel intron mutation (c.4127+11 C>T) was observed at COL4A4 gene. Thus the novel missense mutation c.4195 A>T (p.Met1399Leu) and the intron mutation (c.4127+11 C>T) at COL4A4 gene might be responsible for ADAS of this family. Our results broadened the spectrum of mutations in COL4A4 and had important implications in the diagnosis, prognosis, and genetic counselling of ADAS.

  15. Determination of a quantitative relationship between hepatic CYP3A5*1/*3 and CYP3A4 expression for use in the prediction of metabolic clearance in virtual populations.

    PubMed

    Barter, Z E; Perrett, H F; Yeo, K Rowland; Allorge, D; Lennard, M S; Rostami-Hodjegan, A

    2010-11-01

    The creation of virtual populations allows the estimation of pharmacokinetic parameters, such as metabolic clearance in extreme individuals rather than the 'average human'. Prediction of variability in metabolic clearance within genetically diverse populations relies on understanding the covariation in the expression of enzymes. A number of statistically significant positive correlations have been observed in the hepatic expression of cytochrome P450 drug metabolising enzymes. However, these rarely provided a quantitative description of the relationships which is required in creating virtual populations. Collation of data from 40 human liver microsomal samples in the current study indicated a significant positive relationship between hepatic microsomal CYP3A5*1/*3 and CYP3A4 content. Having developed a model describing the relationship between hepatic CYP3A4 and CYP3A5*1/*3, the Simcyp Population-based Simulator(®) was used to investigate the consequences of either incorporating or ignoring the relationship between the two enzymes on estimates of drug clearance. Simulations indicated that for a compound with greater metabolism by CYP3A5 than CYP3A4, such as tacrolimus, incorporation of the correlation between CYP3A4 and CYP3A5 does have an impact on the prediction of oral clearance. Failure to consider the relationship between CYP3A4 and CYP3A5 when creating the virtual population led to a 32% lower estimate of oral clearance in individuals possessing both the CYP3A5*1/*3 genotype and high basal concentrations of CYP3A4. Potential clinical implications may include an inadequate dose estimation during clinical study design, the consequences of which may include organ rejection in transplant recipients using immunosuppressants such as tacrolimus or toxicity due to elevated concentrations of circulating metabolites. Copyright © 2010 John Wiley & Sons, Ltd.

  16. Feasibility and safety of transfemoral intra-arterial chemotherapy for head and neck cancer using a 3-French catheter system: comparison with a 4-French catheter system.

    PubMed

    Watanabe, Shigeru; Yamamoto, Akira; Torigoe, Teruyuki; Kanki, Akihiko; Tamada, Tsutomu; Ito, Katsuyoshi

    2016-02-01

    To assess the technical feasibility of transfemoral intra-arterial chemotherapy for head and neck cancer using a 3-French catheter system (3-Fr). Sixty-two patients with head and neck cancer who underwent transfemoral intra-arterial chemotherapy were included in this study. Thirty-three patients underwent treatment using a 3-Fr (group 3-Fr). Twenty-nine patients underwent treatment using a 4-French catheter system (group 4-Fr). The technical success rate, duration of the procedure with fluoroscopy, and rate of procedure-related complications were compared between group 3-Fr and group 4-Fr. In addition, in group 3-Fr, bleeding at the puncture site after 1.5 h of bed rest was evaluated. The technical success rate was 100% in both groups. The duration of the procedure with fluoroscopy didn't differ between group 3-Fr (mean 28.0 min) and group 4-Fr (mean 30.2 min) (p = 0.524). There was no procedure-related complication in either group. In group 3-Fr, no hemorrhagic complication was observed. A 3-French catheter system can be used to perform transfemoral intra-arterial chemotherapy for head and neck cancer and is technically feasible with approximately the same duration of the procedure with fluoroscopy. Furthermore, this method may shorten the bed rest time without hemorrhagic complication, and may reduce the risk of pulmonary embolism.

  17. Biomechanical Testing of a 3-Hole versus a 4-Hole Sliding Hip Screw in the presence of a Retrograde Intramedullary Nail for Ipsilateral Intertrochanteric and Femur Shaft Fractures.

    PubMed

    Olsen, Michael; Goshulak, Peter; Crookshank, Meghan C; Moktar, Joel; Brazda, Ignace J; Schemitsch, Emil H; Zdero, Radovan

    2018-04-03

    The goal of this study was to compare a 3-hole vs. a 4-hole sliding hip screw (SHS) in the presence of a retrograde intramedullary (RIM) nail for fixing intertrochanteric and comminuted midshaft femur fractures. Mechanical tests were performed on 10 matched pairs of human cadaveric femurs that were osteotomized and then fixed using a 3-hole SHS vs. the traditional "gold standard" 4-hole SHS in the presence of a RIM nail. Data showed no differences between the 3-hole SHS with RIM nail vs. 4-hole SHS with RIM nail for stiffness (281 +/- 127 vs. 260 +/- 118 N/mm, p=0.76), clinical failure at 10 mm of hip displacement (2014 +/- 363 vs. 2134 +/- 614 N, p=0.52), or ultimate mechanical failure (3476 +/- 776 vs. 3669 +/- 755 N, p=0.12). For this fracture pattern, a 3-hole SHS with RIM nail may be a suitable surgical alternative to the traditional "gold standard" method, since it provides the same biomechanical properties while potentially reducing surgical time, blood loss, and hardware used. Level III biomechanical study.

  18. Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?

    PubMed

    Kudzi, William; Dodoo, Alexander N O; Mills, Jeremy J

    2010-07-14

    Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies. Using PCR-RFLP, relevant polymorphic alleles of MDR1 and CYP3A4 genes were analysed in 204 randomly selected individuals and in 42 ivermectin treated patients. We recorded significantly higher MDR1 (3435T) variant allele frequency in suboptimal responders (21%) than in patients who responded to treatment (12%) or the random population sample (11%). CYP3A4*1B, CYP3A5*3 and CYP3A5*6 alleles were detected at varied frequencies for the sampled Ghanaian population, responders and suboptimal responders to ivermectin. CYP3A5*1/CYP3A5*1 and CYP3A5*1/CYP3A5*3 genotypes were also found to be significantly different for responders and suboptimal responders. Haplotype (*1/*1/*3/*1) was determined to be significantly different between responders and suboptimal responders indicating a possible role of these haplotypes in treatment response with ivermectin. A profile of pharmacogenetically relevant variants for MDR1, CYP3A4 and CYP3A5 genes has been generated for a random population of 204 Ghanaians to address the scarcity of data within indigenous African populations. In 42 patients treated with ivermectin, difference in MDR1 variant allele frequency was observed between suboptimal responders and responders.

  19. Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes.

    PubMed

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

    2013-08-01

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

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

    PubMed Central

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

    2014-01-01

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

  1. CeLAND: search for a 4th light neutrino state with a 3 PBq 144Ce- 144Pr electron antineutrino generator in KamLAND

    SciTech Connect

    Gando, A; Gando, Y; Hayashida, S

    The reactor neutrino and gallium anomalies can be tested with a 3-4 PBq (75-100 kCi scale) 144Ce- 144Pr antineutrino beta-source deployed at the center or next to a large low-background liquid scintillator detector. The antineutrino generator will be produced by the Russian reprocessing plant PA Mayak as early as 2014, transported to Japan, and deployed in the Kamioka Liquid Scintillator Anti-Neutrino Detector (KamLAND) as early as 2015. KamLAND's 13 m diameter target volume provides a suitable environment to measure the energy and position dependence of the detected neutrino flux. A characteristic oscillation pattern would be visible for a baseline of about 10 m or less, providing a very clean signal of neutrino disappearance into a yet-unknown, sterile neutrino state. This will provide a comprehensive test of the electron dissaperance neutrino anomalies and could lead to the discovery of a 4th neutrino state for Δmmore » $$2\\atop{new}$$ ≳ 0.1 eV 2 and sin 2(2θ new) > 0.05.« less

  2. 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.

  3. Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?

    PubMed Central

    2010-01-01

    Background Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies. Methods Using PCR-RFLP, relevant polymorphic alleles of MDR1 and CYP3A4 genes were analysed in 204 randomly selected individuals and in 42 ivermectin treated patients. Results We recorded significantly higher MDR1 (3435T) variant allele frequency in suboptimal responders (21%) than in patients who responded to treatment (12%) or the random population sample (11%). CYP3A4*1B, CYP3A5*3 and CYP3A5*6 alleles were detected at varied frequencies for the sampled Ghanaian population, responders and suboptimal responders to ivermectin. CYP3A5*1/CYP3A5*1 and CYP3A5*1/CYP3A5*3 genotypes were also found to be significantly different for responders and suboptimal responders. Haplotype (*1/*1/*3/*1) was determined to be significantly different between responders and suboptimal responders indicating a possible role of these haplotypes in treatment response with ivermectin. Conclusion A profile of pharmacogenetically relevant variants for MDR1, CYP3A4 and CYP3A5 genes has been generated for a random population of 204 Ghanaians to address the scarcity of data within indigenous African populations. In 42 patients treated with ivermectin, difference in MDR1 variant allele frequency was observed between suboptimal responders and responders. PMID:20630055

  4. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women.

    PubMed

    Floyd, Michael D; Gervasini, Guillermo; Masica, Andrew L; Mayo, Gail; George, Alfred L; Bhat, Kolari; Kim, Richard B; Wilkinson, Grant R

    2003-10-01

    CYP3A activity in adults varies between individuals and it has been suggested that this has a genetic basis, possibly related to variant alleles in CYP3A4 and CYP3A5 genes. Accordingly, genotype-phenotype associations were investigated under constitutive and induced conditions. Midazolam's systemic and oral clearances, and the erythromycin breath test (ERBT) were determined in 57 healthy subjects: 23 (11 men, 12 women) European- and 34 (14 men, 20 women) African-Americans. Studies were undertaken in the basal state and after 14-15 days pretreatment with rifampin. DNA was characterized for the common polymorphisms CYP3A4*1B, CYP3A5*3, CYP3A5*6 and CYP3A5*7 by direct sequencing, and for exon 21 and exon 26 variants of MDR1 by allele-specific, real-time polymerase chain reaction. In 95% of subjects, the basal systemic clearance of midazolam was unimodally distributed and variability was less than four-fold whereas, in 98% of the study population, oral clearance varied five-fold. No population or sex-related differences were apparent. Similar findings were observed with the ERBT. Rifampin pretreatment markedly increased the systemic (two-fold) and oral clearance (16-fold) of midazolam, and the ERBT (two-fold) but the variabilities were unchanged. No associations were noted between these phenotypic measures and any of the studied genotypes, except for oral clearance and its fold-increase after rifampin. These were related to the presence of CYP3A4*1B and the inversely linked CYP3A5*3 polymorphism, with the extent of induction being approximately 50% greater in CYP3A5*3 homozygotes compared to wild-type subjects. In most healthy subjects, variability in intestinal and hepatic CYP3A activity, using midazolam as an in-vivo probe, is modest and common polymorphisms in CYP3A4 and CYP3A5 do not appear to have important functional significance.

  5. The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells.

    PubMed

    Rubio, María E; Matsui, Ko; Fukazawa, Yugo; Kamasawa, Naomi; Harada, Harumi; Itakura, Makoto; Molnár, Elek; Abe, Manabu; Sakimura, Kenji; Shigemoto, Ryuichi

    2017-11-01

    The neurotransmitter receptor subtype, number, density, and distribution relative to the location of transmitter release sites are key determinants of signal transmission. AMPA-type ionotropic glutamate receptors (AMPARs) containing GluA3 and GluA4 subunits are prominently expressed in subsets of neurons capable of firing action potentials at high frequencies, such as auditory relay neurons. The auditory nerve (AN) forms glutamatergic synapses on two types of relay neurons, bushy cells (BCs) and fusiform cells (FCs) of the cochlear nucleus. AN-BC and AN-FC synapses have distinct kinetics; thus, we investigated whether the number, density, and localization of GluA3 and GluA4 subunits in these synapses are differentially organized using quantitative freeze-fracture replica immunogold labeling. We identify a positive correlation between the number of AMPARs and the size of AN-BC and AN-FC synapses. Both types of AN synapses have similar numbers of AMPARs; however, the AN-BC have a higher density of AMPARs than AN-FC synapses, because the AN-BC synapses are smaller. A higher number and density of GluA3 subunits are observed at AN-BC synapses, whereas a higher number and density of GluA4 subunits are observed at AN-FC synapses. The intrasynaptic distribution of immunogold labeling revealed that AMPAR subunits, particularly GluA3, are concentrated at the center of the AN-BC synapses. The central distribution of AMPARs is absent in GluA3-knockout mice, and gold particles are evenly distributed along the postsynaptic density. GluA4 gold labeling was homogenously distributed along both synapse types. Thus, GluA3 and GluA4 subunits are distributed at AN synapses in a target-cell-dependent manner.

  6. Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction.

    PubMed

    Zhang, TianHong; Zhang, KeRong; Ma, Li; Li, Zheng; Wang, Juan; Zhang, YunXia; Lu, Chuang; Zhu, Mingshe; Zhuang, XiaoMei

    2018-04-01

    Icotinib is the first self-developed small molecule drug in China for targeted therapy of non-small cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction of icotinib were limited. By identifying metabolite generated in human liver microsomes and revealing the contributions of major cytochromes P450 (CYPs) in the formation of major metabolites, the aim of the present work was to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A liquid chromatography/UV/high-resolution mass spectrometer method was developed to characterize the icotinib metabolites. The formation of 6 major metabolites was studied in recombinant CYP isozymes and human liver microsomes with specific inhibitors to identify the CYPs responsible for icotinib metabolism. The metabolic pathways observed in vitro are consistent with those observed in human. Results demonstrated that the metabolites are predominantly catalyzed by CYP3A4 (77%∼87%), with a moderate contribution from CYP3A5 (5%∼15%) and CYP1A2 (3.7%∼7.5%). The contribution of CYP2C8, 2C9, 2C19, and 2D6 is insignificant. Based on our observations, to minimize drug-drug interaction risk in clinic, coprescription of icotinib with strong CYP3A inhibitors or inducers must be weighed. CYP1A2, a highly inducible enzyme in the smoking population, may also represent a determinant of pharmacokinetic and pharmacological variability of icotinib, especially in lung cancer patients with smoking history. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  7. Peptide selectivity between the PDZ domains of human pregnancy-related serine proteases (HtrA1, HtrA2, HtrA3, and HtrA4) can be reshaped by different halogen probes.

    PubMed

    Sun, Mei-Ling; Sun, Li-Mei; Wang, Yong-Qing

    2018-06-01

    The human HtrA family of serine proteases (HtrA1, HtrA2, HtrA3, and HtrA4) are the key enzymes associated with pregnancy and closely related to the development and progression of many pathological events. Previously, it was found that halogen substitution at the indole moiety of peptide Trp-1 residue can form a geometrically satisfactory halogen bond with the Drosophila discs large, zona occludens-1 (PDZ) domain of HtrA proteases. Here, we attempt to systematically investigate the effect of substitution with 4 halogen types and 2 indole positions on the binding affinity and specificity of peptide ligands to the 4 HtrA PDZ domains. The complex structures, interaction energies, halogen-bonding strength, and binding affinity of domain-peptide systems were modeled, analyzed, and measured via computational modeling and fluorescence-based assay. It is revealed that there is a compromise between the local rearrangement of halogen bond involving different halogen atoms and the global optimization of domain-peptide interaction; the substitution position is fundamentally important for peptide-binding affinity, while the halogen type can effectively shift peptide selectivity between the 4 domains. The HtrA1-PDZ and HtrA4-PDZ as well as HtrA2-PDZ and HtrA3-PDZ respond similarly to different halogen substitutions of peptide; -Br substitution at R2-position and -I substitution at R4-position are most effective in improving peptide selectivity for HtrA1-PDZ/HtrA4-PDZ and HtrA2-PDZ/HtrA3-PDZ, respectively; -F substitution would not address substantial effect on peptide selectivity for all the 4 domains. Consequently, the binding affinities of a native peptide ligand DSRIWWV -COOH as well as its 4 R2-halogenated counterparts were determined as 1.9, 1.4, 0.5, 0.27, and 0.92 μM, which are basically consistent with computational analysis. This study would help to rationally design selective peptide inhibitors of HtrA family members by using different halogen substitutions. Copyright

  8. 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 rapid, partial removal or covering of contamination to reduce the radiation exposure rate as quickly as practicable to a point where priority work ...should be responsible for planning and implementing all decontamination activities. He could be a city en- gineer, public works engineer, industrial safety...responsibility for a local civil defense or emergency preparedness program. DisaterAnalysis - A review and determination of the extent of damage sufere bya

  9. 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.

  10. 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.

  11. 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.

  12. 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 tightlymore » 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.« less

  13. Isolation of CYP3A5P cDNA from human liver: a reflection of a novel cytochrome P-450 pseudogene.

    PubMed

    Schuetz, J D; Guzelian, P S

    1995-03-14

    We have isolated, from a human liver cDNA library, a 1627 bp CYP3A5 cDNA variant (CYP3A5P) that contains several large insertions, deletions, and in-frame termination codons. By comparison with the genomic structure of other CYP3A genes, the major insertions in CYP3A5P cDNA demarcate the inferred sites of several CYP3A5 exons. The segments inserted in CYP3A5P have no homology with splice donor acceptor sites. It is unlikely that CYP3A5P cDNA represents an artifact of the cloning procedures since Southern blot analysis of human genomic DNA disclosed that CYP3A5P cDNA hybridized with a DNA fragment distinct from fragments that hybridized with either CYP3A5, CYP3A3 or CYP3A4. Moreover, analysis of adult human liver RNA on Northern blots hybridized with a CYP3A5P cDNA fragment revealed the presence of an mRNA with the predicted size of CYP3A5P. We conclude that CYP3A5P cDNA was derived from a separate gene, CYP3A5P, most likely a pseudogene evolved from CYP3A5.

  14. 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.

  15. 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.

  16. Genetic Predictors of Interindividual Variability in Hepatic CYP3A4 ExpressionS⃞

    PubMed Central

    Lamba, Vishal; Panetta, John C.; Strom, Stephen

    2010-01-01

    Variability in hepatic CYP3A4 cannot be explained by common CYP3A4 coding variants. We previously identified polymorphisms in pregnane X receptor (PXR) and ATP-binding cassette subfamily B member 1 (ABCB1) associated with CYP3A4 mRNA levels in small cohorts of human livers. However, the relative contributions of these genetic variations or of polymorphisms in other CYP3A4 regulators to variable CYP3A4 expression were not known. We phenotyped livers from white donors (n = 128) by quantitative real-time polymerase chain reaction for expression of CYP3A4, CYP3A5, and CYP3A7 and nine transcriptional regulators, coactivators, and corepressors. We resequenced hepatic nuclear factor-3-β (HNF3β, FoxA2), HNF4α, HNF3γ (FoxA3), nuclear receptor corepressor 2 (NCoR2), and regions of the CYP3A4 promoter and genotyped informative single-nucleotide polymorphisms in PXR and ABCB1 in the same livers. CYP3A4 mRNA was positively correlated with PXR and FoxA2 and negatively correlated with NCoR2 mRNA. A common silent polymorphism and a polymorphic trinucleotide (CCT) repeat in FoxA2 were associated with CYP3A4 expression. The transcriptional activity of the FoxA2 polymorphic CCT repeat alleles (wild-type, n = 14 and variant, n = 13, 15, and 19) when assayed by luciferase reporter transactivation assays was greatest for the wild-type repeat, with deviations from this number having decreased transcriptional activity. This corresponded with higher expression of FoxA2 mRNA and its targets PXR and CYP3A4 in human livers with (CCT) n = 14 genotypes. Multiple linear regression analysis was used to quantify the contributions of selected genetic polymorphisms to variable CYP3A4 expression. This approach identified sex and polymorphisms in FoxA2, HNF4α, FoxA3, PXR, ABCB1, and the CYP3A4 promoter that together explained as much as 24.6% of the variation in hepatic CYP3A4 expression. PMID:19934400

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Key role of the N-terminus of chicken annexin A5 in vesicle aggregation.

    PubMed

    Turnay, Javier; Guzmán-Aránguez, Ana; Lecona, Emilio; Barrasa, Juan I; Olmo, Nieves; Lizarbe, Ma Antonia

    2009-05-01

    Annexins are calcium-dependent phospholipid-binding proteins involved in calcium signaling and intracellular membrane trafficking among other functions. Vesicle aggregation is a crucial event to make possible the membrane remodeling but this process is energetically unfavorable, and phospholipid membranes do not aggregate and fuse spontaneously. This issue can be circumvented by the presence of different agents such as divalent cations and/or proteins, among them some annexins. Although human annexin A5 lacks the ability to aggregate vesicles, here we demonstrate that its highly similar chicken ortholog induces aggregation of vesicles containing acidic phospholipids even at low protein and/or calcium concentration by establishment of protein dimers. Our experiments show that the ability to aggregate vesicles mainly resides in the N-terminus as truncation of the N-terminus of chicken annexin A5 significantly decreases this process and replacement of the N-terminus of human annexin A5 by that of chicken switches on aggregation; in both cases, there are no changes in the overall protein structure and only minor changes in phospholipid binding. Electrostatic repulsions between negatively charged residues in the concave face of the molecule, mainly in the N-terminus, seem to be responsible for the impairment of dimer formation in human annexin A5. Taking into account that chicken annexin A5 presents a high sequence and structural similarity with mammalian annexins absent in birds, as annexins A3 and A4, some of the physiological functions exerted by these proteins may be carried out by chicken annexin A5, even those that could require calcium-dependent membrane aggregation.

  3. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 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, Defense...

  4. 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, Defense...

  5. 32 CFR 168a.5 - Responsibilities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  6. 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...

  7. 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...

  8. 46 CFR 147A.5 - General requirement.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 5 2013-10-01 2013-10-01 false General requirement. 147A.5 Section 147A.5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.5 General requirement. No person may cause or authorize shipboard...

  9. 46 CFR 147A.5 - General requirement.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 5 2011-10-01 2011-10-01 false General requirement. 147A.5 Section 147A.5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.5 General requirement. No person may cause or authorize shipboard...

  10. 46 CFR 147A.5 - General requirement.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 5 2014-10-01 2014-10-01 false General requirement. 147A.5 Section 147A.5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.5 General requirement. No person may cause or authorize shipboard...

  11. 46 CFR 147A.5 - General requirement.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 5 2010-10-01 2010-10-01 false General requirement. 147A.5 Section 147A.5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.5 General requirement. No person may cause or authorize shipboard...

  12. 46 CFR 147A.5 - General requirement.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 5 2012-10-01 2012-10-01 false General requirement. 147A.5 Section 147A.5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.5 General requirement. No person may cause or authorize shipboard...

  13. Proceedings: 1995 SO{sub 2} control symposium. Volume 2, Sessions 4a, 4b, 5a, 5b

    SciTech Connect

    NONE

    1995-06-01

    Cosponsored by EPRI, DOE, and EPA, this conference provided a forum for the exchange of economic, technical, and regulatory information on sulfur dioxide control technology. From March 28--31, 1995, participants presented 100 technical papers to an audience of 525 people from around the world. Given in thirteen technical sessions, the papers included regulatory and economic issues, wet and dry SO{sub 2} control processes, emerging technologies, and experience with Clean Air Act Amendments (CAAA) Phase I startups. The fifteenth in a series of symposia over the past two decades, the conference included these key points: the domestic flue gas desulfurization (FGD)more » market is likely to be modest over the next ten years, with most activity overseas; FGD awards could reach over $4 billion a year from 1996--2003, with more than half going to Eastern Europe and Asia; worldwide, at the start of 1994, FGD systems were installed on 609 coal-fired power plants; the average capital cost for Phase I retrofits has been $233/kW; and, trends point to simpler designs, such as towers that operate at higher gas velocities with fewer internals. Published proceedings from these regularly scheduled symposia are valuable resources for engineers and utility planners who need up-to-date information to comply with clean air legislation. Selected papers have been processed separately for inclusion in the Energy Science and Technology database.« less

  14. 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

    ... 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 that...

  15. 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 that...

  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

    ... 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 that...

  17. 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

    ... liquids suppliers (subpart NN): (A) All fractionators. (B) Local natural gas distribution companies that... (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt. A... a Applicable in 2010 and Future Years Coal-to-liquids suppliers (subpart LL): (A) All producers of...

  18. 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

  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... Department of Defense in which NDSEG fellowships are to be awarded. (3) Prepare a regulation, in accordance...

  20. 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 health-related...

  1. 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...

  2. 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...

  3. 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...

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

    Code of Federal Regulations, 2014 CFR

    2014-01-01

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

  5. 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...

  6. 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...

  7. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  8. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  9. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  10. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  11. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Fees. 261a.4 Section 261a.4 Banks and Banking... TO PERSONAL INFORMATION UNDER THE PRIVACY ACT OF 1974 General Provisions § 261a.4 Fees. (a) Copies of... Availability of Information, § 261.10 of this part. (b) No fee. Documents may be furnished without charge where...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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) [DDDR&E(R&AT)], shall: (1) Administer this part... coordination with a representative of the Deputy Director, Defense Research and Engineering (Research and...

  17. 26 CFR 1.401(a)(4)-1 - Nondiscrimination requirements of section 401(a)(4).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...)(4). 1.401(a)(4)-1 Section 1.401(a)(4)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE.... § 1.401(a)(4)-1 Nondiscrimination requirements of section 401(a)(4). (a) In general. Section 401(a)(4...). (b) Requirements a plan must satisfy—(1) In general. In order to satisfy section 401(a)(4), a plan...

  18. 32 CFR 169a.4 - Policy.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Policy. 169a.4 Section 169a.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... shall consider the overall DoD mission and the defense objective of maintaining readiness and...

  19. 32 CFR 169a.4 - Policy.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Policy. 169a.4 Section 169a.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... shall consider the overall DoD mission and the defense objective of maintaining readiness and...

  20. 32 CFR 169a.4 - Policy.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Policy. 169a.4 Section 169a.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... shall consider the overall DoD mission and the defense objective of maintaining readiness and...

  1. 32 CFR 169a.4 - Policy.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Policy. 169a.4 Section 169a.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... shall consider the overall DoD mission and the defense objective of maintaining readiness and...

  2. 32 CFR 169a.4 - Policy.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 false Policy. 169a.4 Section 169a.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... shall consider the overall DoD mission and the defense objective of maintaining readiness and...

  3. Gibberellin A3 Is Biosynthesized from Gibberellin A20 via Gibberellin A5 in Shoots of Zea mays L. 1

    PubMed Central

    Fujioka, Shozo; Yamane, Hisakazu; Spray, Clive R.; Phinney, Bernard O.; Gaskin, Paul; MacMillan, Jake; Takahashi, Nobutaka

    1990-01-01

    [17-13C,3H]-Labeled gibberellin A20 (GA20), GA5, and GA1 were fed to homozygous normal (+/+), heterozygous dominant dwarf (D8/+), and homozygous dominant dwarf (D8/D8) seedlings of Zea mays L. (maize). 13C-Labeled GA29, GA8, GA5, GA1, and 3-epi-GA1, as well as unmetabolized [13C]GA20, were identified by gas chromatography-selected ion monitoring (GC-SIM) from feeds of [17-13C, 3H]GA20 to all three genotypes. 13C-Labeled GA8 and 3-epi-G1, as well as unmetabolized [13C]GA1, were identified by GC-SIM from feeds of [17-13C, 3H]GA1 to all three genotypes. From feeds of [17-13C, 3H]GA5, 13C-labeled GA3 and the GA3-isolactone, as well as unmetabolized [13C]GA5, were identified by GC-SIM from +/+ and D8/D8, and by full scan GC-MS from D8/+. No evidence was found for the metabolism of [17-13C, 3H]GA5 to [13C]GA1, either by full scan GC-mass spectrometry or by GC-SIM. The results demonstrate the presence in maize seedlings of three separate branches from GA20, as follows: (a) GA20 → GA1 → GA8; (b) GA20 → GA5 → GA3; and (c) GA20 → GA29. The in vivo biogenesis of GA3 from GA5, as well as the origin of GA5 from GA20, are conclusively established for the first time in a higher plant (maize shoots). PMID:16667678

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ....4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall be... on the life of the veteran shall remain at a constant level until the principal amount of the...

  9. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 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.4 Religious activities. No funds provided directly from SAMHSA or the relevant State or local government to organizations participating in applicable programs may be expended...

  10. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 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.4 Religious activities. No funds provided directly from SAMHSA or the relevant State or local government to organizations participating in applicable programs may be expended...

  11. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 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.4 Religious activities. No funds provided directly from SAMHSA or the relevant State or local government to organizations participating in applicable programs may be expended...

  12. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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.4 Religious activities. No funds provided directly from SAMHSA or the relevant State or local government to organizations participating in applicable programs may be expended...

  13. 42 CFR 54a.4 - Religious activities.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 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.4 Religious activities. No funds provided directly from SAMHSA or the relevant State or local government to organizations participating in applicable programs may be expended...

  14. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  15. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  16. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  17. 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.

  18. 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.

  19. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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...

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

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... outlet operated by an unrelated person. Example 7. D owns and operates retail grocery stores where... each store location constitute less than 5 percent of the gross receipts from all sales made at that store, D is not considered a retailer by reason of such sales. Example 8. Lessee E sells natural gas to...

  1. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Reconciliation Act of 1990) or the taxable income limitation contained in section 613A(d)(1); (ii) Any net... jurisdiction in which such trust was created requires all or a portion of the gross or net proceeds of any... half of the net income of the estate (ignoring depletion). Under section 611(b)(4), the percentage...

  2. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Reconciliation Act of 1990) or the taxable income limitation contained in section 613A(d)(1); (ii) Any net... jurisdiction in which such trust was created requires all or a portion of the gross or net proceeds of any... half of the net income of the estate (ignoring depletion). Under section 611(b)(4), the percentage...

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Reconciliation Act of 1990) or the taxable income limitation contained in section 613A(d)(1); (ii) Any net... jurisdiction in which such trust was created requires all or a portion of the gross or net proceeds of any... half of the net income of the estate (ignoring depletion). Under section 611(b)(4), the percentage...

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Reconciliation Act of 1990) or the taxable income limitation contained in section 613A(d)(1); (ii) Any net... jurisdiction in which such trust was created requires all or a portion of the gross or net proceeds of any... half of the net income of the estate (ignoring depletion). Under section 611(b)(4), the percentage...

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

    PubMed

    Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis; Tekin, Mustafa

    2013-03-01

    Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

  12. 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.

  13. CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects.

    PubMed

    Yamaori, Satoshi; Yamazaki, Hiroshi; Iwano, Shunsuke; Kiyotani, Kazuma; Matsumura, Keiko; Honda, Goro; Nakagawa, Kazuko; Ishizaki, Takashi; Kamataki, Tetsuya

    2004-04-01

    The purpose of this study was to evaluate a contribution of polymorphic cytochrome P450 (CYP) 3A5 to the oxidation of diltiazem, midazolam and testosterone by liver microsomes from Japanese subjects. Twenty-seven liver samples were classified into three groups according to the CYP3A5 genotypes; CYP3A5(*)1/(*)1 (n=3), (*)1/(*)3 (n=12) and (*)3/(*)3 (n=12). The results of genotyping and immunochemical quantitation of CYP3A5 protein showed a good accordance between the CYP3A5 genotype and CYP3A5 content but not CYP3A4 content in liver microsomes. The expression levels of hepatic CYP3A5 protein ranged from 20 to 60% of the sum of CYP3A4 and CYP3A5 contents in subjects with at least one wild type allele ((*)1). The CYP3A5 contents correlated well with liver microsomal activities of diltiazem N-demethylation, midazolam 1'- and 4-hydroxylations and testosterone 6beta-hydroxylation among subjects carrying at least one (*)1 allele. In addition, the correlation coefficients of CYP3A5 contents with the rates of diltiazem N-demethylation, midazolam 1'-hydroxylation and testosterone 6beta- hydroxylation were higher than those of CYP3A4, although the value of CYP3A5 with the midazolam 4-hydroxylation rate was similar to that of CYP3A4. Kinetic analyses revealed a biphasic diltiazem N-demethylation in liver microsomes from subjects carrying the (*)1 allele. The apparent V(max)/K(m) values for recombinant CYP3A5 indicated the greater contributions to diltiazem N-demethylation and midazolam 1'-hydroxylation as compared with CYP3A4. These results suggest that polymorphic CYP3A5 contributes markedly to the drug oxidations, particularly diltiazem N-demethylation, midazolam 1'- hydroxylation and testosterone 6beta-hydroxylation by liver microsomes from Japanese subjects.

  14. CYP3A5 mRNA degradation by nonsense-mediated mRNA decay.

    PubMed

    Busi, Florent; Cresteil, Thierry

    2005-09-01

    The total CYP3A5 mRNA level is significantly greater in carriers of the CYP3A5*1 allele than in CYP3A5*3 homozygotes. Most of the CYP3A5*3 mRNA includes an intronic sequence (exon 3B) containing premature termination codons (PTCs) between exons 3 and 4. Two models were used to investigate the degradation of CYP3A5 mRNA: a CYP3A5 minigene consisting of CYP3A5 exons and introns 3 to 6 transfected into MCF7 cells, and the endogenous CYP3A5 gene expressed in HepG2 cells. The 3'-untranslated region g.31611C>T mutation has no effect on CYP3A5 mRNA decay. Splice variants containing exon 3B were more unstable than wild-type (wt) CYP3A5 mRNA. Cycloheximide prevents the recognition of PTCs by ribosomes: in transfected MCF7 and HepG2 cells, cycloheximide slowed down the degradation of exon 3B-containing splice variants, suggesting the participation of nonsense-mediated decay (NMD). When PTCs were removed from pseudoexon 3B or when UPF1 small interfering RNA was used to impair the NMD mechanism, the decay of the splice variant was reduced, confirming the involvement of NMD in the degradation of CYP3A5 splice variants. Induction could represent a source of variability for CYP3A5 expression and could modify the proportion of splice variants. The extent of CYP3A5 induction was investigated after exposure to barbiturates or steroids: CYP3A4 was markedly induced in a pediatric population compared with untreated neonates. However, no effect could be detected in either the total CYP3A5 RNA, the proportion of splice variant RNA, or the protein level. Therefore, in these carriers, induction is unlikely to switch on the phenotypic CYP3A5 expression in carriers of CYP3A5*3/*3.

  15. 22 CFR 9a.5 - Declassification and downgrading.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Declassification and downgrading. 9a.5 Section 9a.5 Foreign Relations DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO... of such information or material. ...

  16. 22 CFR 9a.5 - Declassification and downgrading.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Declassification and downgrading. 9a.5 Section 9a.5 Foreign Relations DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO... of such information or material. ...

  17. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Sale of automobile truck bodies and chassis. 48..., Tread Rubber, and Taxable Fuel Automotive and Related Items § 48.4061(a)-5 Sale of automobile truck bodies and chassis. (a) Sale of completed vehicle. An automobile truck (as defined by § 48.4061(a)-3(a...

  18. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Sale of automobile truck bodies and chassis. 48..., Tread Rubber, and Taxable Fuel Automotive and Related Items § 48.4061(a)-5 Sale of automobile truck bodies and chassis. (a) Sale of completed vehicle. An automobile truck (as defined by § 48.4061(a)-3(a...

  19. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Sale of automobile truck bodies and chassis. 48..., Tread Rubber, and Taxable Fuel Automotive and Related Items § 48.4061(a)-5 Sale of automobile truck bodies and chassis. (a) Sale of completed vehicle. An automobile truck (as defined by § 48.4061(a)-3(a...

  20. 26 CFR 48.4061(a)-5 - Sale of automobile truck bodies and chassis.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Sale of automobile truck bodies and chassis. 48..., Tread Rubber, and Taxable Fuel Automotive and Related Items § 48.4061(a)-5 Sale of automobile truck bodies and chassis. (a) Sale of completed vehicle. An automobile truck (as defined by § 48.4061(a)-3(a...

  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. 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...

  3. 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...

  4. 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...

  5. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

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

  6. 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 Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.5 Advice and...

  7. 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 Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.5 Advice and...

  8. 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, electrotin...

  9. 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, electrotin...

  10. 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, electrotin...

  11. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.5 Advice and recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority... 29 Labor 7 2011-07-01 2011-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor...

  12. 29 CFR 1912a.5 - Advice and recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.5 Advice and recommendations. Any advice or recommendations of the Committee shall be given or made with approval of a majority... 29 Labor 7 2010-07-01 2010-07-01 false Advice and recommendations. 1912a.5 Section 1912a.5 Labor...

  13. 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...

  14. 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...

  15. 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. [Reserved] 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. [Reserved] ...

  16. 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. [Reserved] 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. [Reserved] ...

  17. 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. [Reserved] 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. [Reserved] ...

  18. 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. [Reserved] 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. [Reserved] ...

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Funding. [Reserved] 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. [Reserved] ...

  20. Identification of epitopes of the A1aBx and A5A4B3 subunits of glycinin antigenic in three animal species

    USDA-ARS?s Scientific Manuscript database

    Soybean meal is commonly added to a variety of animal feeds to supplement protein sources and to optimize growth. While soybean protein is a valuable food supplement it has also been recognized as an important food allergen. At least 16 allergenic soybean proteins have been identified, including the...

  1. Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene.

    PubMed

    Cervera-Acedo, C; Coloma, A; Huarte-Loza, E; Sierra-Carpio, M; Domínguez-Garrido, E

    2017-10-31

    Alport syndrome is an inherited renal disorder characterized by glomerular basement membrane lesions with hematuria, proteinuria and frequent hearing defects and ocular abnormalities. The disease is associated with mutations in genes encoding α3, α4, or α5 chains of type IV collagen, namely COL4A3 and COL4A4 in chromosome 2 and COL4A5 in chromosome X. In contrast to the well-known X-linked and autosomal recessive phenotypes, there is very little information about the autosomal dominant. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. We investigated a Spanish family with variable phenotype of autosomal dominant Alport syndrome using clinical, histological, and genetic analysis. Mutational analysis of COL4A3 and COL4A4 genes showed a novel heterozygous mutation (c. 998G > A; p.G333E) in exon 18 of the COL4A3 gene. Among relatives carrying the novel mutation, the clinical phenotype was variable. Two additional COL4A3 mutations were found, a Pro-Leu substitution in exon 48 (p.P1461L) and a Ser-Cys substitution in exon 49 (p.S1492C), non-pathogenics alone. Carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 gene appear to be more severely affected than carriers of only p.G333E mutation, and the clinical findings has an earlier onset. In this way, we could speculate on a synergistic effect of compound heterozygosity that could explain the different phenotype observed in this family.

  2. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. A5: Automated Analysis of Adversarial Android Applications

    DTIC Science & Technology

    2014-06-03

    algorithm is fairly intuitive. First, A5 invokes the DED [11] decompiler to create Java classes from the Android application code. Next, A5 uses Soot [30...implemented such as Bluetooth, Wi-Fi, sensors , etc. These hardware features are very common in physical devices and are simply not present in the...such as Androguard [1] and Soot [30]. Deficiencies in these tools may also manifest in A5. The bytecode static analysis is limited to finding only

  4. 49 CFR 178.33a-5 - Material.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  5. 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 GRANTS...

  6. 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 GRANTS...

  7. 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 GRANTS...

  8. 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 GRANTS...

  9. 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 GRANTS...

  10. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 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 from...

  11. 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 from...

  12. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 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 from...

  13. 15 CFR 4a.5 - Duration of classification.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 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 from...

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

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  16. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  17. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  18. A Biosensor of S100A4 Metastasis Factor Activation: Inhibitor Screening and Cellular Activation Dynamics†

    PubMed Central

    Garrett, Sarah C.; Hodgson, Louis; Rybin, Andrew; Toutchkine, Alexei; Hahn, Klaus M.; Lawrence, David S.; Bresnick, Anne R.

    2011-01-01

    S100A4, a member of the S100 family of Ca2+-binding proteins, displays elevated expression in malignant human tumors compared with benign tumors, and increased expression correlates strongly with poor patient survival. S100A4 has a direct role in metastatic progression, likely due to the modulation of actomyosin cytoskeletal dynamics, which results in increased cellular motility. We developed a fluorescent biosensor (Mero-S100A4) that reports on the Ca2+-bound, activated form of S100A4. Direct attachment of a novel solvatochromatic reporter dye to S100A4 results in a sensor that, upon activation, undergoes a 3-fold enhancement in fluorescence, thus providing a sensitive assay for use in vitro and in vivo. In cells, localized activation of S100A4 at the cell periphery is observed during random migration and following stimulation with lysophosphatidic acid, a known activator of cell motility and proliferation. Additionally, a screen against a library of FDA-approved drugs with the biosensor identified an array of phenothiazines as inhibitors of myosin-II associated S100A4 function. These data demonstrate the utility of the new biosensor both for drug discovery and for probing the cellular dynamics controlled by the S100A4 metastasis factor. PMID:18154362

  19. 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...

  20. 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...

  1. 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...

  2. 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 an...

  3. 46 CFR 147A.3 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 5 2014-10-01 2014-10-01 false Applicability. 147A.3 Section 147A.3 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.3 Applicability. This part prescribes the rules for shipboard fumigation on vessels...

  4. 46 CFR 147A.3 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 5 2012-10-01 2012-10-01 false Applicability. 147A.3 Section 147A.3 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.3 Applicability. This part prescribes the rules for shipboard fumigation on vessels...

  5. 46 CFR 147A.3 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 5 2010-10-01 2010-10-01 false Applicability. 147A.3 Section 147A.3 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.3 Applicability. This part prescribes the rules for shipboard fumigation on vessels...

  6. 46 CFR 147A.3 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 5 2013-10-01 2013-10-01 false Applicability. 147A.3 Section 147A.3 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.3 Applicability. This part prescribes the rules for shipboard fumigation on vessels...

  7. 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 FUMIGATION General § 147A.3 Applicability. This part prescribes the rules for shipboard fumigation on vessels...

  8. 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... § 242a.3 Open meetings. (a) Members shall not jointly conduct or dispose of business of the Board of... Regents or any committee of the Board shall be open to public observation subject to the exceptions...

  9. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Open meetings. 242a.3 Section 242a.3 National... § 242a.3 Open meetings. (a) Members shall not jointly conduct or dispose of business of the Board of... Regents or any committee of the Board shall be open to public observation subject to the exceptions...

  10. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  11. 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... § 242a.3 Open meetings. (a) Members shall not jointly conduct or dispose of business of the Board of... Regents or any committee of the Board shall be open to public observation subject to the exceptions...

  12. 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... § 242a.3 Open meetings. (a) Members shall not jointly conduct or dispose of business of the Board of... Regents or any committee of the Board shall be open to public observation subject to the exceptions...

  13. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

  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 V max values in HLM and rhCYP3A5 with no significant changes in K m values. By adding CYP3cide with ICO to the incubation, the V max values increased 2-fold over the CYP3cide control. Addition of ketoconazole with ICO alone or ICO plus CYP3cide resulted in an increase in V max values and decrease in K m 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. Enhancement of A5/1 encryption algorithm

    NASA Astrophysics Data System (ADS)

    Thomas, Ria Elin; Chandhiny, G.; Sharma, Katyayani; Santhi, H.; Gayathri, P.

    2017-11-01

    Mobiles have become an integral part of today’s world. Various standards have been proposed for the mobile communication, one of them being GSM. With the rising increase of mobile-based crimes, it is necessary to improve the security of the information passed in the form of voice or data. GSM uses A5/1 for its encryption. It is known that various attacks have been implemented, exploiting the vulnerabilities present within the A5/1 algorithm. Thus, in this paper, we proceed to look at what these vulnerabilities are, and propose the enhanced A5/1 (E-A5/1) where, we try to improve the security provided by the A5/1 algorithm by XORing the key stream generated with a pseudo random number, without increasing the time complexity. We need to study what the vulnerabilities of the base algorithm (A5/1) is, and try to improve upon its security. This will help in the future releases of the A5 family of algorithms.

  16. A new CYP3A5 variant, CYP3A5*11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system

    PubMed Central

    Lee, Su-Jun; van der Heiden, Ilse P; Goldstein, Joyce A; van Schaik, Ron HN

    2012-01-01

    A new CYP3A5 variant, CYP3A5*11, was found in a single white European by DNA sequencing. The CYP3A5*11 allele contains a single nucleotide polymorphism (SNP) (g.3775 A>G) in exon 2 which results in a Tyr53Cys substitution and a g.6986A>G splice change, the latter SNP previously reported in the defective CYP3A5*3 allele. However, the CYP3A5*3 is not a null allele because this variant is associated with leaky splicing, resulting in small amounts of functional protein still being produced. We therefore constructed a cDNA coding for the newly identified CYP3A5.11 protein by site-directed mutagenesis, expressed it in Escherichia coli and partially purified it. While bacteria transformed with wild-type CYP3A5*1 cDNA expressed predominantly cytochrome P450, those transfected with CYP3A5*11 expressed a significant amount of denatured cytochrome P420 in addition to cytochrome P450, suggesting the protein to be unstable. CYP3A5.11 exhibited a 38% decrease in the Vmax for nifedipine metabolism, a 2.7-fold increase in the Km, and a 4.4-fold decrease in the CLint of nifedipine compared with CYP3A5.1. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping procedure was developed, and used to genotyping DNA of 500 white individuals for CYP3A5*11. No additional examples of this allele were identified. In summary, individuals carrying the rare CYP3A5*11 allele are predicted to have lower metabolism of CYP3A5 substrates than individuals expressing CYP3A5*3. PMID:17035598

  17. 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 and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a...

  18. 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 and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a...

  19. 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 and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a...

  20. 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 and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a...

  1. 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 and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a...

  2. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... qualified tuition and related expenses for purposes of the Lifetime Learning Credit. (d) Effective date. The... 26 Internal Revenue 1 2014-04-01 2013-04-01 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...

  3. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... qualified tuition and related expenses for purposes of the Lifetime Learning Credit. (d) Effective date. The... 26 Internal Revenue 1 2011-04-01 2009-04-01 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...

  4. 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...

  5. 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...

  6. 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...

  7. 26 CFR 1.168A-4 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Definitions. 1.168A-4 Section 1.168A-4 Internal... TAXES (CONTINUED) Itemized Deductions for Individuals and Corporations § 1.168A-4 Definitions. As used... authority designated by the President by Executive order. (b) “Emergency facility” means any facility, land...

  8. 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 How...

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

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 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. 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...

  11. Fluticasone Propionate Pharmacogenetics: CYP3A4*22 Polymorphism and Pediatric Asthma Control

    PubMed Central

    Stockmann, Chris; Fassl, Bernhard; Gaedigk, Roger; Nkoy, Flory; Uchida, Derek A.; Monson, Steven; Reilly, Christopher A.; Leeder, J. Steven; Yost, Garold S.; Ward, Robert M.

    2012-01-01

    Objective To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP. Study design The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping nine single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP3A7. Genotype information was compared with asthma control scores (0 = well-controlled to 15 = poorly-controlled), determined by using a questionnaire modified from the National Heart Lung and Blood Institute Expert Panel 3 guidelines. Results Our study cohort was comprised of 734 children with asthma (mean age 8.8 ± 4.3 years), who were predominantly male (61%) and non-Hispanic Whites (53%); 413 children (56%) were receiving inhaled glucocorticoids daily, of which FP was prescribed most frequently (65%). Among the children receiving daily FP, SNPs in the genes CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved among 20 (7%) children with the CYP3A4*22 allele (median 3, range 0-6), as compared with the 201 patients without the CYP3A4*22 allele (median 4, range 0-15) (P=0.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI: 0.5-3.8). Conclusions The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control among FP treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP. PMID:23290512

  12. A search for new CYP3A4 variants as determinants of tacrolimus dose requirements in renal-transplanted patients.

    PubMed

    Tavira, Beatriz; Coto, Eliecer; Diaz-Corte, Carmen; Alvarez, Victoria; López-Larrea, Carlos; Ortega, Francisco

    2013-08-01

    The CYP3A5*3 and CYP3A4*1B alleles have been related with tacrolimus (Tac) dose requirements. The rare CYP3A4*22 variant has also been associated with a significantly lower Tac dose. We genotyped the three single-nucleotide polymorphisms in 206 kidney-transplanted patients who received Tac as the primary immunosuppressor. CYP3A5*1 and CYP3A4*1B allele carriers received a significantly higher Tac dose (P<0.01) compared with wild-type homozygotes. We did not find significant differences between the CYP3A4*22 genotypes, either nominally or according to the CYP3A5 genotype (expressers vs. nonexpressers). Sequencing of CYP3A4 coding exons in a total of 15 patients revealed only one nonreported missense change (p.P227>T) in one patient. We concluded that CYP3A5*3 and CYP3A4*1B were the main determinants of the Tac dose-adjusted blood concentration in our cohort of renal-transplanted patients.

  13. Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma.

    PubMed

    Planagumà, Anna; Kazani, Shamsah; Marigowda, Gautham; Haworth, Oliver; Mariani, Thomas J; Israel, Elliot; Bleecker, Eugene R; Curran-Everett, Douglas; Erzurum, Serpil C; Calhoun, William J; Castro, Mario; Chung, Kian Fan; Gaston, Benjamin; Jarjour, Nizar N; Busse, William W; Wenzel, Sally E; Levy, Bruce D

    2008-09-15

    Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A(4) (LXA(4)) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA(4) and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA(4) receptors were monitored by flow cytometry. Individuals with severe asthma had significantly less LXA(4) in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 +/- 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA(4) receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.

  14. 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

  15. A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

    PubMed

    Webb, B D; Brandt, T; Liu, L; Jalas, C; Liao, J; Fedick, A; Linderman, M D; Diaz, G A; Kornreich, R; Trachtman, H; Mehta, L; Edelmann, L

    2014-08-01

    Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Mission. 383a.3 Section 383a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS... wartime and, as circumstances dictate, troop issue subsistence support to military dining facilities...

  17. 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...

  18. 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...

  19. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Effective date. 8a.3... INSURANCE § 8a.3 Effective date. (a) Where the grant was approved prior to August 11, 1971, VMLI shall be effective August 11, 1971, if on that date, the eligible veteran was obligated under a mortgage loan, and...

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

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Effective date. 8a.3... INSURANCE § 8a.3 Effective date. (a) Where the grant was approved prior to August 11, 1971, VMLI shall be effective August 11, 1971, if on that date, the eligible veteran was obligated under a mortgage loan, and...

  2. 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...

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

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  4. 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... E.O. 12958. The levels established by E.O. 12958 (Top Secret, Secret, and Confidential) are the only...

  5. 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... E.O. 12958. The levels established by E.O. 12958 (Top Secret, Secret, and Confidential) are the only...

  6. 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... E.O. 12958. The levels established by E.O. 12958 (Top Secret, Secret, and Confidential) are the only...

  7. 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... E.O. 12958. The levels established by E.O. 12958 (Top Secret, Secret, and Confidential) are the only...

  8. 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 only...

  9. 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... § 1.25A-1(c), for taxable years beginning before 2003, the Lifetime Learning Credit amount is 20...

  10. Novel mutations of CYP3A4 in Chinese.

    PubMed

    Hsieh, K P; Lin, Y Y; Cheng, C L; Lai, M L; Lin, M S; Siest, J P; Huang, J D

    2001-03-01

    Human cytochrome P450 3A4 is a major P450 enzyme in the liver and gastrointestinal tract. It plays important roles in the metabolism of a wide variety of drugs, some endogenous steroids, and harmful environmental contaminants. CYP3A4 exhibits a remarkable interindividual activity variation as high as 20-fold. To investigate whether the interindividual variation in CYP3A4 levels can be partly explained by genetic polymorphism, we analyzed DNA samples from 102 Chinese subjects by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis for novel point mutation in the CYP3A4 coding sequence and promoter region. Using PCR and directed sequencing method to establish the complete intron sequence of CYP3A4 from leukocytes, the complete genomic sequence from exon 1 through 13 of CYP3A4 was determined and published in the GenBank database (accession no. AF209389). CYP3A4-specific primers were designed accordingly. After PCR-single-strand conformation polymorphism and restriction fragment length polymorphism screening, we found three novel mutations; two are point mutations and one is insertion. The first variant allele (CYP3A4*4), an Ile118Val change, was found in 3 of 102 Chinese subjects. The next allele (CYP3A4*5), which causes a Pro218Arg amino acid change, was found in 2 of 102 subjects. We found an insertion in A(17776), designated as CYP3A4*6, which causes frame shift and an early stop codon in exon 9, in one heterozygous subject. We also investigated the CYP3A4 activity in these mutant subjects by measuring the morning spot urinary 6beta-hydroxycortisol to free cortisol ratio with the enzyme-linked immunosorbent assay method. When compared with healthy Chinese population data, the 6beta-hydroxycortisol to free cortisol ratio data suggested that these alleles (CYP3A4*4, CYP3A4*5, and CYP3A4*6) may decrease the CYP3A4 activity. Incidences of these mutations in Chinese subjects are rare. The prevalence of these point mutations in other ethnic

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

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Federal Reserve System, 20th Street and Constitution Avenue, NW., Washington, DC 20551. (2) If you request... 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...

  12. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... expression of its religious beliefs. The organization may not expend funds that it receives directly from... 42 Public Health 1 2014-10-01 2014-10-01 false Religious character and independence. 54a.5 Section... CHOICE REGULATIONS APPLICABLE TO STATES, LOCAL GOVERNMENTS AND RELIGIOUS ORGANIZATIONS RECEIVING...

  13. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... expression of its religious beliefs. The organization may not expend funds that it receives directly from... 42 Public Health 1 2010-10-01 2010-10-01 false Religious character and independence. 54a.5 Section... CHOICE REGULATIONS APPLICABLE TO STATES, LOCAL GOVERNMENTS AND RELIGIOUS ORGANIZATIONS RECEIVING...

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

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... expression of its religious beliefs. The organization may not expend funds that it receives directly from... 42 Public Health 1 2011-10-01 2011-10-01 false Religious character and independence. 54a.5 Section... CHOICE REGULATIONS APPLICABLE TO STATES, LOCAL GOVERNMENTS AND RELIGIOUS ORGANIZATIONS RECEIVING...

  15. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... expression of its religious beliefs. The organization may not expend funds that it receives directly from... 42 Public Health 1 2013-10-01 2013-10-01 false Religious character and independence. 54a.5 Section... CHOICE REGULATIONS APPLICABLE TO STATES, LOCAL GOVERNMENTS AND RELIGIOUS ORGANIZATIONS RECEIVING...

  16. 42 CFR 54a.5 - Religious character and independence.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... expression of its religious beliefs. The organization may not expend funds that it receives directly from... 42 Public Health 1 2012-10-01 2012-10-01 false Religious character and independence. 54a.5 Section... CHOICE REGULATIONS APPLICABLE TO STATES, LOCAL GOVERNMENTS AND RELIGIOUS ORGANIZATIONS RECEIVING...

  17. 32 CFR 242a.5 - Procedure for announcing meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... THE HEALTH SCIENCES § 242a.5 Procedure for announcing meetings. (a) Except to the extent such...; (4) Whether the meeting or parts thereof are to be open or closed to the public; and (5) The name and... subject matter of such meeting, and whether open or closed to the public, at the earliest practicable time...

  18. 12 CFR 708a.5 - Notice to NCUA.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... of directors approves a proposal to convert, it must provide the Regional Director with notice of its... part of the notice required by § 708a.5(a) if its state chartering law permits it to convert to a..., including any internal governance requirements, such as the requisite membership vote for conversion and the...

  19. 42 CFR 68a.4 - Who is eligible to participate?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible to participate? 68a.4 Section 68a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL RESEARCH LOAN REPAYMENT PROGRAM FOR INDIVIDUALS FROM...

  20. 26 CFR 1.475(a)-4 - Valuation safe harbor.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Inventories § 1.475(a)-4 Valuation safe harbor. (a) Overview—(1) Purpose. This... portions of the payments have been recognized for tax purposes before the valuation and appropriate...

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... qualified tuition and related expenses for purposes of the Lifetime Learning Credit. (d) Effective date. The... 26 Internal Revenue 1 2013-04-01 2013-04-01 false Lifetime Learning Credit. 1.25A-4 Section 1.25A... Changes in Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1...

  2. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... qualified tuition and related expenses for purposes of the Lifetime Learning Credit. (d) Effective date. The... 26 Internal Revenue 1 2012-04-01 2012-04-01 false Lifetime Learning Credit. 1.25A-4 Section 1.25A... Changes in Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1...

  3. 26 CFR 1.401(a)(4)-12 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... annuity means an annuity payable in equal installments for the life of the employee that terminates upon... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit... employees means employees of a prior employer who become employed by the employer in a transaction between...

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

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... annuity means an annuity payable in equal installments for the life of the employee that terminates upon... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit... employees means employees of a prior employer who become employed by the employer in a transaction between...

  5. 26 CFR 1.401(a)(4)-12 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... annuity means an annuity payable in equal installments for the life of the employee that terminates upon... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit... employees means employees of a prior employer who become employed by the employer in a transaction between...

  6. 26 CFR 1.401(a)(4)-12 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... annuity means an annuity payable in equal installments for the life of the employee that terminates upon... §§ 1.401(a)(4)-1 through 1.401(a)(4)-13. Accumulation plan. Accumulation plan means a defined benefit... employees means employees of a prior employer who become employed by the employer in a transaction between...

  7. 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... in interference with, or prevention of, the orderly accomplishment of the mission of an installation...

  8. 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... in interference with, or prevention of, the orderly accomplishment of the mission of an installation...

  9. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 6 2011-07-01 2011-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... in interference with, or prevention of, the orderly accomplishment of the mission of an installation...

  10. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 6 2012-07-01 2012-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... in interference with, or prevention of, the orderly accomplishment of the mission of an installation...

  11. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 6 2014-07-01 2014-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... in interference with, or prevention of, the orderly accomplishment of the mission of an installation...

  12. 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 Securities...

  13. 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 Securities...

  14. 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 Securities...

  15. 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 Securities...

  16. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....4161(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-4 Use considered sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or...

  17. 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.

  18. 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.

  19. 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.

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

    PubMed Central

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

    2000-01-01

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

  1. Involvement of CYP 3A5 In the Interaction Between Tacrolimus and Nicardipine: A Case Report.

    PubMed

    Sassi, Mouna B; Gaies, Emna; Salouage, Issam; Trabelsi, Sameh; Lakhal, Mohamed; Klouz, Anis

    2015-01-01

    Tacrolimus is a calcineurin inhibitor primarily metabolized by CYP3A4 and secondarily by CYP3A5. Several drugs can modify tacrolimus blood levels as calcium channel blockers (CCBs). Interaction with nicardipine was reported in some cases. A man with a history of malignant arterial hypertension treated with nicardipine, underwent kidney transplantation. After transplantation, he was treated with tacrolimus, mycophenolate mofetil and corticoids. Therapeutic drug monitoring of tacrolimus was done regularly showing a mean trough concentration (C0) of 24.39 ng/mL with some concentrations reaching 52 ng/mL. After changing nicardipine by prazosine, the first tacrolimus C0 after stopping nicardipine was 3.2 ng/mL. Increase of tacrolimus trough concentrations is due to the inhibition of CYP3A4. Very high levels of tacrolimus suggest the non expression of CYP3A5. Thus, because of the possible lack of the secondary pathway, therapeutic drug monitoring of tacrolimus is highly recommended at the introduction of CCBs and also at its stopping.

  2. Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

    PubMed

    Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M; Largiadèr, Carlo R; Mohacsi, Paul; Sistonen, Johanna

    2015-12-01

    Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts. While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction. Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. A 5MV Tandetron to Universidad Autonoma de Madrid

    SciTech Connect

    Tengblad, Olof

    1999-11-16

    A 5MV Tandetron accelerator is being projected for the Center of Material Analysis of the Universidad Autonoma de Madrid. The accelerator will be dedicated to Material Science but it meant to be open to all fields of science and industry that can profit from this kind of installations. Estimated construction time and delivery of the accelerator implies that the first experiments can be performed in the spring 2001.

  4. Association between cytochrome P450 3A5 polymorphism and the lung function in Saskatchewan grain workers.

    PubMed

    Seo, Takayuki; Pahwa, Punam; McDuffie, Helen H; Yurube, Keigo; Egoshi, Masayoshi; Umemoto, Yuichiro; Ghosh, Sunita; Fukushima, Yumi; Nakagawa, Kazuko

    2008-06-01

    The activity of the enzymes that metabolize tobacco smoke may affect the susceptibility to chronic obstructive pulmonary disease (COPD). Cytochrome P450 (CYP) 3A5 is expressed selectively over CYP3A4 in human lung, but the association between the CYP3A5 polymorphisms and the airway injury is unknown. Two hundred and six male Saskatchewan grain workers participated in this longitudinal study, and their lung function values of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), respiratory symptoms, smoking status, and the occupational history were analyzed. A significant interactive effect was observed between the CYP3A5 genotype and current smoking status on FEV1, and the annual decline rates of FEV1 and FVC in current smokers were greater among CYP3A5*1/*3 carriers than CYP3A5*3/*3 carriers (-48.7+/-16.4 vs. -31.5+/-4.7 ml/years, P=0.02; -27.4+/-18.9 vs. -5.8+/-6.5 ml/years, P=0.04). The incidences of chronic cough and COPD were also higher in current smokers with CYP3A5*1/*3 than in nonsmokers and current smokers with CYP3A5*3/*3. The adjusted odds ratios for chronic cough and COPD current smokers with CYP3A5*1/*3 versus nonsmokers with the CYP3A5*3/*3 genotype were 11.4 (P=0.009) and 4.3 (P=0.13), respectively. The results suggest that CYP3A5*1 may be a novel genetic risk factor for airway injury in smokers, and that CYP3A5 may play a role in airway injury owing to the bioactivation of chemicals in tobacco smoke.

  5. 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

    ... Airworthiness Directives; International Aero Engines AG (IAE) V2500-A1, V2522-A5, V2524-A5, V2525-D5, V2527-A5, V2527E-A5, V2527M-A5, V2528-D5, V2530-A5, and V2533-A5 Turbofan Engines AGENCY: Federal Aviation... airworthiness directive (AD) for all International Aero Engines AG (IAE) V2500-A1, V2525-D5 and V2528-D5...

  6. M60A3 Tank Procedure Guides

    DTIC Science & Technology

    1985-02-01

    no longer needed. Pleai do not return it to the U.S. Army Research Institute for the Behavioral and Social Sciencis . NOTE, This Research Product Is not...B. L., Vaughan, J. J., Jr., and Schaefer, R. H. Development of M1 Abrams Tank Sustainment Training Material . ARI Research Report 1334, June 1982. .5...place of the M60A3 Operator’s Manual or M60A3 training materials . The guides will aid you in remembering long or difficult sets of procedures. In

  7. 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.

  8. 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.

  9. 22 CFR 9a.3 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO CERTAIN INTERNATIONAL ENERGY PROGRAMS; RELATED MATERIAL § 9a.3 Scope. These regulations apply to all information and material classified... “Classification of Certain Information and Material Obtained From Advisory Bodies Created To Implement The...

  10. 22 CFR 9a.3 - Scope.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO CERTAIN INTERNATIONAL ENERGY PROGRAMS; RELATED MATERIAL § 9a.3 Scope. These regulations apply to all information and material classified... “Classification of Certain Information and Material Obtained From Advisory Bodies Created To Implement The...

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. Evolution of the thermopsin peptidase family (A5).

    PubMed

    Rawlings, Neil D

    2013-01-01

    Thermopsin is a peptidase from Sulfolobus acidocaldarius that is active at low pH and high temperature. From reversible inhibition with pepstatin, thermopsin is thought to be an aspartic peptidase. It is a member of the only family of peptidases to be restricted entirely to the archaea, namely peptidase family A5. Evolution within this family has been mapped, using a taxonomic tree based on the known classification of archaea. Homologues are found only in archaeans that are both hyperthermophiles and acidophiles, and this implies lateral transfer of genes between archaea, because species with homologues are not necessarily closely related. Despite the remarkable stability and activity in extreme conditions, no tertiary structure has been solved for any member of the family, and the catalytic mechanism is unknown. Putative catalytic residues have been predicted here by examination of aligned sequences.

  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. 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.

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

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

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  1. 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…

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

  3. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

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

  5. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

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

  6. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

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

  7. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

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

  8. Synthesis and biological evaluation of vinylogous combretastatin A-4 derivatives.

    PubMed

    Kaffy, Julia; Pontikis, Renée; Florent, Jean-Claude; Monneret, Claude

    2005-07-21

    Stereospecific syntheses of the Z-E and E-Z vinylogues of combretastatin A-4, and two B-ring related analogues, were achieved through a Suzuki-Miyaura coupling. As compared to CA4, the derivative with a phenyl moiety has shown increased potency in its ability to inhibit tubulin polymerisation.

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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... underrepresented in science and engineering. (3) Without regard to the geographic region in which the applicant...

  14. 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... underrepresented in science and engineering. (3) Without regard to the geographic region in which the applicant...

  15. 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... underrepresented in science and engineering. (3) Without regard to the geographic region in which the applicant...

  16. 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... underrepresented in science and engineering. (3) Without regard to the geographic region in which the applicant...

  17. 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....16a-4 Derivative securities. (a) For purposes of section 16 of the Act, both derivative securities and... securities, except that the acquisition or disposition of any derivative security shall be separately...

  18. 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... underrepresented in science and engineering. (3) Without regard to the geographic region in which the applicant...

  19. 26 CFR 1.56A-4 - Certain taxpayers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-4 Certain taxpayers. For application of the minimum tax in the case of estates and trusts, electing small business corporations, common....58-2 through 1.58-6. [T.D. 7564, 43 FR 40468, Sept. 12, 1978. Redesignated by T.D. 8138, 52 FR 15309...

  20. 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 A 4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A 4 to leukotriene B 4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B 4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B 4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A 4 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 A 4 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 A 4 hydrolase using in vivo models. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. 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.

  2. 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.

  3. 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

  4. Glucose Regulates the Expression of the Apolipoprotein A5 Gene

    SciTech Connect

    Fruchart, Jamila; Nowak, Maxime; Helleboid-Chapman, Audrey

    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.more » 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.« less

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

    PubMed

    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

    2015-10-01

    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 k z . Despite being predominantly composed of d-orbital character, the conduction band is remarkably steep, with an average effective mass of only 1.14m e. Moreover, the sharp spectral features observed in photoemission remain well defined with little additional broadening for more than 500 meV below E F, 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.

  6. Localized cowpox infection in a 5-month-old Rottweiler.

    PubMed

    von Bomhard, Wolf; Mauldin, Elizabeth A; Breuer, Wolfram; Pfleghaar, Stephan; Nitsche, Andreas

    2011-02-01

    Cowpox virus (CPXV) infections are a sporadic cause of localized or disseminated skin disease in domestic animals and humans in Europe. Rodents are considered the primary reservoir host for CPXV. Cats can become infected by close contact with rodents and are the most important source of human infections. Recently, public awareness has also been drawn to CPXV infections by an outbreak of rat to human infections in central Europe. In dogs, CPXV infections are rare. Here we report a case of a 5-month-old Rottweiler with a focal nodule on the muzzle. The lesion was fully excised, and recovery was uneventful. The preliminary diagnosis of a CPXV infection was established by the characteristic inclusion bodies on histopathological examination. The diagnosis was confirmed by electron microscopy and polymerase chain reaction (PCR). Sequencing of the PCR product led to a 231 bp sequence of the orthopoxvirus HA gene that was identical to a CPXV strain previously isolated from a cat. This is the third documented case of a canine CPXV infection. © 2010 The Authors. Journal compilation © 2010 ESVD and ACVD.

  7. Magnetic Nature of Light Transmission through a 5-nm Gap.

    PubMed

    Yang, Hyosim; Kim, Dai-Sik; Kim, Richard H Joon-Yeon; Ahn, Jae Sung; Kang, Taehee; Jeong, Jeeyoon; Lee, Dukhyung

    2018-02-09

    Slot antennas have been exploited as important building blocks of optical magnetism because their radiations are invoked by the magnetic fields along the axes, as vectorial Babinet principle predicts. However, optical magnetism of a few-nanometer-width slit, for which fascinating applications are found due to the colossal field enhancement but Babinet principle fails due to the nonnegligible thickness, has not been investigated. In this paper, we demonstrated that the magnetic field plays a dominant role in light transmission through a 5-nm slit on a 150-nm-thick gold film. The 5-nm slit was fabricated by atomic layer lithography, and the transmission was investigated for various incident angles by experiment and simulation at 785-nm wavelength. We found that, due to the deep subwavelength gap width, the transmission has the same incident angle dependence as the tangential magnetic field on the metal surface and this magnetic nature of a nanogap holds up to ~100-nm width. Our analysis establishes conditions for nanogap optical magnetism and suggests new possibilities in realizing magnetic-field-driven optical nonlinearities.

  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 havemore » 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.« less

  9. 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.

  10. Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

    PubMed

    Qiu, F H; Devchand, P R; Wada, K; Serhan, C N

    2001-12-01

    Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

  11. Data Processing of LAPAN-A3 Thermal Imager

    NASA Astrophysics Data System (ADS)

    Hartono, R.; Hakim, P. R.; Syafrudin, AH

    2018-04-01

    As an experimental microsatellite, LAPAN-A3/IPB satellite has an experimental thermal imager, which is called as micro-bolometer, to observe earth surface temperature for horizon observation. The imager data is transmitted from satellite to ground station by S-band video analog signal transmission, and then processed by ground station to become sequence of 8-bit enhanced and contrasted images. Data processing of LAPAN-A3/IPB thermal imager is more difficult than visual digital camera, especially for mosaic and classification purpose. This research aims to describe simple mosaic and classification process of LAPAN-A3/IPB thermal imager based on several videos data produced by the imager. The results show that stitching using Adobe Photoshop produces excellent result but can only process small area, while manual approach using ImageJ software can produce a good result but need a lot of works and time consuming. The mosaic process using image cross-correlation by Matlab offers alternative solution, which can process significantly bigger area in significantly shorter time processing. However, the quality produced is not as good as mosaic images of the other two methods. The simple classifying process that has been done shows that the thermal image can classify three distinct objects, i.e.: clouds, sea, and land surface. However, the algorithm fail to classify any other object which might be caused by distortions in the images. All of these results can be used as reference for development of thermal imager in LAPAN-A4 satellite.

  12. Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital.

    PubMed

    Hariparsad, Niresh; Nallani, Srikanth C; Sane, Rucha S; Buckley, Donna J; Buckley, Arthur R; Desai, Pankaj B

    2004-11-01

    The antiretroviral agent efavirenz enhances the systemic clearance of coadministered drugs that are cytochrome P450 (CYP) 3A4 substrates. The mechanism of the apparent increase in CYP3A4 activity by efavirenz and the magnitude of change relative to other known inducers are not known. The authors tested the hypothesis that increased enzymatic activity by efavirenz entails CYP3A4 induction and activation of the human pregnane X receptor (hPXR), a key transcriptional regulator of CYP3A4. Employing primary cultures of human hepatocytes, they compared the CYP3A4 inductive effects of efavirenz (1-10 microM) to rifampin (10 microM) and phenobarbital (2 mM). A cell-based reporter assay was employed to assess hPXR activation. The authors observed that efavirenz caused a concentration-dependent CYP3A4 induction and hPXR activation. Based on the CYP3A4 activity assay, the average magnitude of induction by efavirenz (5-10 microM) was approximately 3- to 4-fold. In comparison, phenobarbital (2 mM) and rifampin (10 microM) caused a 5- and 6-fold induction, respectively.

  13. Solution structure of leptospiral LigA4 Big domain

    SciTech Connect

    Mei, Song; Zhang, Jiahai; Zhang, Xuecheng

    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 Bigmore » 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.« less

  14. 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∘.

  15. A 3 MV Pelletron at Fudan University

    NASA Astrophysics Data System (ADS)

    Sun, Chuan-Chen; Lu, Cheng-Rong; Fe, Zhi-Yu; Yuan, Dao-Sheng; Yang, Fujia

    1989-04-01

    A 3 MV Pelletron tandem, model 9SDH-2, the fourth machine manufactured by NEC was installed and has been operating at Fudan University since 1987. The operating experiences obtained during the past year are described. Three beam lines have been established: one is for Auger-ESCA and RBS in an ultrahigh-vacuum chamber in which Al(100) clean surfaces have been studied; the second beam line is used as a mubeam analysis system using a 2 μ proton beam for resonant prefitting studies. The third is a general purpose beam line, for studies of the effect of nuclear resonance on K X-ray yield. At present, the third beam line is also used for ion beam analysis studies of 8.8 MeV He 2+ non-Rutherford scattering on high Tc superconductors.

  16. 26 CFR 1.6038A-4 - Monetary penalty.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... time and manner prescribed in § 1.6038A-2 (d) and (e), fails to maintain or cause another to maintain records as required by § 1.6038A-3, or (in the case of records maintained outside the United States) fails... transactions so attributed. (3) Calculation of monetary penalty. If a reporting corporation fails to maintain...

  17. 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

  18. Personalized tacrolimus doses determined by CYP3A5 genotype for induction and maintenance phases of kidney transplantation.

    PubMed

    Vannaprasaht, Suda; Reungjui, Sirirat; Supanya, Darika; Sirivongs, Dhavee; Pongskul, Cholatip; Avihingsanon, Yingyos; Tassaneeyakul, Wichittra

    2013-11-01

    Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy. This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients. Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method. The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus

  19. 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

  20. 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

    ... could result in an uncontained failure of the high-pressure (HP) compressor stage 3-8 drum and..., V2527M-A5, V2528-D5, V2530-A5, and V2533-A5 turbofan engines with high-pressure (HP) compressor stage 3-8...

  1. A 4D Hyperspherical Interpretation of q-Space

    PubMed Central

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

    2015-01-01

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

  2. Acute localized exanthem due to Coxsackievirus A4.

    PubMed

    Drago, Francesco; Ciccarese, Giulia; Gariazzo, Lodovica; Cioni, Margherita; Parodi, Aurora

    2017-09-01

    Enteroviruses are the leading cause of exanthems in children, especially during summer and autumn. Enterovirus infections may occur in epidemics or small outbreaks. A 30-year-old woman presented with a three-day history of an erythematous maculopapular skin rash with petechiae localized exclusively under the nipple of the right breast. The skin eruption was associated with an erythematous-petechial enanthem. The patient complained of low-grade fever, headache, asthenia, sore throat and arthromyalgias. IgM (1:128) and IgG (1:640) antibodies against Coxsackievirus A4 were detected by the virus neutralization test. Reverse transcriptase real time polymerase chain reaction (PCR) assay detected enterovirus RNA in the patient's plasma and faeces. Diagnosis of an acute localized exanthem due to Coxsachievirus A4 was performed. Skin lesions improved in seven days and completely cleared in two weeks without any systemic or topical treatment. Physicians should be aware of the possibility that enteroviruses may determine localized skin eruptions in addition to hand-foot-mouth disease and atypical exanthems. Viral infections should be considered in the differential diagnosis of localized dermatitis especially when the skin eruption is associated with enanthems and with systemic symptoms.

  3. A 4D hyperspherical interpretation of q-space.

    PubMed

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

    2015-04-01

    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH). Using this orthonormal basis, we derive several well-established q-space indices and numerically estimate the diffusion orientation distribution function (dODF). We also derive the integral transform describing the relationship between the diffusion signal and propagator on a hypersphere. Most importantly, we will demonstrate that for hybrid diffusion imaging (HYDI) acquisitions low order linear expansion of the HSH basis is sufficient to characterize diffusion in neural tissue. In fact, the HSH basis achieves comparable signal and better dODF reconstructions than other well-established methods, such as Bessel Fourier orientation reconstruction (BFOR), using fewer fitting parameters. All in all, this work provides a new way of looking at q-space. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. 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.

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

    SciTech Connect

    Dutro, J.A.; Santanello, S.A.; Unger, F.

    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 obtainedmore » and demonstrated no abnormalities. The abdominal technetium scan was abnormal. An exploratory laparotomy was performed later on the day of admission.« less

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

    PubMed

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

    2014-01-01

    Female, 4 FINAL DIAGNOSIS: Tumoral calcinosis Symptoms: Hard immobile mass Medication: - Clinical Procedure: - Specialty: Surgery. Congenital defects. 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. 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. Total excision appears to lead to a good clinical outcome and a low incidence of local relapse.

  7. 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

  8. Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, REK7/EphA5, and its ligand, AL-1/Ephrin-A5.

    PubMed

    Gao, W Q; Shinsky, N; Armanini, M P; Moran, P; Zheng, J L; Mendoza-Ramirez, J L; Phillips, H S; Winslow, J W; Caras, I W

    1998-08-01

    The Eph-related tyrosine kinase receptor, REK7/EphA5, mediates the effects of AL-1/Ephrin-A5 and related ligands and is involved in the guidance of retinal, cortical, and hippocampal axons during development. The continued expression of REK7/EphA5 in the adult brain, in particular in areas associated with a high degree of synaptic plasticity such as the hippocampus, raises the question of its function in the mature nervous system. In this report we examined the role of REK7/EphA5 in synaptic remodeling by asking if agents that either block or activate REK7/EphA5 affect synaptic strength in hippocampal slices from adult mouse brain. We show that a REK7/EphA5 antagonist, soluble REK7/EphA5-IgG, impairs the induction of long-term potentiation (LTP) without affecting other synaptic parameters such as normal synaptic transmission or paired-pulse facilitation. In contrast, perfusion with AL-1/Ephrin-A5-IgG, an activator of REK7/EphA5, induces a sustained increase in normal synaptic transmission that partially mimics LTP. The sustained elevation of normal synaptic transmission could be attributable to a long-lasting binding of the AL-1/Ephrin-A5-IgG to the endogenous REK7/EphA5 receptor, as revealed by immunohistochemistry. Furthermore, maximal electrical induction of LTP occludes the potentiating effects of subsequent treatment with AL-1/Ephrin-A5-IgG. Taken together these results implicate REK7/EphA5 in the regulation of synaptic plasticity in the mature hippocampus and suggest that REK7/EphA5 activation is recruited in the LTP induced by tetanization. Copyright 1998 Academic Press.

  9. Multisite Phosphorylation of Human Liver Cytochrome P450 3A4 Enhances Its gp78- and CHIP-mediated Ubiquitination

    PubMed Central

    Wang, YongQiang; Guan, Shenheng; Acharya, Poulomi; Liu, Yi; Thirumaran, Ranjit K.; Brandman, Relly; Schuetz, Erin G.; Burlingame, Alma L.; Correia, Maria Almira

    2012-01-01

    CYP3A4, an integral endoplasmic reticulum (ER)-anchored protein, is the major human liver cytochrome P450 enzyme responsible for the disposition of over 50% of clinically relevant drugs. Alterations of its protein turnover can influence drug metabolism, drug-drug interactions, and the bioavailability of chemotherapeutic drugs. Such CYP3A4 turnover occurs via a classical ER-associated degradation (ERAD) process involving ubiquitination by both UBC7/gp78 and UbcH5a/CHIP E2-E3 complexes for 26 S proteasomal targeting. These E3 ligases act sequentially and cooperatively in CYP3A4 ERAD because RNA interference knockdown of each in cultured hepatocytes results in the stabilization of a functionally active enzyme. We have documented that UBC7/gp78-mediated CYP3A4 ubiquitination requires protein phosphorylation by protein kinase (PK) A and PKC and identified three residues (Ser-478, Thr-264, and Ser-420) whose phosphorylation is required for intracellular CYP3A4 ERAD. We document herein that of these, Ser-478 plays a pivotal role in UBC7/gp78-mediated CYP3A4 ubiquitination, which is accelerated and enhanced on its mutation to the phosphomimetic Asp residue but attenuated on its Ala mutation. Intriguingly, CYP3A5, a polymorphically expressed human liver CYP3A4 isoform (containing Asp-478) is ubiquitinated but not degraded to a greater extent than CYP3A4 in HepG2 cells. This suggests that although Ser-478 phosphorylation is essential for UBC7/gp78-mediated CYP3A4 ubiquitination, it is not sufficient for its ERAD. Additionally, we now report that CYP3A4 protein phosphorylation by PKA and/or PKC at sites other than Ser-478, Thr-264, and Ser-420 also enhances UbcH5a/CHIP-mediated ubiquitination. Through proteomic analyses, we identify (i) 12 additional phosphorylation sites that may be involved in CHIP-CYP3A4 interactions and (ii) 8 previously unidentified CYP3A4 ubiquitination sites within spatially associated clusters of Asp/Glu and phosphorylatable Ser/Thr residues that may

  10. 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.

  11. A logarithmic detection system suitable for a 4π array

    NASA Astrophysics Data System (ADS)

    Westfall, G. D.; Yurkon, J. E.; van der Plicht, J.; Koenig, Z. M.; Jacak, B. V.; Fox, R.; Crawley, G. M.; Maier, M. R.; Hasselquist, B. E.; Tickle, R. S.; Horn, D.

    1985-08-01

    A low pressure multiwire proportional counter, a Bragg curve counter, and an array of CaF2/plastic scintillator telescopes have been developed in a geometry suitable for close packing into a 4π detector designed to study nucleus-nucleus reactions at 100-200 MeV/nucleon. The multiwire counter is hexagonal in shape and gives X-Y position information using resistive charge division from nichrome-coated stretched polypropylene foils. The Bragg curve counter is a hexagonal pyramid with the charge taken from a Frisch gridded anode. A field shaping grid gives the Bragg curve counter a radial field. The scintillator telescopes are shaped as truncated triangular pyramids such that when stacked together they form a truncated hexagonal pyramid. The light signal of the CaF2-plastic combination is read with one phototube using a phoswich technique to separate the ΔE signal from the E signal. The entire system has been tested so far for particles with 1 <= Z <= 18 and gives good position, charge, and time resolution.

  12. Working Health Services Scotland: a 4-year evaluation

    PubMed Central

    Hanson, M; Bakhshi, A; Kennedy, M; Macdonald, E B

    2018-01-01

    Abstract Background Working Health Service Scotland (WHSS) supports the self-employed and employees of small and medium-sized enterprises (SMEs) in Scotland with a health condition affecting their ability to work, who are either absent or at risk of becoming absent due to it. Aims To evaluate the impact on health and work outcomes of WHSS clients over a 4-year period. Methods Data were collected at enrolment, entry, discharge and follow-up at 3 and 6 months after discharge. Clients completed up to three validated health questionnaires at entry and discharge—EuroQol five dimensions (EQ-5D) and visual analogue scale (VAS); Hospital Anxiety and Depression Scale (HADS); and Canadian Occupational Performance Measure (COPM). Results A total of 13463 referrals occurred in the 4-year period; 11748 (87%) were eligible and completed entry assessment and 60% of the latter completed discharge paperwork. The majority of referrals were due to musculoskeletal conditions (84%) while 12% were referred with mental health conditions. Almost a fifth (18%) of cases were absent at entry and back at work at discharge. Work days lost while in WHSS was associated with age, length of absence prior to entering WHSS, primary health condition and time in programme. All health measures showed significant improvements from entry to discharge. Improvement in general health was sustained at 3- and 6-month follow-up. Conclusions The WHSS evaluation findings indicate that participation was associated with positive changes to health and return-to-work. The extent of the positive change in health measures and work ability can be highly important economically for employees and employers. PMID:29390161

  13. Working Health Services Scotland: a 4-year evaluation.

    PubMed

    Demou, E; Hanson, M; Bakhshi, A; Kennedy, M; Macdonald, E B

    2018-02-16

    Working Health Service Scotland (WHSS) supports the self-employed and employees of small and medium-sized enterprises (SMEs) in Scotland with a health condition affecting their ability to work, who are either absent or at risk of becoming absent due to it. To evaluate the impact on health and work outcomes of WHSS clients over a 4-year period. Data were collected at enrolment, entry, discharge and follow-up at 3 and 6 months after discharge. Clients completed up to three validated health questionnaires at entry and discharge-EuroQol five dimensions (EQ-5D) and visual analogue scale (VAS); Hospital Anxiety and Depression Scale (HADS); and Canadian Occupational Performance Measure (COPM). A total of 13463 referrals occurred in the 4-year period; 11748 (87%) were eligible and completed entry assessment and 60% of the latter completed discharge paperwork. The majority of referrals were due to musculoskeletal conditions (84%) while 12% were referred with mental health conditions. Almost a fifth (18%) of cases were absent at entry and back at work at discharge. Work days lost while in WHSS was associated with age, length of absence prior to entering WHSS, primary health condition and time in programme. All health measures showed significant improvements from entry to discharge. Improvement in general health was sustained at 3- and 6-month follow-up. The WHSS evaluation findings indicate that participation was associated with positive changes to health and return-to-work. The extent of the positive change in health measures and work ability can be highly important economically for employees and employers. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Occupational Medicine.

  14. A 4-meter Telescope for the US Air Force Academy

    NASA Astrophysics Data System (ADS)

    Buzasi, D.; Andersen, G.; Wetterer, C.

    2004-05-01

    The United States Air Force Academy (USAFA) in Colorado Springs has obtained a 4m-diameter, lightweight telescope from the discontinued Space Based Laser project. Originally designed and constructed for space, this segmented telescope is being reconfigured for use in a ground-based facility. The current optical design is an afocal Mersenne configuration with an extremely thin (17mm) glass primary. The telescope has 312 fine figure actuators for active shaping of the primary, as well as 42 piston actuators for phasing of the segments and adaptive optics capability with a 300-actuator deformable mirror and wavefront sensor. We are recoating and redesigning the optics (with new secondary and tertiary mirrors) and constructing a new truss and an alt-az mount with two Nasmyth foci capable of both sidereal and low-Earth object tracking down to altitudes of 200km. The telescope will be located in a new facility to be built next to the current USAFA Observatory. The primary use of the telescope will be for education by involving cadets in a wide range of Air Force experiments including active ranging, communication, and imaging and characterization of satellites. We envision, however, that substantial time will also be available for astronomy. Although the Colorado Springs site is not ideal for many astronomical uses, it does lend itself to easy access by cadets, faculty, and visitors, and is appropriate for spectroscopy and bright-object work. Compared to similar facilities around the world, we expect to have a large amount of time available for outside users.

  15. Fragrance contact allergy: a 4-year retrospective study.

    PubMed

    Cuesta, Laura; Silvestre, Juan Francisco; Toledo, Fernando; Lucas, Ana; Pérez-Crespo, María; Ballester, Irene

    2010-08-01

    Fragrance chemicals are the second most frequent cause of contact allergy. The mandatory labelling of 26 fragrance chemicals when present in cosmetics has facilitated management of patients allergic to fragrances. The study was aimed to define the characteristics of the population allergic to perfumes detected in our hospital district, to determine the usefulness of markers of fragrance allergy in the baseline GEIDAC series, and to describe the contribution made by the fragrance series to the data obtained with the baseline series. We performed a 4-year retrospective study of patients tested with the Spanish baseline series and/or fragrance series. There are four fragrance markers in the baseline series: fragrance mix I (FM I), Myroxylon pereirae, fragrance mix II (FM II), and hydroxyisohexyl 3-cyclohexene carboxaldehyde. A total of 1253 patients were patch tested, 117 (9.3%) of whom were positive to a fragrance marker. FM I and M. pereirae detected 92.5% of the cases of fragrance contact allergy. FM II and hydroxyisohexyl 3-cyclohexene carboxaldehyde detected 6 additional cases and provided further information in 8, enabling improved management. A fragrance series was tested in a selected group of 86 patients and positive results were obtained in 45.3%. Geraniol was the allergen most frequently found in the group of patients tested with the fragrance series. Classic markers detect the majority of cases of fragrance contact allergy. We recommend incorporating FM II in the Spanish baseline series, as in the European baseline series, and using a specific fragrance series to study patients allergic to a fragrance marker.

  16. 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...

  17. 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...

  18. 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...

  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 to...

  20. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Tax-free sales. 48.4161(a)-5 Section 48.4161(a)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For...

  1. 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 grant...

  2. 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 grant...

  3. 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 grant...

  4. 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 grant...

  5. 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 grant...

  6. 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...

  7. 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...

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

    PubMed

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

    2012-02-01

    We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  9. Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplant patients.

    PubMed

    Elens, Laure; van Schaik, Ron H; Panin, Nadtha; de Meyer, Martine; Wallemacq, Pierre; Lison, Dominique; Mourad, Michel; Haufroid, Vincent

    2011-10-01

    CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the immunosuppressants tacrolimus (Tac) and cyclosporine (CsA). The objective of the study was to assess the potential influence of a new functional SNP in CYP3A4 on the pharmacokinetic parameters assessed by dose requirements and trough blood levels of both calcineurin inhibitors (CNI) in stable renal transplant patients. A total of 99 stable renal transplant patients receiving either Tac (n = 49) or CsA (n = 50) were genotyped for the CYP3A4 intron 6 C>T (rs35599367) and CYP3A5*3 SNPs. Trough blood levels ([Tac](0) or [CsA](0) in ng/ml), dose-adjusted [Tac](0) or [CsA](0) (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4 and CYP3A5. Dose-adjusted concentrations were 2.0- and 1.6-fold higher in T-variant allele carriers for the CYP3A4 intron 6 C>T SNP compared with homozygous CC for Tac and CsA, respectively. When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.6- and 4.1-fold higher for Tac, and 1.5- and 2.2-fold higher for CsA than the intermediate metabolizer and extensive metabolizer groups, respectively. Multiple linear regression analysis revealed that, taken together, both CYP3A4 intron 6 and CYP3A5*3 SNPs explained more than 60 and 20% of the variability observed in dose-adjusted [Tac](0) and [CsA](0), respectively. The CYP3A4 intron 6 C>T polymorphism is associated with altered Tac and CsA metabolism. CYP3A4 intron 6 C>T along with CYP3A5*3 (especially for Tac) pharmacogenetic testing performed just before transplantation may help identifying patients at risk of CNI overexposure and contribute to limit CNI-related nephrotoxicity by refining the starting dose according to their genotype. Original submitted 5 May 2011; Revision

  10. Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons.

    PubMed

    Sullivan, Chelsea S; Gotthard, Ingo; Wyatt, Elliott V; Bongu, Srihita; Mohan, Vishwa; Weinberg, Richard J; Maness, Patricia F

    2018-04-18

    Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.

  11. Thoracoscopic Lobectomy in Infants and Children Utilizing a 5 mm Stapling Device.

    PubMed

    Rothenberg, Steven

    2016-12-01

    Thoracoscopic lobectomy for congenital cystic lung disease has become an accepted and in many institutions the preferred technique. However, the technical challenges are many. Previous endoscopic staplers (12 mm) used commonly in adults are too large for use in infants This study evaluates the safety and efficacy of using a 5 mm stapling device to seal and divide major pulmonary structures. From July 2014 to March 2016, 26 patients of age 6 weeks to 13 months underwent thoracoscopic lobectomy for CPAM or sequestration. Weights ranged from 3.2 to 11.4 kg. There were 7 upper lobectomies, 2 middle, and 17 lower lobectomies. In each case, the 5 mm stapler (Justright Surgical; Louisville, Colorado) was the primary device for vessel and bronchial sealing and division. It is 4.8 mm in diameter with an anvil length of 25 mm and lays down four rows of staples and divides between them. A 3 mm sealing device was used for dissection and to take smaller segmental vessels as necessary. Stump lines were evaluated for bleeding or air leak in all cases. All procedures were accomplished successfully thoracoscopically. The stapler was used on the main lobar artery cases and vein in 24 cases, a large systemic sequestration vessel in 5 cases, and the bronchus in all 26. The stapler was also used to complete the minor fissure in 1 case and the major fissure in 1 case. A total of 96 staple loads were fired. Operative times ranged from 35 to 135 minutes. There was no significant bleeding of any vascular stump. In 1 case, the edge of the bronchial stump had to be reinforced, this was thought to be secondary to too much tissue being enclosed in the jaws. There were no postoperative complications. The use of a 5 mm stapling device appears to be safe and effective in thoracoscopic lobectomy in infants. It allows for safe management of major pulmonary vessels and bronchi in the confined chest of an infant through a single 5 mm port.

  12. 26 CFR 1.512(a)-3 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  14. 32 CFR 237a.3 - Objective and policy.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Objective and policy. 237a.3 Section 237a.3...) MISCELLANEOUS PUBLIC AFFAIRS LIAISON WITH INDUSTRY § 237a.3 Objective and policy. (a) It is important that... subchapter, DoD components shall cooperate with industry at local and regional levels. However, they will...

  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. 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...

  18. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

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

  19. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

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

  20. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit agency...

  1. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit agency...

  2. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit agency...

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true [Reserved] 1.512(a)-3 Section 1.512(a)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.512(a)-3 [Reserved] ...

  4. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

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

  5. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit agency...

  6. TaCYP78A5 regulates seed size in wheat (Triticum aestivum).

    PubMed

    Ma, Meng; Zhao, Huixian; Li, Zhaojie; Hu, Shengwu; Song, Weining; Liu, Xiangli

    2016-03-01

    Seed size is an important agronomic trait and a major component of seed yield in wheat. However, little is known about the genes and mechanisms that determine the final seed size in wheat. Here, we isolated TaCYP78A5, the orthologous gene of Arabidopsis CYP78A5/KLUH in wheat, from wheat cv. Shaan 512 and demonstrated that the expression of TaCYP78A5 affects seed size. TaCYP78A5 encodes the cytochrome P450 (CYP) 78A5 protein in wheat and rescued the phenotype of the Arabidopsis deletion mutant cyp78a5. By affecting the extent of integument cell proliferation in the developing ovule and seed, TaCYP78A5 influenced the growth of the seed coat, which appears to limit seed growth. TaCYP78A5 silencing caused a 10% reduction in cell numbers in the seed coat, resulting in a 10% reduction in seed size in wheat cv. Shaan 512. By contrast, the overexpression of TaCYP78A5 increased the number of cells in the seed coat, resulting in seed enlargement of ~11-35% in Arabidopsis. TaCYP78A5 activity was positively correlated with the final seed size. However, TaCYP78A5 overexpression significantly reduced seed set in Arabidopsis, possibly due to an ovule development defect. TaCYP78A5 also influenced embryo development by promoting embryo integument cell proliferation during seed development. Accordingly, a working model of the influence of TaCYP7A5 on seed size was proposed. This study provides direct evidence that TaCYP78A5 affects seed size and is a potential target for crop improvement. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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

    SciTech Connect

    Kim, Sangsoo Daniel; Antenos, Monica; Squires, E. James

    2013-07-15

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-01-01

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

  9. Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo.

    PubMed

    Zhao, Tianxiao; Song, Yun; Liu, Baomin; Qiu, Qianqian; Jiao, Lei; Li, Yunman; Huang, Wenlong; Qian, Hai

    2015-01-01

    The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L(-1)) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.

  10. CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions.

    PubMed

    Galetin, Aleksandra; Ito, Kiyomi; Hallifax, David; Houston, J Brian

    2005-07-01

    The complexity of in vitro kinetic phenomena observed for CYP3A4 substrates (homo- or heterotropic cooperativity) confounds the prediction of drug-drug interactions, and an evaluation of alternative and/or pragmatic approaches and substrates is needed. The current study focused on the utility of the three most commonly used CYP3A4 in vitro probes for the prediction of 26 reported in vivo interactions with azole inhibitors (increase in area under the curve ranged from 1.2 to 24, 50% in the range of potent inhibition). In addition to midazolam, testosterone, and nifedipine, quinidine was explored as a more "pragmatic" substrate due to its kinetic properties and specificity toward CYP3A4 in comparison with CYP3A5. Ki estimates obtained in human liver microsomes under standardized in vitro conditions for each of the four probes were used to determine the validity of substrate substitution in CYP3A4 drug-drug interaction prediction. Detailed inhibitor-related (microsomal binding, depletion over incubation time) and substrate-related factors (cooperativity, contribution of other metabolic pathways, or renal excretion) were incorporated in the assessment of the interaction potential. All four CYP3A4 probes predicted 69 to 81% of the interactions with azoles within 2-fold of the mean in vivo value. Comparison of simple and multisite mechanistic models and interaction prediction accuracy for each of the in vitro probes indicated that midazolam and quinidine in vitro data provided the best assessment of a potential interaction, with the lowest bias and the highest precision of the prediction. Further investigations with a wider range of inhibitors are required to substantiate these findings.

  11. COL4A4 gene study of a European population: description of new mutations causing autosomal dominant Alport syndrome.

    PubMed

    Rosado, Consolación; Bueno, Elena; Felipe, Carmen; González-Sarmiento, Rogelio

    2014-01-01

    Autosomal forms of Alport syndrome represent 20% of all patients (15% recessive and 5% dominant). They are caused by mutations in the COL4A3 and COL4A4 genes, which encode a-3 and a-4 collagen IV chains of the glomerular basement membrane, cochlea and eye. Thin basement membrane nephropathy may affect up to 1% of the population. The pattern of inheritance in the 40% of cases is the same as autosomal dominant Alport syndrome: heterozygous mutations in these genes. The aim of this study is to detect new pathogenic mutations in the COL4A4 gene in the patients previously diagnosed with autosomal Alport syndrome and thin basement membrane nephropathy in our hospital. We conducted a clinical and genetic study in eleven patients belonging to six unrelated families with aforementioned clinical symptoms and a negative study of COL4A3 gene. The molecular study was made by conformation of sensitive gel electrophoresis (CSGE) and direct sequencing of the fragments that show an altered electrophoretic migration pattern. We found two pathogenic mutations, not yet described: IVS3 + 1G > C is a replacement of Guanine to Cytosine in position +1 of intron 3, in the splicing region, which leads to a pathogenic mutation. c.4267C > T; p.P1423S is a missense mutation, also considered pathogenic. We also found seven new polymorphisms. We describe two new pathogenic mutations, responsible for autosomal dominant Alport syndrome. The other families of the study were undiagnosed owing to problems in the method employed and the possibility of mutations in other genes, giving rise to other diseases with similar symptoms.

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

    PubMed

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

    2016-01-15

    Eph receptors and their corresponding membrane-bound ephrin ligands regulate cell positioning and establish tissue patterns during embryonic and oncogenic development. Emerging evidence suggests that assembly of polymeric Eph signalling clusters relies on cytoskeletal reorganisation and underlies regulation by protein tyrosine phosphatases (PTPs). PTP-PEST (also known as PTPN12) is a central regulator of actin cytoskeletal dynamics. Here, we demonstrate that an N-terminal fragment of PTP-PEST, generated through an ephrinA5-triggered and spatially confined cleavage mediated by caspase-3, attenuates EphA3 receptor activation and its internalisation. Isolation of EphA3 receptor signalling clusters within intact plasma membrane fragments obtained by detergent-free cell fractionation reveals that stimulation of cells with ephrin triggers effective recruitment of this catalytically active truncated form of PTP-PEST together with key cytoskeletal and focal adhesion proteins. Importantly, modulation of actin polymerisation using pharmacological and dominant-negative approaches affects EphA3 phosphorylation in a similar manner to overexpression of PTP-PEST. We conclude that PTP-PEST regulates EphA3 activation both by affecting cytoskeletal remodelling and through its direct action as a PTP controlling EphA3 phosphorylation, indicating its multifaceted regulation of Eph signalling. © 2016. Published by The Company of Biologists Ltd.

  13. 17 CFR 260.7a-5 - Filing of amendments; number of copies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Filing of amendments; number of copies. 260.7a-5 Section 260.7a-5 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-5 Filing of amendments; number of copie...

  14. 17 CFR 260.7a-5 - Filing of amendments; number of copies.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Filing of amendments; number of copies. 260.7a-5 Section 260.7a-5 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-5 Filing of amendments; number of copie...

  15. 17 CFR 260.7a-5 - Filing of amendments; number of copies.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Filing of amendments; number of copies. 260.7a-5 Section 260.7a-5 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-5 Filing of amendments; number of copie...

  16. 17 CFR 260.7a-5 - Filing of amendments; number of copies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Filing of amendments; number of copies. 260.7a-5 Section 260.7a-5 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-5 Filing of amendments; number of copie...

  17. 17 CFR 260.7a-5 - Filing of amendments; number of copies.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Filing of amendments; number of copies. 260.7a-5 Section 260.7a-5 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-5 Filing of amendments; number of copie...

  18. 17 CFR 240.17a-5 - Reports to be made by certain brokers and dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... or carries customer accounts shall file Part I of Form X-17A-5 (§ 249.617 of this chapter) within 10... clears transactions or carries customer accounts shall file Part II of Form X-17A-5 (§ 249.617 of this... accounts shall file Part IIA of Form X-17A-5 (§ 249.617 of this chapter) within 17 business days after the...

  19. 45 CFR 12a.5 - Real property reported excess to GSA.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Real property reported excess to GSA. 12a.5 Section 12a.5 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.5 Real property reported excess to GSA. (a) Each landholding agency must submit a report to GSA of...

  20. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 1 2014-04-01 2013-04-01 true Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In general. Subject to the phaseout of the education tax credit described in § 1.25A-1(c), the Hope Scholarship Credit...

  1. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 1 2013-04-01 2013-04-01 false Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In general. Subject to the phaseout of the education tax credit described in § 1.25A-1(c), the Hope Scholarship Credit...

  2. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 1 2012-04-01 2012-04-01 false Hope Scholarship Credit. 1.25A-3 Section 1.25A-3... Rates During A Taxable Year § 1.25A-3 Hope Scholarship Credit. (a) Amount of the credit—(1) In general. Subject to the phaseout of the education tax credit described in § 1.25A-1(c), the Hope Scholarship Credit...

  3. Donor CYP3A5 genotype influences tacrolimus disposition on the first day after paediatric liver transplantation.

    PubMed

    Calvo, Pier Luigi; Serpe, Loredana; Brunati, Andrea; Nonnato, Antonello; Bongioanni, Daniela; Olio, Dominic Dell'; Pinon, Michele; Ferretti, Carlo; Tandoi, Francesco; Carbonaro, Giulia; Salizzoni, Mauro; Amoroso, Antonio; Romagnoli, Renato; Canaparo, Roberto

    2017-06-01

    The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation. The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C 0 ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years. Donor CYP3A5 genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C 0 and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02). Donor CYP3A5 genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner. © 2017 The British Pharmacological Society.

  4. Effect of a 5-min cold-water immersion recovery on exercise performance in the heat.

    PubMed

    Peiffer, J J; Abbiss, C R; Watson, G; Nosaka, K; Laursen, P B

    2010-05-01

    This study examined the effect of a 5-min cold-water immersion (14 degrees C) recovery intervention on repeated cycling performance in the heat. 10 male cyclists performed two bouts of a 25-min constant-paced (254 (22) W) cycling session followed by a 4-km time trial in hot conditions (35 degrees C, 40% relative humidity). The two bouts were separated by either 15 min of seated recovery in the heat (control) or the same condition with 5-min cold-water immersion (5th-10th minute), using a counterbalanced cross-over design (CP(1)TT(1) --> CWI or CON --> CP(2)TT(2)). Rectal temperature was measured immediately before and after both the constant-paced sessions and 4-km timed trials. Cycling economy and Vo(2) were measured during the constant-paced sessions, and the average power output and completion times were recorded for each time trial. Compared with control, rectal temperature was significantly lower (0.5 (0.4) degrees C) in cold-water immersion before CP(2) until the end of the second 4-km timed trial. However, the increase in rectal temperature (0.5 (0.2) degrees C) during CP(2) was not significantly different between conditions. During the second 4-km timed trial, power output was significantly greater in cold-water immersion (327.9 (55.7) W) compared with control (288.0 (58.8) W), leading to a faster completion time in cold-water immersion (6.1 (0.3) min) compared with control (6.4 (0.5) min). Economy and Vo(2) were not influenced by the cold-water immersion recovery intervention. 5-min cold-water immersion recovery significantly lowered rectal temperature and maintained endurance performance during subsequent high-intensity exercise. These data indicate that repeated exercise performance in heat may be improved when a short period of cold-water immersion is applied during the recovery period.

  5. Reduced Methylprednisolone Clearance Causing Prolonged Pharmacodynamics in a Healthy Subject Was Not Associated With CYP3A5*3 Allele or a Change in Diet Composition

    PubMed Central

    Lee, Su-Jun; Jusko, William J.; Salaita, Christine G.; Calis, Karim A.; Jann, Michael W.; Spratlin, Vicky E.; Goldstein, Joyce A.; Hon, Yuen Yi

    2014-01-01

    The influence of diet and genetics was investigated in a healthy white person who had distinctly low methylprednisolone clearance. Pharmacokinetic and pharmacodynamic parameter values were similar on 2 occasions during the consumption of a low-carbohydrate diet and a Weight Watchers diet, indicating that the decreased clearance was unlikely attributable to a change in diet composition. Although the subject was found to be homozygous for CYP3A5*3, genetic findings were not significant for a number of other CYP3A4 and CYP3A5 allelic variants. Because of the high prevalence of CYP3A5*3/*3 in whites and because 5 of 7 white control subjects are also homozygous for CYP3A5*3, this genotype cannot fully explain the reduced metabolism of the drug. Other genetic or contributing factors might have been involved. New polymerase chain reaction–based genotyping methods for functionally defective CYP3A5*6, *8, *9, and *10 alleles were developed in this study. These assays will be useful for CYP3A5 genotype analysis in future clinical studies. PMID:16638735

  6. Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats.

    PubMed

    Suo, Guihai; Shen, Feifei; Sun, Baolan; Song, Honghua; Xu, Meiyu; Wu, Youjia

    2018-05-14

    EphA5 and its ligand ephrin-A5 interaction can trigger synaptogenesis during early hippocampus development. We have previously reported that abnormal EphA5 expression can result in synaptogenesis disorder in congenital hypothyroidism (CH) rats. To better understand its precise molecular mechanism, we further analyzed the characteristics of ephrin-A5 expression in the hippocampus of CH rats. Our study revealed that ephrin-A5 expression was downregulated by thyroid hormone deficiency in the developing hippocampus and hippocampal neurons in rats. Thyroxine treatment for hypothyroid hippocampus and triiodothyronine treatment for hypothyroid hippocampal neurons significantly improved ephrin-A5 expression but could not restore its expression to control levels. Hypothyroid hippocampal neurons in-vitro showed synaptogenesis disorder characterized by a reduction in the number and length of neurites. Furthermore, the synaptogenesis-associated molecular expressions of NMDAR-1 (NR1), PSD95 and CaMKII were all downregulated correspondingly. These results suggest that ephrin-A5 expression may be decreased in CH, and abnormal activation of ephrin-A5/EphA5 signaling affects synaptogenesis during brain development. Such findings provide an important basis for exploring the pathogenesis of CH genetically.

  7. The paradox of ApoA5 modulation of triglycerides: evidence from clinical and basic research.

    PubMed

    Garelnabi, Mahdi; Lor, Kenton; Jin, Jun; Chai, Fei; Santanam, Nalini

    2013-01-01

    Apolipoprotein A5 (ApoA5) is a key regulator of plasma triglycerides (TG), even though its plasma concentration is very low compared to other known apoproteins. Over the years, researchers have attempted to elucidate the molecular mechanisms by which ApoA5 regulates plasma TG in vivo. Though still under debate, two theories broadly describe how ApoA5 modulates TG levels: (i) ApoA5 enhances the catabolism of TG-rich lipoproteins and (ii) it inhibits the rate of production of very low-density lipoprotein (VLDL), the major carrier of TGs. This review will summarize the basic and clinical studies that describe the importance of ApoA5 in TG metabolism. Population studies conducted in various countries have demonstrated an association between single nucleotide polymorphisms (SNPs) in ApoA5 and the increased risk to cardiovascular disease and metabolic syndrome (including diabetes and obesity). ApoA5 is also highly expressed during liver regeneration and is an acute phase protein associated with HDL, which is independent of its effects on TG metabolism. Despite considerable evidences available from clinical and basic research studies on the role of ApoA5 in TG metabolism and its indirect link to metabolic diseases, additional investigations are needed to understand the paradoxical role of this important apoprotein is modulated by both diet and its polymorphism variants. Copyright © 2012 The Canadian Society of Clinical Chemists. All rights reserved.

  8. The Paradox of ApoA5 Modulation of Triglycerides: Evidences from Clinical and Basic Research

    PubMed Central

    Garelnabi, Mahdi; Lor, Kenton; Jin, Jun; Chai, Fei; Santanam, Nalini

    2012-01-01

    Apolipoprotein A5 (ApoA5) is a key regulator of plasma triglycerides (TG), although its plasma concentration is very low compared to other known apoproteins. Over the years, researchers have attempted to elucidate the molecular mechanisms by which ApoA5 regulates plasma TG in vivo. Though still under debate, two theories broadly describe how ApoA5 modulates TG levels: (i) ApoA5 enhances the catabolism of TG-rich lipoproteins and (ii) it inhibits the rate of production of very low-density lipoprotein (VLDL), the major carrier of TGs. This review will summarize the basic and clinical studies that have attempted to describe the importance of ApoA5 in TG metabolism. Population studies conducted in various countries have demonstrated an association between single nucleotide polymorphisms (SNPs) in ApoA5 and the increased risk to cardiovascular disease and metabolic syndrome (including diabetes and obesity). ApoA5 is also highly expressed during liver regeneration and is an acute phase protein associated with HDL which was independent of its effects on TG metabolism. Conclusion Despite considerable evidences available from clinical and basic research studies, on the role of ApoA5 in TG metabolism and its indirect link to metabolic diseases, additional investigations are needed to understand the paradoxical role of this important apoprotein shown modulated by diet and from it polymorphism variants. PMID:23000317

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

    PubMed

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

    2015-07-07

    The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c(+) M1-macrophages (MΦs), while restoring CD206(+) M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    PubMed Central

    2013-01-01

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

  11. Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity.

    PubMed

    Rand, Jacob H; Wu, Xiao-Xuan; Lin, Elaine Y; Griffel, Alexander; Gialanella, Philip; McKitrick, John C

    2012-01-01

    Annexin A5 (AnxA5) has a high affinity for phosphatidylserine. The protein is widely used to detect apoptotic cells because phosphatidylserine, a phospholipid that is normally present in the inner leaflets of cytoplasmic membranes, becomes translocated to the outer leaflets during programmed cell death. Here we report the novel observation that AnxA5 binds to Gram-negative bacteria via the lipid A domain of lipopolysaccharide (LPS). Binding of AnxA5 to bacteria was measured quantitatively, confirmed by fluorescence microscopy, and found to be inhibited by antibodies against lipid A. AnxA5 also bound to purified dot-blotted LPS and lipid A. Through ellipsometry, we found that the binding of AnxA5 to purified LPS was calcium dependent and rapid and showed a high affinity-characteristics similar to those of AnxA5 binding to phosphatidylserine. Initial functional studies indicated that AnxA5 can affect LPS activities. AnxA5 inhibited LPS-mediated gelation in the Limulus amebocyte lysate assay. Incubation of LPS with the protein reduced the quantity of tumor necrosis factor alpha (TNF-α) released by cultured monocytes compared to that released upon incubation with LPS alone. Initial in vivo experiments indicated that injection of mice with LPS preincubated with AnxA5 produced serum TNF-α levels lower than those seen after injection of LPS alone. These data demonstrate that AnxA5 binds to LPS and open paths to investigation of the potential biological and therapeutic implications of this interaction. AnxA5 is highly expressed in cells that have a barrier function-including, among others, vascular endothelium, placental trophoblasts, and epithelial cells lining bile ducts, renal tubules, mammary ducts, and nasal epithelium. The protein has been well characterized for its binding to phospholipid bilayers that contain phosphatidylserine. This report of a previously unrecognized activity of AnxA5 opens the door to investigation of the possibility that this binding may have

  12. Annexin A5 Binds to Lipopolysaccharide and Reduces Its Endotoxin Activity

    PubMed Central

    Rand, Jacob H.; Wu, Xiao-Xuan; Lin, Elaine Y.; Griffel, Alexander; Gialanella, Philip; McKitrick, John C.

    2012-01-01

    ABSTRACT Annexin A5 (AnxA5) has a high affinity for phosphatidylserine. The protein is widely used to detect apoptotic cells because phosphatidylserine, a phospholipid that is normally present in the inner leaflets of cytoplasmic membranes, becomes translocated to the outer leaflets during programmed cell death. Here we report the novel observation that AnxA5 binds to Gram-negative bacteria via the lipid A domain of lipopolysaccharide (LPS). Binding of AnxA5 to bacteria was measured quantitatively, confirmed by fluorescence microscopy, and found to be inhibited by antibodies against lipid A. AnxA5 also bound to purified dot-blotted LPS and lipid A. Through ellipsometry, we found that the binding of AnxA5 to purified LPS was calcium dependent and rapid and showed a high affinity—characteristics similar to those of AnxA5 binding to phosphatidylserine. Initial functional studies indicated that AnxA5 can affect LPS activities. AnxA5 inhibited LPS-mediated gelation in the Limulus amebocyte lysate assay. Incubation of LPS with the protein reduced the quantity of tumor necrosis factor alpha (TNF-α) released by cultured monocytes compared to that released upon incubation with LPS alone. Initial in vivo experiments indicated that injection of mice with LPS preincubated with AnxA5 produced serum TNF-α levels lower than those seen after injection of LPS alone. These data demonstrate that AnxA5 binds to LPS and open paths to investigation of the potential biological and therapeutic implications of this interaction. PMID:22415004

  13. MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma.

    PubMed

    Wang, Wenzhao; Tang, Shi; Li, Hongfei; Liu, Ronghan; Su, Yanlin; Shen, Lin; Sun, Mingjie; Ning, Bin

    2018-06-05

    Traumatic spinal cord injury (SCI) causes permanent disability to at least 180,000 people per year worldwide. Early regulation of spinal fibroblast proliferation may inhibit fibrotic scar formation, allowing the creation of a favorable environment for neuronal regeneration and thereby enhancing recovery from traumatic SCIs. In this study, we aimed to identify the role of microRNA-21a-5p (miR-21a-5p) in regulating spinal fibroblasts after mechanical trauma and to investigate the dysregulation of miR-21a-5p in the pathological process of spinal SCI. We investigated the differential expression of microRNAs in primary spinal fibroblasts after mechanical trauma and found that the expression of miR-21a-5p was higher in spinal fibroblasts after scratch damage (SD). In addition, mouse spinal fibroblasts were transfected with miR-21a-5p mimics/inhibitor, and the role of miR-21a-5p in spinal fibrogenic activation was analyzed. These experiments demonstrated that miR-21a-5p overexpression promoted fibrogenic activity in spinal fibroblasts after mechanical trauma, as well as enhancing proliferation and attenuating apoptosis in spinal fibroblasts. Finally, the potential role of miR-21a-5p in regulating the Smad signaling pathway was examined. MiR-21a-5p activated the Smad signaling pathway by enhancing Smad2/3 phosphorylation. These results suggest that miR-21a-5p promotes spinal fibrosis after mechanical trauma. Based on these findings, we propose a close relationship between miR-21a-5p and spinal fibrosis, providing a new potential therapeutic target for SCI. Copyright © 2018. Published by Elsevier Inc.

  14. 26 CFR 1.691(a)-5 - Installment obligations acquired from decedent.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 453. Under the provisions of section 691(a)(4), an amount equal to the excess of the face value of the... at the time of the transfer or the consideration received for the transfer of the installment....691(a)-4 includes the satisfaction of an installment obligation at other than face value. (c) The...

  15. 42 CFR 68a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible to apply? 68a.3 Section 68a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL RESEARCH LOAN REPAYMENT PROGRAM FOR INDIVIDUALS FROM...

  16. Using Toyota's A3 Thinking for Analyzing MBA Business Cases

    ERIC Educational Resources Information Center

    Anderson, Joe S.; Morgan, James N.; Williams, Susan K.

    2011-01-01

    A3 Thinking is fundamental to Toyota's benchmark management philosophy and to their lean production system. It is used to solve problems, gain agreement, mentor team members, and lead organizational improvements. A structured problem-solving approach, A3 Thinking builds improvement opportunities through experience. We used "The Toyota…

  17. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2) Federally...

  18. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2) Federally...

  19. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2) Federally...

  20. A-3 Test Stand continues with test cell installation

    NASA Image and Video Library

    2010-07-20

    Employees at Stennis Space Center continue work on the A-3 Test Stand. As shown, a section of the test cell is lifted for installation on the stand's structural steel frame. Work on the A-3 Test Stand began in 2007. It is scheduled for activation in 2012.

  1. 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... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2) Federally...

  2. 26 CFR 1.401(a)(5)-1 - Special rules relating to nondiscrimination requirements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...(a)(5) sets out certain provisions that will not of themselves be discriminatory within the meaning... employees. (d) Certain disparity permitted. Under section 401(a)(5)(C), a plan does not discriminate in... compensation within the meaning of section 3231(e). For this purpose, a plan maintained for a self-employed...

  3. 17 CFR 240.12a-5 - Temporary exemption of substituted or additional securities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Temporary exemption of substituted or additional securities. 240.12a-5 Section 240.12a-5 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934...

  4. Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity.

    PubMed

    Wolf, Sabine; Janzen, Annette; Vékony, Nicole; Martiné, Ursula; Strand, Dennis; Closs, Ellen I

    2002-06-15

    Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional.

  5. Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity.

    PubMed Central

    Wolf, Sabine; Janzen, Annette; Vékony, Nicole; Martiné, Ursula; Strand, Dennis; Closs, Ellen I

    2002-01-01

    Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional. PMID:12049641

  6. Methylation of miR-145a-5p promoter mediates adipocytes differentiation

    SciTech Connect

    Du, Jingjing; Cheng, Xiao; Shen, Linyuan

    MicroRNAs (miRNAs, miR) play important roles in adipocyte development. Recent studies showed that the expression of several miRNAs is closely related with promoter methylation. However, it is not known whether miRNA mediates adipocytes differentiation by means of DNA methylation. Here, we showed that miR-145a-5p was poorly expressed in adipose tissue from mice fed a high fat diet (HFD). Overexpression or inhibition of miR-145a-5p was unfavorable or beneficial, respectively, for adipogenesis, and these effects were achieved by regulating adipocyte-specific genes involved in lipogenic transcription, fatty acid synthesis, and fatty acid transportation. Particularly, we first suggested that miR-145a-5p mimics or inhibitors promotedmore » or repressed adipocytes proliferation by regulating p53 and p21, which act as cell cycle regulating factors. Surprisingly, the miR-145a-5p-repressed adipocyte differentiation was enhanced or rescued when cells treated with 5-Aza-dC were transfected with miR-145a-5p mimics or inhibitors, respectively. These data indicated that, as a new mean to positively regulate adipocyte proliferation, the process of miR-145a-5p-inhibited adipogenesis may be regulated by DNA methylation. -- Highlights: •MiR-145a-5p promotes adipocytes proliferation. •MiR-145a-5p is negatively correlated with obesity. •MiR-145a-5p mediates adipocytes differentiation via regulating pathway related adipocytes differentiation. MiR-145a-5p mediating adipocytes differentiation was regulated by DNA methylation.« less

  7. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.

    PubMed

    Hong, Feng; Si, Chuanping; Gao, Pengfei; Cederbaum, Arthur I; Xiong, Huabao; Lu, Yongke

    2016-01-01

    Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison. Acute and subchronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1 (-/-) mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5 (-/-) mice developed comparable acute liver injury induced by a single injection of CCL4 as well as subchronic liver injury including fibrosis induced by 1 month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5 (-/-) mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5 (-/-) mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for 1 month, while subchronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5 (-/-) mice, liver fibrosis was more severe in cyp2a5 (-/-) mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it does not affect CCL4 hepatotoxicity.

  8. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Calculation of income inclusion. [Reserved] 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY.... § 1.409A-4 Calculation of income inclusion. [Reserved] ...

  9. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Calculation of income inclusion. [Reserved] 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY.... § 1.409A-4 Calculation of income inclusion. [Reserved] ...

  10. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Calculation of income inclusion. [Reserved] 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY.... § 1.409A-4 Calculation of income inclusion. [Reserved] ...

  11. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Calculation of income inclusion. [Reserved] 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY.... § 1.409A-4 Calculation of income inclusion. [Reserved] ...

  12. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  13. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  14. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  15. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  16. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.4 What information must each application contain? Each...

  17. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a training...

  18. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a training...

  19. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a training...

  20. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a training...

  1. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a training...

  2. Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

    SciTech Connect

    Abu-Bakar, A'edah, E-mail: a.abubakar@uq.edu.au; Arthur, Dionne Maioha; Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide

    2011-11-15

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic 'BR oxidase'. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR tomore » biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible 'BR oxidase' where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced. -- Highlights: Black-Right-Pointing-Pointer CYP2A5 metabolizes bilirubin to biliverdin and dipyrroles. Black-Right-Pointing-Pointer Bilirubin increased the hepatic CYP2A5 protein and activity levels. Black-Right-Pointing-Pointer Bilirubin does not change the

  3. Purification and Characterization of a Novel Subtype A3 Botulinum Neurotoxin

    PubMed Central

    Tepp, William H.; Lin, Guangyun

    2012-01-01

    Botulinum neurotoxins (BoNTs) produced by Clostridium botulinum are of considerable importance due to their being the cause of human and animal botulism, their potential as bioterrorism agents, and their utility as important pharmaceuticals. Type A is prominent due to its high toxicity and long duration of action. Five subtypes of type A BoNT are currently recognized; BoNT/A1, -/A2, and -/A5 have been purified, and their properties have been studied. BoNT/A3 is intriguing because it is not effectively neutralized by polyclonal anti-BoNT/A1 antibodies, and thus, it may potentially replace BoNT/A1 for patients who have become refractive to treatment with BoNT/A1 due to antibody formation or other modes of resistance. Purification of BoNT/A3 has been challenging because of its low levels of production in culture and the need for innovative purification procedures. In this study, modified Mueller-Miller medium was used in place of traditional toxin production medium (TPM) to culture C. botulinum A3 (CDC strain) and boost toxin production. BoNT/A3 titers were at least 10-fold higher than those produced in TPM. A purification method was developed to obtain greater than 95% pure BoNT/A3. The specific toxicity of BoNT/A3 as determined by mouse bioassay was 5.8 × 107 50% lethal doses (LD50)/mg. Neutralization of BoNT/A3 toxicity by a polyclonal anti-BoNT/A1 antibody was approximately 10-fold less than the neutralization of BoNT/A1 toxicity. In addition, differences in symptoms were observed between mice that were injected with BoNT/A3 and those that were injected with BoNT/A1. These results indicate that BoNT/A3 has novel biochemical and pharmacological properties compared to those of other subtype A toxins. PMID:22367089

  4. Purification and characterization of a novel subtype a3 botulinum neurotoxin.

    PubMed

    Tepp, William H; Lin, Guangyun; Johnson, Eric A

    2012-05-01

    Botulinum neurotoxins (BoNTs) produced by Clostridium botulinum are of considerable importance due to their being the cause of human and animal botulism, their potential as bioterrorism agents, and their utility as important pharmaceuticals. Type A is prominent due to its high toxicity and long duration of action. Five subtypes of type A BoNT are currently recognized; BoNT/A1, -/A2, and -/A5 have been purified, and their properties have been studied. BoNT/A3 is intriguing because it is not effectively neutralized by polyclonal anti-BoNT/A1 antibodies, and thus, it may potentially replace BoNT/A1 for patients who have become refractive to treatment with BoNT/A1 due to antibody formation or other modes of resistance. Purification of BoNT/A3 has been challenging because of its low levels of production in culture and the need for innovative purification procedures. In this study, modified Mueller-Miller medium was used in place of traditional toxin production medium (TPM) to culture C. botulinum A3 (CDC strain) and boost toxin production. BoNT/A3 titers were at least 10-fold higher than those produced in TPM. A purification method was developed to obtain greater than 95% pure BoNT/A3. The specific toxicity of BoNT/A3 as determined by mouse bioassay was 5.8 × 10(7) 50% lethal doses (LD(50))/mg. Neutralization of BoNT/A3 toxicity by a polyclonal anti-BoNT/A1 antibody was approximately 10-fold less than the neutralization of BoNT/A1 toxicity. In addition, differences in symptoms were observed between mice that were injected with BoNT/A3 and those that were injected with BoNT/A1. These results indicate that BoNT/A3 has novel biochemical and pharmacological properties compared to those of other subtype A toxins.

  5. 32 CFR 237a.3 - Objective and policy.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) MISCELLANEOUS PUBLIC AFFAIRS LIAISON WITH INDUSTRY § 237a.3 Objective and policy. (a) It is important that... community, consistent with national security, and (2) cooperation with industry in public relations...

  6. Laser Anemometer Measurements of the Flow Field in a 4:1 Pressure Ratio Centrifugal Impeller

    NASA Technical Reports Server (NTRS)

    Skoch, G. J.; Prahst, P. S.; Wernet, M. P.; Wood, J. R.; Strazisar, A. J.

    1997-01-01

    A laser-doppler anemometer was used to obtain flow-field velocity measurements in a 4:1 pressure ratio, 4.54 kg/s (10 lbm/s), centrifugal impeller, with splitter blades and backsweep, which was configured with a vaneless diffuser. Measured through-flow velocities are reported for ten quasi-orthogonal survey planes at locations ranging from 1% to 99% of main blade chord. Measured through-flow velocities are compared to those predicted by a 3-D viscous steady flow analysis (Dawes) code. The measurements show the development and progression through the impeller and vaneless diffuser of a through-flow velocity deficit which results from the tip clearance flow and accumulation of low momentum fluid centrifuged from the blade and hub surfaces. Flow traces from the CFD analysis show the origin of this deficit which begins to grow in the inlet region of the impeller where it is first detected near the suction surface side of the passage. It then moves toward the pressure side of the channel, due to the movement of tip clearance flow across the impeller passage, where it is cut by the splitter blade leading edge. As blade loading increases toward the rear of the channel the deficit region is driven back toward the suction surface by the cross-passage pressure gradient. There is no evidence of a large wake region that might result from flow separation and the impeller efficiency is relatively high. The flow field in this impeller is quite similar to that documented previously by NASA Lewis in a large low-speed backswept impeller.

  7. Isolation of Copper from a 5-Cent Coin: An Example of Electrorefining

    ERIC Educational Resources Information Center

    Sogo, Steven G.

    2004-01-01

    Copper is isolated from a 5-cent coin with the help of electrolysis. This experiment is useful for conceptual understanding of the significance of reduction potentials in situation of competition for electrons.

  8. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer.

    PubMed

    Staquicini, Fernanda I; Qian, Ming D; Salameh, Ahmad; Dobroff, Andrey S; Edwards, Julianna K; Cimino, Daniel F; Moeller, Benjamin J; Kelly, Patrick; Nunez, Maria I; Tang, Ximing; Liu, Diane D; Lee, J Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R M; Lobb, Roy R; Edelman, Martin J; Sidman, Richard L; Wistuba, Ignacio I; Arap, Wadih; Pasqualini, Renata

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    DOE PAGES

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; ...

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lungmore » cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.« less

  10. CRISPR/Cas9 Genetic Modification of CYP3A5 *3 in HuH-7 Human Hepatocyte Cell Line Leads to Cell Lines with Increased Midazolam and Tacrolimus Metabolism.

    PubMed

    Dorr, Casey R; Remmel, Rory P; Muthusamy, Amutha; Fisher, James; Moriarity, Branden S; Yasuda, Kazuto; Wu, Baolin; Guan, Weihua; Schuetz, Erin G; Oetting, William S; Jacobson, Pamala A; Israni, Ajay K

    2017-08-01

    Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 engineering of the CYP3A5 *3 locus (rs776746) in human liver cell line HuH-7 ( CYP3A5 *3/*3 ) has led to three CYP3A5 *1 cell lines by deletion of the exon 3B splice junction or point mutation. Cell lines CYP3A5 *1/*3 sd (single deletion), CYP3A5 *1/*1 dd (double deletion), or CYP3A5 *1/*3 pm (point mutation) expressed the CYP3A5 *1 mRNA and had elevated CYP3A5 mRNA ( P < 0.0005 for all engineered cell lines) and protein expression compared with HuH-7. In metabolism assays, HuH-7 had less tacrolimus (all P < 0.05) or midazolam (MDZ) (all P < 0.005) disappearance than all engineered cell lines. HuH-7 had less 1-OH MDZ (all P < 0.0005) or 4-OH (all P < 0.005) production in metabolism assays than all bioengineered cell lines. We confirmed CYP3A5 metabolic activity with the CYP3A4 selective inhibitor CYP3CIDE. This is the first report of genomic CYP3A5 bioengineering in human cell lines with drug metabolism analysis. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  11. 26 CFR 48.4161(a)-5 - Tax-free sales.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Tax-free sales. 48.4161(a)-5 Section 48.4161(a... EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(a)-5 Tax-free sales. For provisions relating to the tax-free sales of articles referred to in section 4161(a) see: (a) Section 4221...

  12. Impaired osteoblast differentiation in Annexin A2- and -A5-deficient cells

    SciTech Connect

    Genetos, Damian C.; Wong, Alice; Weber, Thomas J.

    Annexins are a class of calcium-binding proteins with diverse functions in the regulation of lipid rafts inflammation,fibrinolysis, transcriptional programming and ion transport. Within bone, they are well-characterized as components of mineralizing matrix vesicles, although little else is known as to their function during osteogenesis. We generated annexin A2 (AnxA2)- or annexin A5 (AnxA5)-knockdown pre-osteoblasts, and asked whether proliferation or osteogenic differentiation was altered in knockdown cells, compared to vector controls. We report that DNA content, a marker of proliferation, was significantly reduced in both AnxA2 and AnxA5 knockdown cells. Alkaline phosphatase expression and staining activity were also suppressed in AnxA2-more » or AnxA5-knockdown after 14 days of culture. The pattern of osteogenic gene expression was altered in knockdown cells, with Col1a1 expressed more rapidly in knock-down cells, compared to controls. In contrast, Runx2, Ibsp, and Bglap all revealed decreased expression after 14 days of culture. Using a murine fracture model, we demonstrate that AnxA2 and AnxA5 are rapidly expressed within the fracture callus. These data demonstrate that AnxA2 and AnxA5 can influence bone formation via regulation of osteoprogenitor proliferation and differentiation in addition to their well-studied function in matrix vesicles.« less

  13. HYDROXYCHLOROQUINE REDUCES BINDING OF ANTIPHOSPHOLIPID ANTIBODIES TO SYNCYTIOTROPHOBLASTS AND RESTORES ANNEXIN A5 EXPRESSION

    PubMed Central

    Wu, Xiao-Xuan; Guller, Seth; Rand, Jacob H.

    2011-01-01

    Objectives Antibody-mediated disruption of the annexin A5 (AnxA5) anticoagulant shield has been posited to be a thrombogenic mechanism in the antiphospholipid syndrome. We recently showed that the antimalarial drug, hydroxychloroquine, dissociates antiphospholipid immune complexes and restores AnxA5 binding to planar phospholipid bilayer. Using quantitative immunoassays, we demonstrated similar effects on BeWo trophoblasts. We therefore investigated the effects of the drug on localization of AnxA5 in primary cultures of human placental syncytiotrophoblasts (SCTs). Study Laser confocal microscopy with computer-based morphometric analysis was used to localize AnxA5 and antiphospholipid antibodies on SCTs exposed to polyclonal and monoclonal antiphospholipid and control IgGs. Results Hydroxychloroquine reversed the effects of the antiphospholipid antibodies on the SCTs by markedly reducing IgG binding and restoring AnxA5 expression. Conclusions These results provide the first morphologic evidence for this effect of hydroxychloroquine on human placental SCTs and support the possibility of novel treatments that target antiphospholipid antibody binding. PMID:21871597

  14. EPHRIN-A5 REGULATES INTER-MALE AGGRESSION IN MICE

    PubMed Central

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

    2015-01-01

    The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5−/−) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5−/− mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5−/− mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice. PMID:25746458

  15. 26 CFR 1.25A-3 - Hope Scholarship Credit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... academic period beginning in the taxable year (or treated as beginning in the taxable year, see § 1.25A-5(e...) Degree requirement. For at least one academic period that begins during the taxable year, the student... least one academic period that begins during the taxable year, the student enrolls for at least one-half...

  16. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference

    PubMed Central

    Hong, Feng; Si, Chuanping; Gao, Pengfei; Cederbaum, Arthur I.; Xiong, Huabao; Lu, Yongke

    2015-01-01

    Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild type (WT) mice and CYP2A5 knockout (cyp2a5−/−) mice as well as in CYP2E1 knockout (cyp2e1−/−) mice as a comparison. Acute and sub-chronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1−/− mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5−/− mice developed comparable acute liver injury induced by a single injection of CCL4 as well as sub-chronic liver injury including fibrosis induced by one month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5−/− mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5−/− mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for one month, while sub-chronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5−/− mice, liver fibrosis was more severe in cyp2a5−/− mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it doesn’t affect CCL4 hepatotoxicity. PMID:26363552

  17. In vitro inhibition of cytochrome P450 3A4 by Aronia melanocarpa constituents.

    PubMed

    Bräunlich, Marie; Christensen, Hege; Johannesen, Siri; Slimestad, Rune; Wangensteen, Helle; Malterud, Karl E; Barsett, Hilde

    2013-01-01

    Extracts, subfractions, isolated anthocyanins and procyanidins, and two phenolic acids from aronia [Aronia melanocarpa] were investigated for their CYP3A4 inhibitory effects, using midazolam as the probe substrate and recombinant insect cell microsomes expressing CYP3A4 as the enzyme source. Procyanidin B5 was a considerably stronger CYP3A4 inhibitor in vitro than the isomeric procyanidin B2 and comparable to bergamottin, a known CYP3A4 inhibitor from grapefruit juice. The inhibitory activity of proanthocyanidin-containing fractions was correlated to the degree of polymerization. Among the anthocyanins, cyanidin 3-arabinoside showed stronger CYP3A4 inhibition than cyanidin 3-galactoside and cyanidin 3-glucoside. Thus, the ability to inhibit CYP3A4 in vitro seems to be influenced by the sugar unit linked to the anthocyanidin. Georg Thieme Verlag KG Stuttgart · New York.

  18. Contrasting exome constancy and regulatory region variation in the gene encoding CYP3A4: an examination of the extent and potential implications.

    PubMed

    Creemer, Olivia J; Ansari-Pour, Naser; Ekong, Rosemary; Tarekegn, Ayele; Plaster, Christopher; Bains, Ripudaman K; Itan, Yuval; Bekele, Endashaw; Bradman, Neil

    2016-06-01

    CYP3A4 expression varies up to 100-fold among individuals, and, to date, genetic causes remain elusive. As a major drug-metabolizing enzyme, elucidation of such genetic causes would increase the potential for introducing personalized dose adjustment of therapies involving CYP3A4 drug substrates. The foetal CYP3A isoform, CYP3A7, is reported to be expressed in ∼10% of European adults and may thus contribute towards the metabolism of endogenous substances and CYP3A drug substrates. However, little is known about the distribution of the variant expressed in the adult. We resequenced the exons, flanking introns, regulatory elements and 3'UTR of CYP3A4 in five Ethiopian populations and incorporated data from the 1000 Genomes Project. Using bioinformatic analysis, we assessed likely consequences of observed CYP3A4 genomic variation. We also conducted the first extensive geographic survey of alleles associated with adult expression of CYP3A7 - that is, CYP3A7*1B and CYP3A7*1C. Ethiopia contained 60 CYP3A4 variants (26 novel) and more variants (>1%) than all non-African populations combined. No nonsynonymous mutation was found in the homozygous form or at more than 2.8% in any population. Seventy-nine per cent of haplotypes contained 3'UTR and/or regulatory region variation with striking pairwise population differentiation, highlighting the potential for interethnic variation in CYP3A4 expression. Conversely, coding region variation showed that significant interethnic variation is unlikely at the protein level. CYP3A7*1C was found at up to 17.5% in North African populations and in significant linkage disequilibrium with CYP3A5*3, indicating that adult expression of the foetal isoform is likely to be accompanied by reduced or null expression of CYP3A5.

  19. Evaluating a 5 year climate change research teacher professional development program in Southern Nevada

    NASA Astrophysics Data System (ADS)

    Buck, P.; Rudd, L.; McAlister, J.; Bonde, A.

    2013-12-01

    We present results of a 5 yr NSF funded project, part of Nevada ';s Climate Change Research Education and Outreach EPSCoR award. Goals of the K-12 portion of the project included: a replicable professional development model of K-12 climate change science education for Nevada and other institutions; strengthened relationships between secondary school teachers and NSHE climate change researchers; and greater teacher pedagogical content knowledge in climate change science and greater confidence in ability to teach effectively. Two overarching research questions formed the foundation of our teacher professional development program: 1) How will climate change affect Nevada's baseline water resources (groundwater and surface water) and linked ecosystem services? 2) How will climate change affect natural and anthropogenic disturbances (e.g., wildland fires, invasive species, and insect outbreaks)? All teachers participated in at least one (2-week long) summer institute and academic year follow up focused on one of two overarching research questions forming the basis of the award assisted by a disciplinary graduate student . An on-line class (ENV 794) was a 3 credit graduate credit bearing class from UNLV based on the fundamentals of climate change science was available free to participating teachers. A supplemental program in the final award year was added following advisory board recommendations to develop a cohort or "learning community" approach at an interested high school. The 'About Climate Change' Integrated Curriculum spans several subject areas and cuts across national standards for STEM English and Social Studies; a 2-week unit developed by Clark HS teachers for their classes. Our teachers increased their content knowledge about climate change science. This is indicated in student evaluations of the on-line course ENV 794, and in the summer institute post test of content knowledge which included about 25 questions. There was improvement for our one focus

  20. Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome

    SciTech Connect

    Renieri, A.; Galli, L.; Bruttini, M.

    1995-11-20

    Mutations in the COL4A5 gene, which encodes the {alpha}5 chain of type IV collagen, are found in a large fraction of patients with X-linked Alport syndrome. The recently discovered COL4A6, tightly linked and highly homologous to COL4A5, represents a second candidate gene for Alport syndrome. We analyzed 177 Italian Alport syndrome families by Southern blotting using cDNA probes from both COL4A5 and COL4A6. Nine unrelated families, accounting for 5% of the cases, were found to have a rearrangement in COL4A5. No rearrangements were found in COL4A6, with the exception of a deletion encompassing the 5{prime} ends of both COL4A5 andmore » COL4A6 genes in a patient with Alport syndrome and leiomyomatosis. COL4A5 rearrangements were all intragenic and included 1 duplication and 7 deletions. Polymerase chain reaction (PCR) analysis was carried out to characterize deletion and duplication boundaries and to predict the resulting protein abnormality. The two smallest deletions involved a single exon (exons 17 and 40, respectively), while the largest ones spanned exons 1 to 36. The clinical phenotype of patients in whom a rearrangement in COL4A5 was detected was severe, with progression to end-stage renal failure in juvenile age and hypoacusis occurring in most cases. These data have some important implications in the diagnosis of patients with Alport syndrome. 34 refs., 3 figs., 1 tab.« less

  1. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Plan amendments and plan terminations. 1.401(a)(4)-5 Section 1.401(a)(4)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan...

  2. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Plan amendments and plan terminations. 1.401(a)(4)-5 Section 1.401(a)(4)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan...

  3. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Plan amendments and plan terminations. 1.401(a)(4)-5 Section 1.401(a)(4)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan...

  4. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Plan amendments and plan terminations. 1.401(a)(4)-5 Section 1.401(a)(4)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan terminations. ...

  5. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Plan amendments and plan terminations. 1.401(a)(4)-5 Section 1.401(a)(4)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan...

  6. Isopropyl alcohol tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    An isopropyl alcohol (IPA) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen IPA, water and liquid oxygen (LOX) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  7. Water tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A water tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen water, liquid oxygen (LOX) and isopropyl alcohol (IPA) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  8. Liquid oxygen tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A liquid oxygen (LOX) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen LOX, isopropyl alcohol (IPA) and water tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  9. Liquid oxygen tank installed at A-3 Test Stand

    NASA Image and Video Library

    2009-09-18

    A liquid oxygen (LOX) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen LOX, isopropyl alcohol (IPA) and water tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  10. Isopropyl alcohol tank installed at A-3 Test Stand

    NASA Image and Video Library

    2009-09-18

    An isopropyl alcohol (IPA) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen IPA, water and liquid oxygen (LOX) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  11. Water tank installed at A-3 Test Stand

    NASA Image and Video Library

    2009-08-13

    A water tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen water, liquid oxygen (LOX) and isopropyl alcohol (IPA) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  12. S100A4 interacts with p53 in the nucleus and promotes p53 degradation.

    PubMed

    Orre, L M; Panizza, E; Kaminskyy, V O; Vernet, E; Gräslund, T; Zhivotovsky, B; Lehtiö, J

    2013-12-05

    S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.

  13. SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.

    PubMed

    Huang, Timothy Y; Zhao, Yingjun; Jiang, Lu-Lin; Li, Xiaoguang; Liu, Yan; Sun, Yu; Piña-Crespo, Juan C; Zhu, Bing; Masliah, Eliezer; Willnow, Thomas E; Pasquale, Elena B; Xu, Huaxi

    2017-12-04

    Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer's disease (AD). Although SORLA is known to regulate trafficking of the amyloid β (Aβ) precursor protein to decrease levels of proteotoxic Aβ oligomers, whether SORLA can counteract synaptic dysfunction induced by Aβ oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand-induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SORLA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by Aβ oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Aβ-induced neurodegeneration in AD. © 2017 Huang et al.

  14. CYP3A4*18: it is not rare allele in Japanese population.

    PubMed

    Yamamoto, Takehito; Nagafuchi, Nobue; Ozeki, Takeshi; Kubota, Takahiro; Ishikawa, Hiroshi; Ogawa, Seishi; Yamada, Yasuhiko; Hirai, Hisamaru; Iga, Tatsuji

    2003-01-01

    We sequenced all 13 exons of the CYP3A4 gene derived from 48 Japanese subjects. One subject possess the 20070 T>C mutation in the exon 10 (result in leu293Pro substitution, namely CYP3A4(*)18), as heterozygote. Thus, we investigated the frequency of CYP3A4(*)18 in 118 Japanese population using polymerase chain reaction-restriction fragment length polymorphism with Msp I and determined that the frequency of the CYP3A4(*)18 allele was 1.3%.

  15. Genetic analysis of drug metabolizing phase-I enzymes CYP3A4 in Tibetan populations.

    PubMed

    Liu, Lijun; Chang, Yu; Du, Shuli; Shi, Xugang; Yang, Hua; Kang, Longli; Jin, Tianbo; Yuan, Dongya; He, Yongjun

    2017-06-01

    The enzymatic activity of CYP3A4 results in broad interindividual variability in response to certain pharmacotherapies. The present study aimed to screen Tibetan volunteers for CYP3A4 genetic polymorphisms. Previous research has focussed on Han Chinese patients, while little is known about the genetic variation of CYP3A4 in the Tibetan populations. Here, we adopted DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A4 gene in 96 unrelated healthy Tibetan individuals.We identified 20 different CYP3A4 polymorphisms in the Tibetan population, including two novel variants (21824 A>G and 15580 G>C). In addition, we also determined the allele frequencies of CYP3A4*1A and CYP3A4*1H were 82.29% and 28.13%, respectively. CYP3A4*1P and *1G were relatively rare with frequencies of only 1.04% and 0.52%, respectively. Our results provide information on CYP3A4 polymorphisms in Tibetan individuals which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group.

  16. Pregnane X receptor- and CYP3A4-humanized mouse models and their applications

    PubMed Central

    Cheng, Jie; Ma, Xiaochao; Gonzalez, Frank J

    2011-01-01

    Pregnane X receptor (PXR) is a pivotal nuclear receptor modulating xenobiotic metabolism primarily through its regulation of CYP3A4, the most important enzyme involved in drug metabolism in humans. Due to the marked species differences in ligand recognition by PXR, PXR-humanized (hPXR) mice, and mice expressing human PXR and CYP3A4 (Tg3A4/hPXR) were established. hPXR and Tg3A4/hPXR mice are valuable models for investigating the role of PXR in xenobiotic metabolism and toxicity, in lipid, bile acid and steroid hormone homeostasis, and in the control of inflammation. PMID:21091656

  17. In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients.

    PubMed

    Engdal, Silje; Nilsen, Odd Georg

    2009-07-01

    The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6-beta-OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC(50): 73 microg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 microg/mL, respectively). All IC(50) values were high compared with those determined for crude extracts of other herbal remedies. The IC(50)/IC(25) ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright 2009 John Wiley & Sons, Ltd.

  18. EphrinA5 protein distribution in the developing mouse brain

    PubMed Central

    2010-01-01

    Background EphrinA5 is one of the best-studied members of the Eph-ephrin family of guidance molecules, known to be involved in brain developmental processes. Using in situ hybridization, ephrinA5 mRNA expression has been detected in the retinotectal, the thalamocortical, and the olfactory systems; however, no study focused on the distribution of the protein. Considering that this membrane-anchored molecule may act far from the neuron soma expressing the transcript, it is of a crucial interest to localize ephrinA5 protein to better understand its function. Results Using immunohistochemistry, we found that ephrinA5 protein is highly expressed in the developing mouse brain from E12.5 to E16.5. The olfactory bulb, the cortex, the striatum, the thalamus, and the colliculi showed high intensity of labelling, suggesting its implication in topographic mapping of olfactory, retinocollicular, thalamocortical, corticothalamic and mesostriatal systems. In the olfactory nerve, we found an early ephrinA5 protein expression at E12.5 suggesting its implication in the guidance of primary olfactory neurons into the olfactory bulb. In the thalamus, we detected a dynamic graduated protein expression, suggesting its role in the corticothalamic patterning, whereas ephrinA5 protein expression in the target region of mesencephalic dopaminergic neurones indicated its involvement in the mesostriatal topographic mapping. Following E16.5, the signal faded gradually and was barely detectable at P0, suggesting a main role for ephrinA5 in primary molecular events in topographic map formation. Conclusion Our work shows that ephrinA5 protein is expressed in restrictive regions of the developing mouse brain. This expression pattern points out the potential sites of action of this molecule in the olfactory, retinotectal, thalamocortical, corticothalamic and mesostriatal systems, during development. This study is essential to better understand the role of ephrinA5 during developmental topographic

  19. Description and Operation of the A3 Subscale Facility

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.; Varner, D. G.; Grover, J. B.

    2010-01-01

    The purpose of this paper is to give an overview of the general design and operation of the A3 Subscale test facility. The goal is to provide the reader with a general understanding of what the major facility systems are, where they are located, and how they are used to meet the objectives supporting the design of the A3 altitude rocket test facility. This paper also provides the reader with the background information prior to reading the subsequent papers detailing the design and test results of the various systems described herein.

  20. Haplotypes in SLC24A5 Gene as Ancestry Informative Markers in Different Populations

    PubMed Central

    Giardina, Emiliano; Pietrangeli, Ilenia; Martínez-Labarga, Cristina; Martone, Claudia; de Angelis, Flavio; Spinella, Aldo; De Stefano, Gianfranco; Rickards, Olga; Novelli, Giuseppe

    2008-01-01

    Ancestry informative markers (AIMs) are human polymorphisms that exhibit substantially allele frequency differences among populations. These markers can be useful to provide information about ancestry of samples which may be useful in predicting a perpetrator’s ethnic origin to aid criminal investigations. Variations in human pigmentation are the most obvious phenotypes to distinguish individuals. It has been recently shown that the variation of a G in an A allele of the coding single-nucleotide polymorphism (SNP) rs1426654 within SLC24A5 gene varies in frequency among several population samples according to skin pigmentation. Because of these observations, the SLC24A5 locus has been evaluated as Ancestry Informative Region (AIR) by typing rs1426654 together with two additional intragenic markers (rs2555364 and rs16960620) in 471 unrelated individuals originating from three different continents (Africa, Asia and Europe). This study further supports the role of human SLC24A5 gene in skin pigmentation suggesting that variations in SLC24A5 haplotypes can correlate with human migration and ancestry. Furthermore, our data do reveal the utility of haplotype and combined unphased genotype analysis of SLC24A5 in predicting ancestry and provide a good example of usefulness of genetic characterization of larger regions, in addition to single polymorphisms, as candidates for population-specific sweeps in the ancestral population. PMID:19440451

  1. Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab.

    PubMed

    Ma, Huanrong; Wu, Zhenzhen; Peng, Jianjun; Li, Yang; Huang, Hongxiang; Liao, Yi; Zhou, Minyu; Sun, Li; Huang, Na; Shi, Min; Bin, Jianping; Liao, Yulin; Rao, Jinjun; Wang, Lin; Liao, Wangjun

    2018-06-15

    Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC. © 2018 UICC.

  2. Metabolism of aflatoxin B{sub 1} in Turkey liver microsomes: The relative roles of cytochromes P450 1A5 and 3A37

    SciTech Connect

    Rawal, Sumit; Coulombe, Roger A., E-mail: roger@usu.edu

    The extreme sensitivity of turkeys to aflatoxin B{sub 1} (AFB{sub 1}) is associated with efficient epoxidation by hepatic cytochromes P450 (P450) 1A5 and 3A37 to exo-aflatoxin B{sub 1}-8,9-epoxide (exo-AFBO). The combined presence of 1A5 and 3A37, which obey different kinetic models, both of which metabolize AFB{sub 1} to the exo-AFBO and to detoxification products aflatoxin M{sub 1} (AFM{sub 1}) and aflatoxin Q{sub 1} (AFQ{sub 1}), respectively, complicates the kinetic analysis of AFB{sub 1} in turkey liver microsomes (TLMs). Antisera directed against 1A5 and 3A37, thereby individually removing the catalytic contribution of these enzymes, were used to identify the P450 responsiblemore » for epoxidating AFB{sub 1} in TLMs. In control TLMs, AFB{sub 1} was converted to exo-AFBO in addition to AFM{sub 1} and AFQ{sub 1} confirming the presence of functional 1A5 and 3A37. Pretreatment with anti-1A5 inhibited exo-AFBO formation, especially at low, submicromolar ({approx} 0.1 {mu}M), while anti-3A37, resulted in inhibition of exo-AFBO formation, but at higher (> 50 {mu}M) AFB{sub 1} concentrations. Metabolism in immunoinhibited TLMs resembled that of individual enzymes: 1A5 produced exo-AFBO and AFM{sub 1}, conforming to Michaelis-Menten, while 3A37 produced exo-AFBO and AFQ{sub 1} following the kinetic Hill equation. At 0.1 {mu}M AFB{sub 1}, close to concentrations in livers of exposed animals, 1A5 contributed to 98% of the total exo-AFBO formation. At this concentration, 1A5 accounted for a higher activation:detoxification (50:1, exo-AFBO: AFM{sub 1}) compared to 3A37 (0.15: 1, exo-AFBO: AFQ{sub 1}), suggesting that 1A5 is high, while 3A4 is the low affinity enzyme in turkey liver. The data support the conclusion that P450 1A5 is the dominant enzyme responsible for AFB{sub 1} bioactivation and metabolism at environmentally-relevant AFB{sub 1} concentrations in turkey liver. - Graphical abstract: Display Omitted Highlights: > Efficient bioactivation by P450s 1A5 and 3A

  3. Effects of a 4-week high-intensity interval training on pacing during 5-km running trial

    PubMed Central

    Silva, R.; Damasceno, M.; Cruz, R.; Silva-Cavalcante, M.D.; Lima-Silva, A.E.; Bishop, D.J.; Bertuzzi, R.

    2017-01-01

    This study analyzed the influence of a 4-week high-intensity interval training on the pacing strategy adopted by runners during a 5-km running trial. Sixteen male recreational long-distance runners were randomly assigned to a control group (CON, n=8) or a high-intensity interval training group (HIIT, n=8). The HIIT group performed high-intensity interval-training twice per week, while the CON group maintained their regular training program. Before and after the training period, the runners performed an incremental exercise test to exhaustion to measure the onset of blood lactate accumulation, maximal oxygen uptake (VO2max), and peak treadmill speed (PTS). A submaximal constant-speed test to measure the running economy (RE) and a 5-km running trial on an outdoor track to establish pacing strategy and performance were also done. During the 5-km running trial, the rating of perceived exertion (RPE) and time to cover the 5-km trial (T5) were registered. After the training period, there were significant improvements in the HIIT group of ∼7 and 5% for RE (P=0.012) and PTS (P=0.019), respectively. There was no significant difference between the groups for VO2max (P=0.495) or onset of blood lactate accumulation (P=0.101). No difference was found in the parameters measured during the 5-km trial before the training period between HIIT and CON (P>0.05). These findings suggest that 4 weeks of HIIT can improve some traditional physiological variables related to endurance performance (RE and PTS), but it does not alter the perception of effort, pacing strategy, or overall performance during a 5-km running trial. PMID:29069224

  4. Effects of a 4-week high-intensity interval training on pacing during 5-km running trial.

    PubMed

    Silva, R; Damasceno, M; Cruz, R; Silva-Cavalcante, M D; Lima-Silva, A E; Bishop, D J; Bertuzzi, R

    2017-10-19

    This study analyzed the influence of a 4-week high-intensity interval training on the pacing strategy adopted by runners during a 5-km running trial. Sixteen male recreational long-distance runners were randomly assigned to a control group (CON, n=8) or a high-intensity interval training group (HIIT, n=8). The HIIT group performed high-intensity interval-training twice per week, while the CON group maintained their regular training program. Before and after the training period, the runners performed an incremental exercise test to exhaustion to measure the onset of blood lactate accumulation, maximal oxygen uptake (VO2max), and peak treadmill speed (PTS). A submaximal constant-speed test to measure the running economy (RE) and a 5-km running trial on an outdoor track to establish pacing strategy and performance were also done. During the 5-km running trial, the rating of perceived exertion (RPE) and time to cover the 5-km trial (T5) were registered. After the training period, there were significant improvements in the HIIT group of ∼7 and 5% for RE (P=0.012) and PTS (P=0.019), respectively. There was no significant difference between the groups for VO2max (P=0.495) or onset of blood lactate accumulation (P=0.101). No difference was found in the parameters measured during the 5-km trial before the training period between HIIT and CON (P>0.05). These findings suggest that 4 weeks of HIIT can improve some traditional physiological variables related to endurance performance (RE and PTS), but it does not alter the perception of effort, pacing strategy, or overall performance during a 5-km running trial.

  5. Two alleles of the AtCesA3 gene in Arabidopsis thaliana display intragenic complementation.

    PubMed

    Pysh, Leonard D

    2015-09-01

    Cellulose is the most abundant biomolecule on the planet, yet the mechanism by which it is synthesized by higher plants remains largely unknown. In Arabidopsis thaliana (L.) Heynh, synthesis of cellulose in the primary cell wall requires three different cellulose synthase genes (AtCesA1, AtCesA3, and AtCesA6-related genes [AtCesA2, AtCesA5, and AtCesA6]). The multiple response expansion1 (mre1) mutant contains a hypomorphic AtCesA3 allele that results in significantly shorter, expanded roots. Crosses between mre1 and another allele of AtCesA3 (constitutive expression of VSP1, cev1) yielded an F1 with roots considerably longer and thinner than either parent, suggesting intragenic complementation. The F2 generation resulting from self-crossing these F1 showed three different root phenotypes: roots like mre1, roots like cev1, and roots like the F1. The segregation patterns of the three root phenotypes in multiple F2 and F3 generations were determined. Multiple characteristics of the roots and shoots were analyzed both qualitatively and quantitatively at different developmental stages, both on plates and on soil. The trans-heterozygous plants differed significantly from the parental mre1 and cev1 lines. The two alleles display intragenic complementation. A classic genetic interpretation of these results would suggest that cellulose synthesis requires homo-multimerization of cellulose synthase monomers. © 2015 Botanical Society of America.

  6. Polymorphic Imprinting of SLC38A4 Gene in Bovine Placenta.

    PubMed

    Xu, Da; Zhang, Cui; Li, Junliang; Wang, Guannan; Chen, Weina; Li, Dongjie; Li, Shijie

    2018-05-21

    Imprinted genes are characterized by monoallelic expression that is dependent on parental origin. Comparative analysis of imprinted genes between species is a powerful tool for understanding the biological significance of genomic imprinting. The slc38a4 gene encodes a neutral amino acid transporter and is identified as imprinted in mice. In this study, the imprinting status of SLC38A4 was assessed in bovine adult tissues and placenta using a polymorphism-based approach. Results indicate that SLC38A4 is not imprinted in eight adult bovine tissues including heart, liver, spleen, lung, kidney, muscle, fat, and brain. It was interesting to note that SLC38A4 showed polymorphic status in five heterogeneous placentas, with three exhibiting paternal monoallelic expression and two exhibiting biallelic expression. Monoallelic expression of imprinted genes is generally associated with allele-specific differentially methylation regions (DMRs) of CpG islands (CGIs)-encompassed promoter; therefore, the DNA methylation statuses of three CGIs in the SLC38A4 promoter and exon 1 region were tested in three placentas (two exhibiting paternal monoallelic and one showing biallelic expression of SLC38A4) and their corresponding paternal sperms. Unexpectedly, extreme hypomethylation (< 3%) of the DNA was observed in all the three detected placentas and their corresponding paternal sperms. The absence of DMR in bovine SLC38A4 promoter region implied that DNA methylation of these three CGIs does not directly or indirectly affect the polymorphic imprinting of SLC38A4 in bovine placenta. This suggested other epigenetic features other than DNA methylation are needed in regulating the imprinting of bovine SLC38A4, which is different from that of mouse with respect to a DMR existence at the mouse's slc38a4 promoter region. Although further work is needed, this first characterization of polymorphic imprinting status of SLC38A4 in cattle placenta provides valuable information on investigating

  7. A Bitslice Implementation of Anderson's Attack on A5/1

    NASA Astrophysics Data System (ADS)

    Bulavintsev, Vadim; Semenov, Alexander; Zaikin, Oleg; Kochemazov, Stepan

    2018-03-01

    The A5/1 keystream generator is a part of Global System for Mobile Communications (GSM) protocol, employed in cellular networks all over the world. Its cryptographic resistance was extensively analyzed in dozens of papers. However, almost all corresponding methods either employ a specific hardware or require an extensive preprocessing stage and significant amounts of memory. In the present study, a bitslice variant of Anderson's Attack on A5/1 is implemented. It requires very little computer memory and no preprocessing. Moreover, the attack can be made even more efficient by harnessing the computing power of modern Graphics Processing Units (GPUs). As a result, using commonly available GPUs this method can quite efficiently recover the secret key using only 64 bits of keystream. To test the performance of the implementation, a volunteer computing project was launched. 10 instances of A5/1 cryptanalysis have been successfully solved in this project in a single week.

  8. Cooperative binding of Annexin A5 to phosphatidylserine on apoptotic cell membranes

    NASA Astrophysics Data System (ADS)

    Janko, Christina; Jeremic, Ivica; Biermann, Mona; Chaurio, Ricardo; Schorn, Christine; Muñoz, Luis E.; Herrmann, Martin

    2013-12-01

    Healthy cells exhibit an asymmetric plasma membrane with phosphatidylserine (PS) located on the cytoplasmic leaflet of the plasma membrane bilayer. Annexin A5-FITC, a PS binding protein, is commonly used to evaluate apoptosis in flow cytometry. PS exposed by apoptotic cells serves as a major ‘eat-me’ signal for phagocytes. Although exposition of PS has been observed after alternative stimuli, no clearance of viable, PS exposing cells has been detected. Thus, besides PS exposure, membranes of viable and apoptotic cells might exhibit specific characteristics. Here, we show that Annexin A5 binds in a cooperative manner to different types of dead cells. Shrunken apoptotic cells thereby showed the highest Hill coefficient values. Contrarily, parafomaldehyde fixation of apoptotic cells completely abrogates the cooperativity effect seen with dead and dying cells. We tend to speculate that the cooperative binding of Annexin A5 to the membranes of apoptotic cells reflects higher fluidity of the exposed membranes facilitating PS clustering.

  9. Remote sensing for oceanography, hydrology and agriculture; Proceedings of Symposia A5, A3 and A9 of the COSPAR 29th Plenary Meeting, Washington, Aug. 28-Sept. 5, 1992

    NASA Technical Reports Server (NTRS)

    Gower, J. F. R. (Editor); Salomonson, V. V. (Editor); Engman, E. T. (Editor); Ormsby, J. P. (Editor); Gupta, R. K. (Editor)

    1993-01-01

    New results from satellite studies of the ocean and radar mapping of the earth are presented. Atttention is given to data from the ERS-1 satellite. Synthetic aperture radar mapping of land surface features and sea ice, radar backscatter measurements, and orbit altitude measurements are discussed. The use of remote sensing in hydrology, soil moisture determination, precipitation measurement, agricultural meteorology, and crop growth estimation is reviewed.

  10. Interferometer using a 3 × 3 coupler and Faraday mirrors

    NASA Astrophysics Data System (ADS)

    Breguet, J.; Gisin, N.

    1995-06-01

    A new interferometric setup using a 3 \\times 3 coupler and two Faraday mirrors is presented. It has the advantages of being built only with passive components, of freedom from the polarization fading problem, and of operation with a LED. It is well suited for sensing time-dependent signals and does not depend on reciprocal or nonreciprocal constant perturbations.

  11. Verminous arteritis in a 3-month-old thoroughbred foal.

    PubMed

    DeLay, J; Peregrine, A S; Parsons, D A

    2001-04-01

    Strongylus vulgaris migration and cranial mesenteric arterial thrombus formation resulted in fatal colic in a 3-month-old Thoroughbred foal. Vascular damage associated with S. vulgaris occurs early in the course of infection and, despite widespread use of broad-spectrum anthelmintics, appropriate management is still essential to minimize exposure of young animals to this parasite.

  12. Verminous arteritis in a 3-month-old thoroughbred foal.

    PubMed Central

    DeLay, J; Peregrine, A S; Parsons, D A

    2001-01-01

    Strongylus vulgaris migration and cranial mesenteric arterial thrombus formation resulted in fatal colic in a 3-month-old Thoroughbred foal. Vascular damage associated with S. vulgaris occurs early in the course of infection and, despite widespread use of broad-spectrum anthelmintics, appropriate management is still essential to minimize exposure of young animals to this parasite. PMID:11326632

  13. A 3D Serious City Building Game on Waste Disposal

    ERIC Educational Resources Information Center

    Cuccurullo, Stefania; Francese, Rita; Passero, Ignazio; Tortora, Genoveffa

    2013-01-01

    The environmental priority requires structural interventions that will be effective in the long period only if they are accompanied by modifications of behaviors, orientations and beliefs, specially investing in the new generations. This paper presents a 3D Virtual World serious game named Pappi World, designed according to pedagogical theories…

  14. The Coulomb problem on a 3-sphere and Heun polynomials

    SciTech Connect

    Bellucci, Stefano; Yeghikyan, Vahagn; Yerevan State University, Alex-Manoogian st. 1, 00025 Yerevan

    2013-08-15

    The paper studies the quantum mechanical Coulomb problem on a 3-sphere. We present a special parametrization of the ellipto-spheroidal coordinate system suitable for the separation of variables. After quantization we get the explicit form of the spectrum and present an algebraic equation for the eigenvalues of the Runge-Lentz vector. We also present the wave functions expressed via Heun polynomials.

  15. ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

    PubMed Central

    Fares-Taie, Lucas; Gerber, Sylvie; Chassaing, Nicolas; Clayton-Smith, Jill; Hanein, Sylvain; Silva, Eduardo; Serey, Margaux; Serre, Valérie; Gérard, Xavier; Baumann, Clarisse; Plessis, Ghislaine; Demeer, Bénédicte; Brétillon, Lionel; Bole, Christine; Nitschke, Patrick; Munnich, Arnold; Lyonnet, Stanislas; Calvas, Patrick; Kaplan, Josseline; Ragge, Nicola; Rozet, Jean-Michel

    2013-01-01

    Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans. PMID:23312594

  16. ALDH1A3 mutations cause recessive anophthalmia and microphthalmia.

    PubMed

    Fares-Taie, Lucas; Gerber, Sylvie; Chassaing, Nicolas; Clayton-Smith, Jill; Hanein, Sylvain; Silva, Eduardo; Serey, Margaux; Serre, Valérie; Gérard, Xavier; Baumann, Clarisse; Plessis, Ghislaine; Demeer, Bénédicte; Brétillon, Lionel; Bole, Christine; Nitschke, Patrick; Munnich, Arnold; Lyonnet, Stanislas; Calvas, Patrick; Kaplan, Josseline; Ragge, Nicola; Rozet, Jean-Michel

    2013-02-07

    Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  17. A 3D stand generator for central Appalachian hardwood forests

    Treesearch

    Jingxin Wang; Yaoxiang Li; Gary W. Miller

    2002-01-01

    A 3-dimensional (3D) stand generator was developed for central Appalachian hardwood forests. It was designed for a harvesting simulator to examine the interactions of stand, harvest, and machine. The Component Object Model (COM) was used to design and implement the program. Input to the generator includes species composition, stand density, and spatial pattern. Output...

  18. 8 CFR 213a.3 - Notice of change of address.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... SUPPORT ON BEHALF OF IMMIGRANTS § 213a.3 Notice of change of address. (a)(1) If the address of a sponsor... obligation under the affidavit of support remains in effect with respect to any sponsored immigrant, the... 213A(d)(2)(A) of the Act. (ii) If the sponsor, knowing that the sponsored immigrant has received any...

  19. 42 CFR 54a.3 - Nondiscrimination against religious organizations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.3 Nondiscrimination against religious... participate in applicable programs as long as their services are provided consistent with the Establishment... organizations the same eligibility conditions in applicable programs as are applied to any other nonprofit...

  20. 42 CFR 54a.3 - Nondiscrimination against religious organizations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.3 Nondiscrimination against religious... participate in applicable programs as long as their services are provided consistent with the Establishment... organizations the same eligibility conditions in applicable programs as are applied to any other nonprofit...

  1. 42 CFR 54a.3 - Nondiscrimination against religious organizations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.3 Nondiscrimination against religious... participate in applicable programs as long as their services are provided consistent with the Establishment... organizations the same eligibility conditions in applicable programs as are applied to any other nonprofit...

  2. 42 CFR 54a.3 - Nondiscrimination against religious organizations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES § 54a.3 Nondiscrimination against religious... participate in applicable programs as long as their services are provided consistent with the Establishment... organizations the same eligibility conditions in applicable programs as are applied to any other nonprofit...

  3. 29 CFR 1912a.3 - Terms of membership.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for a...

  4. 29 CFR 1912a.3 - Terms of membership.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for a...

  5. 29 CFR 1912a.3 - Terms of membership.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for a...

  6. 26 CFR 1.401(a)(4)-7 - Imputation of permitted disparity.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... + permitted disparity rate (3) Employees whose plan year compensation exceeds taxable wage base. If an... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Imputation of permitted disparity. 1.401(a)(4)-7... Imputation of permitted disparity. (a) Introduction. In determining whether a plan satisfies section 401(a)(4...

  7. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain...

  8. Cree antidiabetic plant extracts display mechanism-based inactivation of CYP3A4.

    PubMed

    Tam, Teresa W; Liu, Rui; Arnason, John T; Krantis, Anthony; Staines, William A; Haddad, Pierre S; Foster, Brian C

    2011-01-01

    Seventeen Cree antidiabetic medicinal plants were studied to determine their potential to inhibit cytochrome P450 3A4 (CYP3A4) through mechanism-based inactivation (MBI). The ethanolic extracts of the medicinal plants were studied for their inhibition of CYP3A4 using the substrates testosterone and dibenzylfluorescein (DBF) in high pressure liquid chromatography (HPLC) and microtiter fluorometric assays, respectively. Using testosterone as a substrate, extracts of Alnus incana, Sarracenia purpurea, and Lycopodium clavatum were identified as potent CYP3A4 MBIs, while those from Abies balsamea, Picea mariana, Pinus banksiana, Rhododendron tomentosum, Kalmia angustifolia, and Picea glauca were identified as less potent inactivators. Not unexpectedly, the other substrate, DBF, showed a different profile of inhibition. Only A. balsamea was identified as a CYP3A4 MBI using DBF. Abies balsamea displayed both NADPH- and time-dependence of CYP3A4 inhibition using both substrates. Overall, several of the medicinal plants may markedly deplete CYP3A4 through MBI and, consequently, decrease the metabolism of CYP3A4 substrates including numerous medications used by diabetics.

  9. Developmental expression of SLC26A4 (Pendrin) during amelogenesis in developing rodent teeth

    PubMed Central

    Bronckers, Antonius LJJ; Guo, Jing; Zandieh-Doulabi, Behrouz; Bervoets, Theodore J; Lyaruu, Donacian M.; Li, Xiangming; Wangemann, Philine; DenBesten, Pamela

    2012-01-01

    Ameloblasts need to regulate pH during formation of enamel crystals, a process that generates protons. Solute carrier family 26A member 4 (SLC26A4, or pendrin) is an anion exchanger for chloride, bicarbonate, iodine and formate. It is expressed in apical membranes of ion-transporting epithelia in kidney, inner ear and thyroid where it regulates luminal pH and fluid transport. We hypothesized that maturation ameloblasts express SLC26A4 to neutralize acidification of enamel fluid in forming enamel. In rodents, secretory and maturation ameloblasts were immunopositive for SLC26A4. Staining was particularly strong in apical membranes of maturation ameloblasts facing forming enamel. RT-PCR confirmed the presence of mRNA transcripts for Slc26a4 in enamel organs. SLC26A4 immunostaining was also found in mineralizing connective tissues including odontoblasts, osteoblasts, osteocytes, osteoclasts, bone lining cells, cellular cementoblasts and cementocytes. However, Slc26a4-null mutant mice had no overt dental phenotype. The presence of SLC26A4 in apical plasma membranes of maturation ameloblasts is consistent with a potential function as pH regulator. SLC26A4 does not appear critical for ameloblast functioning and is likely compensated by other pH regulators. PMID:22243245

  10. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...)(4)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table... rate group. (4) Examples. § 1.401(a)(4)-3Nondiscrimination in amount of employer-provided benefits...

  11. 26 CFR 1.1402(a)-4 - Rentals from real estate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 12 2013-04-01 2013-04-01 false Rentals from real estate. 1.1402(a)-4 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(a)-4 Rentals from real estate. (a) In general. Rentals from real estate and from personal property leased with the real estate...

  12. 26 CFR 1.1402(a)-4 - Rentals from real estate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 12 2014-04-01 2014-04-01 false Rentals from real estate. 1.1402(a)-4 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(a)-4 Rentals from real estate. (a) In general. Rentals from real estate and from personal property leased with the real estate...

  13. 26 CFR 1.1402(a)-4 - Rentals from real estate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 12 2012-04-01 2012-04-01 false Rentals from real estate. 1.1402(a)-4 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(a)-4 Rentals from real estate. (a) In general. Rentals from real estate and from personal property leased with the real estate...

  14. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Calculation of income inclusion. [Reserved] 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Calculation of income inclusion. [Reserved] ...

  15. 26 CFR 1.5000A-4 - Computation of shared responsibility payment.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 13 2014-04-01 2014-04-01 false Computation of shared responsibility payment. 1.5000A-4 Section 1.5000A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... individual was born. For example, an individual born on March 1, 1999, attains the age of 18 on March 1, 2017...

  16. Analysis of CYP3A4 genetic polymorphisms in Han Chinese.

    PubMed

    Zhou, Qing; Yu, Xiaomin; Shu, Chang; Cai, Yimei; Gong, Wei; Wang, Xumin; Wang, Duen-mei; Hu, Songnian

    2011-06-01

    Our study aimed to comprehensively investigate the genetic polymorphisms of CYP3A4 in Han Chinese. We sequenced the gene regions of CYP3A4, including its promoter, exons, surrounding introns and 3' untranslated region (3'UTR), from 100 unrelated-healthy Han Chinese individuals. We detected 11 SNPs, three of which are novel. According to in silico functional prediction of novel variants, 20148 A>G in exon 10, resulting in substitution of Tyr319 with Cys (CYP3A4*21), may induce dramatic alteration of protein conformation, and 26908 G>A in 3'UTR may disrupt post-transcriptional regulation. We identified five alleles in Han Chinese, the allele frequencies of CYP3A4*1, *5, *6, *18 and *21 are 97, 0.5, 1, 1 and 0.5%, respectively. Haplotype inference revealed 14 haplotypes, of which the major haplotype CYP3A4*1A constitutes 59% of the total chromosomes. We also examined the possible role of natural selection in shaping the variation of CYP3A4 and confirmed a trend, consistent with the action of positive selection. We systematically screened the genetic polymorphisms of CYP3A4 in Han Chinese, highlighted possible functional impairment of the novel allele and summarized the distinct allele and haplotype frequency distribution, with an emphasis on detecting the footprint of recent positive selection on the CYP3A4 gene in Han Chinese.

  17. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain...

  18. Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population.

    PubMed

    Hu, Guo-Xin; Dai, Da-Peng; Wang, Hao; Huang, Xiang-Xin; Zhou, Xiao-Yang; Cai, Jie; Chen, Hao; Cai, Jian-Ping

    2017-03-01

    To systematically investigate the genetic polymorphisms of the CYP3A4 gene in a Han Chinese population. The promoter and exons of CYP3A4 gene in 1114 unrelated, healthy Han Chinese subjects were amplified and genotyped by direct sequencing. In total, five previously reported alleles (*1G, *4, *5, *18B and *23) were detected, of which one allele (*23) was reported for the first time in Han Chinese population. Additionally, seven novel exonic variants were also identified and designated as new alleles CYP3A4*28-*34. This study provides the most comprehensive data of CYP3A4 polymorphisms in Han Chinese population and detects the largest number of novel CYP3A4 alleles in one ethnic group.

  19. Spinal meningeal melanocytoma in a 5-year-old child: a case report and review of literature.

    PubMed

    Salah El-Din, Ahmed M; Aboul-Ela, Hashem M; Alsawy, Mohamed F; Koheil, Ahmed; Ashry, Ahmed H

    2018-01-01

    Meningeal melanocytoma is considered a rare lesion arising from leptomeningeal melanocytes. Nearly two thirds of meningeal melanocytomas were reported in the intracranial compartment and the remaining one third in the spine. Spinal melanocytomas can be extradural or intradural, with extradural variant being more common, and the majority of cases have been single reports. A 5-year-old male presented with a 4-month history of non-radiating low back pain persistent at rest, with otherwise non-remarkable medical history. The patient was neurologically intact with no deficits. Preoperatively, routine laboratory investigations were non-remarkable. MRI imaging was done and showed a lesion at the level of T11 to L4, hyperintense on T1 and hypointense on T2 with homogenous contrast enhancement. Intraoperatively, the lesion was hemorrhagic, brownish, and rubbery in consistency attached to the ventral dura. Microscopic picture revealed dense cytoplasmic brown melanin pigments, with no significant mitoses or nuclear atypia. What is unique about our case is the age of the patient (5 years). To the best of our knowledge, after reviewing the literature, this is the youngest case to be reported. SMM is an extremely rare tumor with a benign course. Complete surgical excision should be attempted. Age of presentation may be as young as in our case and the diagnosis of such a tumor should never be excluded in this early age group with persistent low back ache.

  20. Preliminary findings of a 4-month Tai Chi intervention on tenderness, functional capacity, symptomatology, and quality of life in men with fibromyalgia.

    PubMed

    Carbonell-Baeza, Ana; Romero, Alejandro; Aparicio, Virginia A; Ortega, Francisco B; Tercedor, Pablo; Delgado-Fernández, Manuel; Ruiz, Jonatan R

    2011-09-01

    The study aimed to determine the effects of a 4-month Tai Chi intervention on tenderness, functional capacity, symptomatology, and quality of life in men with fibromyalgia. The effect of a 3-month detraining period was also analyzed. Six men with fibromyalgia (age 52.3 ± 9.3 years) followed a 4-month Tai Chi intervention. The outcome variables were tenderness, functional capacity (30-second chair stand, handgrip strength, chair sit and reach, back scratch, blind flamingo, 8 feet up and go, and 6-minute walk tests), and self-administered questionnaires. A significant improvement (p = .028) after the intervention period for the chair sit and reach test was found, such improvement was maintained after the detraining phase. Tenderness, symptomatology, and quality of life did not significantly change after the intervention period or the detraining phase. In summary, a 4-month Tai Chi intervention improved lower body flexibility in men with fibromyalgia. This improvement persisted after the detraining period.