Science.gov

Sample records for a0 a1 a2

  1. Rotational velocity distribution of A stars: Searching for intrinsic slowly rotating normal A0-A1 stars

    NASA Astrophysics Data System (ADS)

    Royer, F.; Gebran, M.; Monier, R.; Caraty, Y.; Kiliçoğlu, T.; Pintado, O.; Adelman, S.; Smalley, B.; Reiners, A.; Hill, G.; Gulliver, A.

    2012-12-01

    Royer et al. (2007) showed that the distribution of rotational velocities for A0-A1 stars is bimodal although all known peculiar and/or binary stars had been excluded from their sample. We present here the preliminary results of the abundance analysis for 47 A0-A1 ``normal'' main sequence stars selected with v sin i slower than 65 kms. These high signal-to-noise spectra collected with ÉLODIE and SOPHIE (OHP) will allow us to obtain a clean sample of low v sin i normal A0-A1 stars and search for intrinsic slow rotators.

  2. Cleavage of a Recombinant Human Immunoglobulin A2 (IgA2)-IgA1 Hybrid Antibody by Certain Bacterial IgA1 Proteases

    PubMed Central

    Senior, Bernard W.; Dunlop, James I.; Batten, Margaret R.; Kilian, Mogens; Woof, Jenny M.

    2000-01-01

    To understand more about the factors influencing the cleavage of immunoglobulin A1 (IgA1) by microbial IgA1 proteases, a recombinant human IgA2/IgA1 hybrid molecule was generated. In the hybrid, termed IgA2/A1 half hinge, a seven-amino-acid sequence corresponding to one half of the duplicated sequence making up the IgA1 hinge was incorporated into the equivalent site in IgA2. Insertion of the IgA1 half hinge into IgA2 did not affect antigen binding capacity or the functional activity of the hybrid molecule, as judged by its ability to bind to IgA Fcα receptors and trigger respiratory bursts in neutrophils. Although the IgA2/A1 hybrid contained only half of the IgA1 hinge, it was found to be cleaved by a variety of different bacterial IgA1 proteases, including representatives of those that cleave IgA1 in the different duplicated halves of the hinge, namely, those of Prevotella melaninogenica, Streptococcus pneumoniae, S. sanguis, Neisseria meningitidis types 1 and 2, N. gonorrhoeae types 1 and 2, and Haemophilus influenzae type 2. Thus, for these enzymes the recognition site for IgA1 cleavage is contained within half of the IgA1 hinge region; additional distal elements, if required, are provided by either an IgA1 or an IgA2 framework. In contrast, the IgA2/A1 hybrid appeared to be resistant to cleavage with S. oralis and some H. influenzae type 1 IgA1 proteases, suggesting these enzymes require additional determinants for efficient substrate recognition. PMID:10639405

  3. Cleavage of a recombinant human immunoglobulin A2 (IgA2)-IgA1 hybrid antibody by certain bacterial IgA1 proteases.

    PubMed

    Senior, B W; Dunlop, J I; Batten, M R; Kilian, M; Woof, J M

    2000-02-01

    To understand more about the factors influencing the cleavage of immunoglobulin A1 (IgA1) by microbial IgA1 proteases, a recombinant human IgA2/IgA1 hybrid molecule was generated. In the hybrid, termed IgA2/A1 half hinge, a seven-amino-acid sequence corresponding to one half of the duplicated sequence making up the IgA1 hinge was incorporated into the equivalent site in IgA2. Insertion of the IgA1 half hinge into IgA2 did not affect antigen binding capacity or the functional activity of the hybrid molecule, as judged by its ability to bind to IgA Fcalpha receptors and trigger respiratory bursts in neutrophils. Although the IgA2/A1 hybrid contained only half of the IgA1 hinge, it was found to be cleaved by a variety of different bacterial IgA1 proteases, including representatives of those that cleave IgA1 in the different duplicated halves of the hinge, namely, those of Prevotella melaninogenica, Streptococcus pneumoniae, S. sanguis, Neisseria meningitidis types 1 and 2, N. gonorrhoeae types 1 and 2, and Haemophilus influenzae type 2. Thus, for these enzymes the recognition site for IgA1 cleavage is contained within half of the IgA1 hinge region; additional distal elements, if required, are provided by either an IgA1 or an IgA2 framework. In contrast, the IgA2/A1 hybrid appeared to be resistant to cleavage with S. oralis and some H. influenzae type 1 IgA1 proteases, suggesting these enzymes require additional determinants for efficient substrate recognition. PMID:10639405

  4. Atomic-resolution studies of epitaxial strain release mechanisms in L a1.85S r0.15Cu O4 /L a0.67C a0.33Mn O3 superlattices

    NASA Astrophysics Data System (ADS)

    Biškup, N.; Das, S.; Gonzalez-Calbet, J. M.; Bernhard, C.; Varela, M.

    2015-05-01

    In this paper we present an atomic-resolution electron microscopy study of superlattices (SLs) where the colossal magnetoresistant manganite L a0.67C a0.33Mn O3 (LCMO) and the high critical temperature superconducting cuprate L a1.85S r0.15Cu O4 (LSCO) are combined. Although good quality epitaxial growth can be achieved, both the choice of substrate and the relatively large lattice mismatch between these materials (around 2%) have a significant impact on the system properties [Phys. C 468, 991 (2008), 10.1016/j.physc.2008.05.001; Nature (London) 394, 453 (1998), 10.1038/28810]. Our samples, grown by pulsed laser deposition, are epitaxial and exhibit high structural quality. By means of cutting-edge electron microscopy and spectroscopy techniques we still find that the epitaxial strain is accommodated by a combination of defects, such as interface steps and antiphase boundaries in the manganite. These defects result in inhomogeneous strain fields through the samples. Also, some chemical inhomogeneities are detected, up to the point that novel phases nucleate. For example, at the LCMO/LSCO interface the AB O3 -type manganite adopts a tetragonal LSCO-like structure forming localized layers that locally resemble the composition of L a2 /3C a4 /3Mn O4 . Structural distortions are detected in the cuprate as well, which may extend over lateral distances of several unit cells. Finally, we also analyze the influence of the substrate-induced strain by examining superlattices grown on two different substrates: (LaAlO3) 0.3(Sr2AlTaO6 ) 0.7 (LSAT) and LaSrAl O4 (LSAO). We observe that SLs grown on LSAT, which are nonsuperconducting, present reduced values of the c axis compared to superlattices grown on LSAO (which are fully superconducting). This finding points to the fact that the proper distance between copper planes in LSCO is essential in obtaining superconductivity in cuprates.

  5. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 2 2013-01-01 2013-01-01 false Determination of A1 and A2 A Appendix A to Part 71 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Pt. 71, App. A Appendix A to Part 71—Determination of A1 and A2 I. Values of A1 and A2 for individual radionuclides, which are the bases for many...

  6. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Determination of A1 and A2 A Appendix A to Part 71 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Pt. 71, App. A Appendix A to Part 71—Determination of A1 and A2 I. Values of A1 and A2 for individual radionuclides, which are the bases for many...

  7. Lattice equations arising from discrete Painlevé systems. I. (A2 + A1)(1) and ( A 1 + A1 ' ) ( 1 ) cases

    NASA Astrophysics Data System (ADS)

    Joshi, Nalini; Nakazono, Nobutaka; Shi, Yang

    2015-09-01

    We introduce the concept of ω-lattice, constructed from τ functions of Painlevé systems, on which quad-equations of ABS (Adler-Bobenko-Suris) type appear. In particular, we consider the A5 ( 1 ) - and A6 ( 1 ) -surface q-Painlevé systems corresponding affine Weyl group symmetries are of (A2 + A1)(1)- and (A1 + A1)(1)-types, respectively.

  8. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    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 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  9. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    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 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  10. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    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 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  11. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    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 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  12. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    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 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  13. Affine Kac-Moody symmetric spaces related with A1^{(1)}, A2^{(1)},} A2^{(2)}

    NASA Astrophysics Data System (ADS)

    Nayak, Saudamini; Pati, K. C.

    2014-08-01

    Symmetric spaces associated with Lie algebras and Lie groups which are Riemannian manifolds have recently got a lot of attention in various branches of Physics for their role in classical/quantum integrable systems, transport phenomena, etc. Their infinite dimensional counter parts have recently been discovered which are affine Kac-Moody symmetric spaces. In this paper we have (algebraically) explicitly computed the affine Kac-Moody symmetric spaces associated with affine Kac-Moody algebras A1^{(1)}, A2^{(1)}, A2^{(2)}. We hope these types of spaces will play similar roles as that of symmetric spaces in many physical systems.

  14. EphA2 Receptor Activation by Monomeric Ephrin-A1 on Supported Membranes

    PubMed Central

    Xu, Qian; Lin, Wan-Chen; Petit, Rebecca S.; Groves, Jay T.

    2011-01-01

    The receptor tyrosine kinase EphA2 interacts with its glycosylphosphatidylinositol (GPI)-linked ephrin-A1 ligand in a juxtacrine configuration. The soluble ephrin-A1 protein, without its GPI membrane linker, fails to activate EphA2. However, preclustered ephrin-A1 protein is active in solution and has been frequently used to trigger the EphA2 receptor. Although this approach has yielded insights into EphA2 signaling, preclustered ligands bypass natural receptor clustering processes and thus mask any role of clustering as a signal regulatory mechanism. Here, we present EphA2-expressing cells with a fusion protein of monomeric ephrin-A1 (mEA1) and enhanced monomeric yellow fluorescent protein that is linked to a supported lipid bilayer via a nickel-decahistidine anchor. The mEA1 is homogeneously dispersed, laterally mobile, and monomeric as measured by fluorescence imaging, correlation spectroscopy, and photon counting histogram analysis, respectively. Ephrin-A1 presented in this manner activates EphA2 on the surface of MDA-MB-231 human breast cancer cells, as measured by EphA2 phosphorylation and degradation. Spatial mutation experiments in which nanopatterns on the underlying substrate restrict mEA1 movement in the supported lipid bilayer reveal spatio-mechanical regulation of this signaling pathway, consistent with recently reported observations using a synthetically cross-linked ephrin-A1 dimer. PMID:22261062

  15. Structure of the nucleotide-binding subunit B of the energy producer A1A0 ATP synthase in complex with adenosine diphosphate.

    PubMed

    Kumar, Anil; Manimekalai, Malathy Sony Subramanian; Grüber, Gerhard

    2008-11-01

    A1A0 ATP synthases are the major energy producers in archaea. Like the related prokaryotic and eukaryotic F1F0 ATP synthases, they are responsible for most of the synthesis of adenosine triphosphate. The catalytic events of A1A0 ATP synthases take place inside the A3B3 hexamer of the A1 domain. Recently, the crystallographic structure of the nucleotide-free subunit B of Methanosarcina mazei Gö1 A1A0 ATP synthase has been determined at 1.5 A resolution. To understand more about the nucleotide-binding mechanism, a protocol has been developed to crystallize the subunit B-ADP complex. The crystallographic structure of this complex has been solved at 2.7 A resolution. The ADP occupies a position between the essential phosphate-binding loop and amino-acid residue Phe149, which are involved in the binding of the antibiotic efrapeptin in the related F1F0 ATP synthases. This trapped ADP location is about 13 A distant from its final binding site and is therefore called the transition ADP-binding position. In the trapped ADP position the structure of subunit B adopts a different conformation, mainly in its C-terminal domain and also in the final nucleotide-binding site of the central alphabeta-domain. This atomic model provides insight into how the substrate enters into the nucleotide-binding protein and thereby into the catalytic A3B3 domain. PMID:19020348

  16. Fluorine substitution enhanced photovoltaic performance of a D-A(1)-D-A(2) copolymer.

    PubMed

    Dang, Dongfeng; Chen, Weichao; Yang, Renqiang; Zhu, Weiguo; Mammo, Wendimagegn; Wang, Ergang

    2013-10-18

    A new alternating donor-acceptor (D-A1-D-A2) copolymer containing two electron-deficient moieties, isoindigo and quinoxaline, was synthesized. The photovoltaic performance of this polymer could be improved by incorporating fluorine atoms into the quinoxaline units, resulting in an efficiency of 6.32%. This result highlights the attractive promise of D-A1-D-A2 copolymers for high-performance bulk heterojunction solar cells. PMID:24000353

  17. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...-GENERAL REQUIREMENTS FOR SHIPMENTS AND PACKAGINGS Class 7 (Radioactive) Materials § 173.435 Table of A1... Radioactive Material, No. TS-R-1” (IBR, see § 171.7 of this subchapter). b The values of A1 and A2 in curies... rate of decay or a measurement of the radiation level at a prescribed distance from the source. d...

  18. Adenosine A1, but not A2, receptor blockade increases anxiety and arousal in Zebrafish.

    PubMed

    Maximino, Caio; Lima, Monica G; Olivera, Karen R M; Picanço-Diniz, Domingos L W; Herculano, Anderson M

    2011-09-01

    Adenosinergic systems have been implicated in anxiety-like states, as caffeine can induce a state of anxiety in human beings. Caffeine is an antagonist at A(1) and A(2) adenosine receptors but it remains unclear whether anxiety is mediated by one or both of these. As the adenosinergic system is rather conserved, we opted to pursue these questions using zebrafish, a widely used model organism in genetics and developmental biology. Zebrafish adenosine 1. 2A.1 and 2A.2 receptors conserve histidine residues in TM6 and TM7 that are responsible for affinity in bovine A1 receptor. We investigated the effects of caffeine, PACPX (an A(1) receptor antagonist) and 1,3-dimethyl-1-propargylxanthine (DMPX) (an A(2) receptor antagonist) on anxiety-like behaviour and locomotor activity of zebrafish in the scototaxis test as well as evaluated the effects of these drugs on pigment aggregation. Caffeine increased anxiety at the dose of 100 mg/kg, while locomotion at the dose of 10 mg/kg was increased. Both doses of 10 and 100 mg/kg induced pigment aggregation. PACPX, on the other hand, increased anxiety at a dose of 6 mg/kg and induced pigment aggregation at the doses of 0.6 and 6 mg/kg, but did not produce a locomotor effect. DMPX, in turn, increased locomotion at the dose of 6 mg/kg but did not produce any effect on pigment aggregation or anxiety-like behaviour. These results indicate that blockade of A(1)-R, but not A(2)-R, induces anxiety and autonomic arousal, while the blockade of A(2)-R induces hyperlocomotion. Thus, as in rodents, caffeine's anxiogenic and arousing effects are probably mediated by A(1) receptors in zebrafish and its locomotor activating effect is probably mediated by A(2) receptors. PMID:21496211

  19. A Function for the hnRNP A1/A2 Proteins in Transcription Elongation

    PubMed Central

    Lemieux, Bruno; Blanchette, Marco; Monette, Anne; Mouland, Andrew J.; Wellinger, Raymund J.; Chabot, Benoit

    2015-01-01

    The hnRNP A1 and A2 proteins regulate processes such as alternative pre-mRNA splicing and mRNA stability. Here, we report that a reduction in the levels of hnRNP A1 and A2 by RNA interference or their cytoplasmic retention by osmotic stress drastically increases the transcription of a reporter gene. Based on previous work, we propose that this effect may be linked to a decrease in the activity of the transcription elongation factor P-TEFb. Consistent with this hypothesis, the transcription of the reporter gene was stimulated when the catalytic component of P-TEFb, CDK9, was inhibited with DRB. While low levels of A1/A2 stimulated the association of RNA polymerase II with the reporter gene, they also increased the association of CDK9 with the repressor 7SK RNA, and compromised the recovery of promoter-distal transcription on the Kitlg gene after the release of pausing. Transcriptome analysis revealed that more than 50% of the genes whose expression was affected by the siRNA-mediated depletion of A1/A2 were also affected by DRB. RNA polymerase II-chromatin immunoprecipitation assays on DRB-treated and A1/A2-depleted cells identified a common set of repressed genes displaying increased occupancy of polymerases at promoter-proximal locations, consistent with pausing. Overall, our results suggest that lowering the levels of hnRNP A1/A2 elicits defective transcription elongation on a fraction of P-TEFb-dependent genes, hence favoring the transcription of P-TEFb-independent genes. PMID:26011126

  20. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Table of A1 and A2 values for radionuclides. 173.435 Section 173.435 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS SHIPPERS-GENERAL REQUIREMENTS FOR SHIPMENTS...

  1. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Table of A1 and A2 values for radionuclides. 173.435 Section 173.435 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS REGULATIONS SHIPPERS-GENERAL REQUIREMENTS FOR SHIPMENTS...

  2. 127. POWER PANEL A1 AND A2 MASTER SHUTOFFS FOR PRIMARY ...

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

    127. POWER PANEL A1 AND A2 MASTER SHUTOFFS FOR PRIMARY POWER ON EAST WALL OF TRANSFORMER ROOM (112), LSB (BLDG. 770) - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

  3. 2-Aminopyrimidines as dual adenosine A1/A2A antagonists.

    PubMed

    Robinson, Sarel J; Petzer, Jacobus P; Terre'Blanche, Gisella; Petzer, Anél; van der Walt, Mietha M; Bergh, Jacobus J; Lourens, Anna C U

    2015-11-01

    In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A2A receptor antagonists. PMID:26462195

  4. Total synthesis of proanthocyanidin A1, A2, and their stereoisomers.

    PubMed

    Sharma, Pradeep K; Romanczyk, Leo J; Kondaveti, Leelakrishna; Reddy, Bollu; Arumugasamy, Jeeva; Lombardy, Richard; Gou, Yanni; Schroeter, Hagen

    2015-05-15

    The first novel stereoselective synthesis of naturally occurring A1 (1) and A2 proanthocyanidins (2) has been achieved. The key synthetic steps involved (a) the formation of a coupled product (13 or 14) between an open chain C-ring C-4 hydroxyethoxy analogue of either (+)-catechin or (-)-epicatechin with 5,7,3',3'-tetra-O-benzyl-(+)-catechin/-(-)-epicatechin in the presence of bentonite clay K-10, (b) removal of benzyl protecting groups under mild catalytic hydrogenation conditions to form the desired A-type compound in situ as a mixture of diastereomers via ketal/oxonium ion/carbonium ion formation, and (c) separation of the diasteromers via silica gel column chromatography. The structures of A1 and A2 proanthocyanidins were unequivocally established by analytical comparison to the natural products. Following this methodology, an additional six diastereomers of proanthocyanidins A1 and A2 have been synthesized. A plausible mechanism for the formation of the A-type linkage in proanthocyanidins has been proposed. PMID:25927567

  5. Mass spectrometry-based ligand binding assays on adenosine A1 and A2A receptors.

    PubMed

    Massink, A; Holzheimer, M; Hölscher, A; Louvel, J; Guo, D; Spijksma, G; Hankemeier, T; IJzerman, A P

    2015-12-01

    Conventional methods to measure ligand-receptor binding parameters typically require radiolabeled ligands as probes. Despite the robustness of radioligand binding assays, they carry inherent disadvantages in terms of safety precautions, expensive synthesis, special lab requirements, and waste disposal. Mass spectrometry (MS) is a method that can selectively detect ligands without the need of a label. The sensitivity of MS equipment increases progressively, and currently, it is possible to detect low ligand quantities that are usually found in ligand binding assays. We developed a label-free MS ligand binding (MS binding) assay on the adenosine A(1) and A(2A) receptors (A(1)AR and A(2A)AR), which are well-characterized members of the class A G protein-coupled receptor (GPCR) family. Radioligand binding assays for both receptors are well established, and ample data is available to compare and evaluate the performance of an MS binding assay. 1,3-Dipropyl-8-cyclopentyl-xanthine (DPCPX) and 4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol (ZM-241,385) are high-affinity ligands selective for the A(1)AR and A(2A)AR, respectively. To proof the feasibility of MS binding on the A(1)AR and A(2A)AR, we first developed an MS detection method for unlabeled DPCPX and ZM-241,385. To serve as internal standards, both compounds were also deuterium-labeled. Subsequently, we investigated whether the two unlabeled compounds could substitute for their radiolabeled counterparts as marker ligands in binding experiments, including saturation, displacement, dissociation, and competition association assays. Furthermore, we investigated the accuracy of these assays if the use of internal standards was excluded. The results demonstrate the feasibility of the MS binding assay, even in the absence of a deuterium-labeled internal standard, and provide great promise for the further development of label-free assays based on MS for other GPCRs. PMID

  6. Role of adenosine A1 and A2A receptors in the alcohol withdrawal syndrome.

    PubMed

    Kaplan, G B; Bharmal, N H; Leite-Morris, K A; Adams, W R

    1999-10-01

    The role of adenosine receptor-mediated signaling was examined in the alcohol withdrawal syndrome. CD-1 mice received a liquid diet containing ethanol (6.7%, v/v) or a control liquid diet that were abruptly discontinued after 14 days of treatment. Mice consuming ethanol showed a progressive increase in signs of intoxication throughout the drinking period. Following abrupt discontinuation of ethanol diet, mice demonstrated reversible signs of handling-induced hyperexcitability that were maximal between 5-8 h. Withdrawing mice received treatment with adenosine receptor agonists at the onset of peak withdrawal (5.5 h) and withdrawal signs were blindly rated (during withdrawal hours 6 and 7). Adenosine A1-receptor agonist R-N6(phenylisopropyl)adenosine (0.15 and 0.3 mg/ kg) reduced withdrawal signs 0.5 and 1.5 h after drug administration in a dose-dependent fashion. Adenosine A2A-selective agonist 2-p-(2-carboxyethyl)phenylethyl-amino-5'-N-ethylcarboxamidoadenosine (0.3 mg/kg) reduced withdrawal signs at both time points. In ethanol-withdrawing mice, there were significant decreases in adenosine transporter sites in striatum without changes in cortex or cerebellum. In ethanol-withdrawing mice, there were no changes in adenosine A1 and A2A receptor concentrations in cortex, striatum, or cerebellum. There appears to be a role for adenosine A1 and A2A receptors in the treatment of the ethanol withdrawal syndrome. Published by Elsevier Science Inc. PMID:10548160

  7. Conical intersections between X2A1 and A2B2 electronic states of NO

    NASA Astrophysics Data System (ADS)

    Sardar, Subhankar; Mukherjee, Saikat; Paul, Amit Kumar; Adhikari, Satrajit

    2013-04-01

    We explore both the general symmetry-allowed accidental (SAA) conical intersections (CIs) and Renner-Teller (RT) interactions prevailed between the ground (X2A1) and first excited (A2B2) electronic states of NO in the configuration space of normal mode coordinates. Global ab initio potential-energy surfaces and Non Adiabatic Coupling Term (NACT) between those states are reported. For each of the three pairs of normal mode (Q1,Q2,Q3), calculated NACT show singularity at different positions, which are used to calculate Adiabatic-to-Diabatic Transformation (ADT) angles and thereby, the diagonal elements of ADT matrix display (i) sign change for odd number of SAA CI (s) and (ii) no sign change for even number of SAA CIs as well as Renner-Teller interactions. Similar to Jahn-Teller CI, the existence of SAA CIs are, further, confirmed by Longuet-Higgins' phase change.

  8. Comparison of Systemic Toxicity between Botulinum Toxin Subtypes A1 and A2 in Mice and Rats.

    PubMed

    Torii, Yasushi; Goto, Yoshitaka; Nakahira, Shinji; Kozaki, Shunji; Kaji, Ryuji; Ginnaga, Akihiro

    2015-06-01

    The adverse events caused by botulinum toxin type A (subtype A1) product, thought to be after-effects of toxin diffusion after high-dose administration, have become serious issues. A preparation showing less diffusion in the body than existing drugs has been sought. We have attempted to produce neurotoxin derived from subtype A2 (A2NTX) with an amino acid sequence different from that of neurotoxin derived from subtype A1 (A1NTX). In this study, to investigate whether A2NTX has the potential to resolve these issues, we compared the safety of A2NTX, a progenitor toxin derived from subtype A1 (A1 progenitor toxin) and A1NTX employing the intramuscular lethal dose 50% (im LD50) in mice and rats and the compound muscle action potential (CMAP) in rats. Mouse im LD50 values for A1 progenitor toxin and A2NTX were 93 and 166 U/kg, respectively, and the rat im LD50 values were 117 and 153 U/kg, respectively. In the rat CMAP test, the dose on the contralateral side, which caused a 50% reduction in the CMAP amplitude, that is, CMAP-TD50 , was calculated as 19.0, 16.6 and 28.7 U/kg for A1 progenitor toxin, A1NTX and A2NTX, respectively. The results indicate that A2NTX is safer than A1 progenitor toxin and A1NTX. PMID:25395371

  9. Structural and functional differences among human surfactant proteins SP-A1, SP-A2 and co-expressed SP-A1/SP-A2: role of supratrimeric oligomerization

    PubMed Central

    Sánchez-Barbero, Fernando; Rivas, Germán; Steinhilber, Wolfram; Casals, Cristina

    2007-01-01

    SP-A (surfactant protein A) is a membrane-associated SP that helps to maintain the lung in a sterile and non-inflamed state. Unlike SP-As from other mammalian species, human SP-A consists of two functional gene products: SP-A1 and SP-A2. In all the functions examined, recombinant human SP-A1 invariably exhibits lower biological activity than SP-A2. The objective of the present study was to investigate why SP-A2 possesses greater biological activity than SP-A1 and what advantage accrues to having two polypeptide chains instead of one. We analysed structural and functional characteristics of recombinant baculovirus-derived SP-A1, SP-A2 and co-expressed SP-A1/SP-A2 using a wide array of experimental approaches such as analytical ultracentrifugation, DSC (differential scanning calorimetry) and fluorescence. We found that the extent of supratrimeric assembly is much lower in SP-A1 than SP-A2. However, the resistance to proteolysis is greater for SP-A1 than for SP-A2. Co-expressed SP-A1/SP-A2 had greater thermal stability than SP-A1 and SP-A2 and exhibited properties of each protein. On the one hand, SP-A1/SP-A2, like SP-A2, had a higher degree of oligomerization than SP-A1, and consequently had lower Kd for binding to bacterial Re-LPS (rough lipopolysaccharide), higher self-association in the presence of calcium and greater capability to aggregate Re-LPS and phospholipids than SP-A1. On the other hand, SP-A1/SP-A2, like SP-A1, was more resistant to trypsin degradation than SP-A2. Finally, the importance of the supratrimeric assembly for SP-A immunomodulatory function is discussed. PMID:17542781

  10. A continuous spectrophotometric assay that distinguishes between phospholipase A1 and A2 activities[S

    PubMed Central

    El Alaoui, Meddy; Soulère, Laurent; Noiriel, Alexandre; Popowycz, Florence; Khatib, Abdallah; Queneau, Yves; Abousalham, Abdelkarim

    2016-01-01

    A new spectrophotometric assay was developed to measure, continuously and specifically, phospholipase A1 (PLA1) or phospholipase A2 (PLA2) activities using synthetic glycerophosphatidylcholines (PCs) containing α-eleostearic acid, either at the sn-1 position [1-α-eleostearoyl-2-octadecyl-rac-glycero-3-phosphocholine (EOPC)] or at the sn-2 position [1-octadecyl-2-α-eleostearoyl-rac-glycero-3-phosphocholine (OEPC)]. The substrates were coated onto the wells of microtiter plates. A nonhydrolyzable ether bond, with a non-UV-absorbing alkyl chain, was introduced at the other sn position to prevent acyl chain migration during lipolysis. Upon enzyme action, α-eleostearic acid is liberated and then solubilized into the micellar phase. The PLA1 or PLA2 activity was measured by the increase in absorbance at 272 nm due to the transition of α-eleostearic acid from the adsorbed to the soluble state. EOPC and OEPC differentiate, with excellent accuracy, between PLA1 and PLA2 activity. Lecitase®, guinea pig pancreatic lipase-related protein 2 (known to be a PLA1 enzyme), bee venom PLA2, and porcine pancreatic PLA2 were all used to validate the assay. Compared with current assays used for continuously measuring PLA1 or PLA2 activities and/or their inhibitors, the development of this sensitive enzymatic method, using coated PC substrate analogs to natural lipids and based on the UV spectroscopic properties of α-eleostearic acid, is a significant improvement. PMID:27194811

  11. A continuous spectrophotometric assay that distinguishes between phospholipase A1 and A2 activities.

    PubMed

    El Alaoui, Meddy; Soulère, Laurent; Noiriel, Alexandre; Popowycz, Florence; Khatib, Abdallah; Queneau, Yves; Abousalham, Abdelkarim

    2016-08-01

    A new spectrophotometric assay was developed to measure, continuously and specifically, phospholipase A1 (PLA1) or phospholipase A2 (PLA2) activities using synthetic glycerophosphatidylcholines (PCs) containing α-eleostearic acid, either at the sn-1 position [1-α-eleostearoyl-2-octadecyl-rac-glycero-3-phosphocholine (EOPC)] or at the sn-2 position [1-octadecyl-2-α-eleostearoyl-rac-glycero-3-phosphocholine (OEPC)]. The substrates were coated onto the wells of microtiter plates. A nonhydrolyzable ether bond, with a non-UV-absorbing alkyl chain, was introduced at the other sn position to prevent acyl chain migration during lipolysis. Upon enzyme action, α-eleostearic acid is liberated and then solubilized into the micellar phase. The PLA1 or PLA2 activity was measured by the increase in absorbance at 272 nm due to the transition of α-eleostearic acid from the adsorbed to the soluble state. EOPC and OEPC differentiate, with excellent accuracy, between PLA1 and PLA2 activity. Lecitase(®), guinea pig pancreatic lipase-related protein 2 (known to be a PLA1 enzyme), bee venom PLA2, and porcine pancreatic PLA2 were all used to validate the assay. Compared with current assays used for continuously measuring PLA1 or PLA2 activities and/or their inhibitors, the development of this sensitive enzymatic method, using coated PC substrate analogs to natural lipids and based on the UV spectroscopic properties of α-eleostearic acid, is a significant improvement. PMID:27194811

  12. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    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, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  13. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    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, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  14. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    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, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  15. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets

    PubMed Central

    Kuo, Debbie S.; Labelle-Dumais, Cassandre; Gould, Douglas B.

    2012-01-01

    Heterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches. PMID:22914737

  16. Analysis of the CYP21A1P pseudogene: indication of mutational diversity and CYP21A2-like and duplicated CYP21A2 genes.

    PubMed

    Tsai, Li-Ping; Cheng, Ching-Feng; Chuang, Shu-Hua; Lee, Hsien-Hsiung

    2011-06-15

    The CYP21A1P gene downstream of the XA gene, carrying 15 deteriorated mutations, is a nonfunctional pseudogene that shares 98% nucleotide sequence homology with CYP21A2 located on chromosome 6p21.3. However, these mutations in the CYP21A1P gene are not totally involved in each individual. From our analysis of 100 healthy ethnic Chinese (i.e., Taiwanese) (n=200 chromosomes) using the polymerase chain reaction (PCR) products combined with an amplification-created restriction site (ACRS) method and DNA sequencing, we found that approximately 10% of CYP21A1P alleles (n=195 chromosomes) presented the CYP21A2 sequence; frequencies of P30, V281, Q318, and R356 in that locus were approximately 24%, 21%, 11%, and 34%, respectively, and approximately 90% of the CYP21A1P alleles had 15 mutated loci. In addition, approximately 2.5% (n=5 chromosomes) showed four haplotypes of the 3.7-kb TaqI-produced fragment of the CYP21A2-like gene and one duplicated CYP21A2 gene. We conclude that the pseudogene of the CYP21A1P mutation presents diverse variants. Moreover, the existence of the CYP21A2-like gene is more abundant than that of the duplicated CYP21A2 gene downstream of the XA gene and could not be distinguished from the CYP21A2-TNXB gene; thus, it may be misdiagnosed by previously established methods for congenital adrenal hyperplasia caused by a 21-hydroxylase deficiency. PMID:21324303

  17. Nanoscale Obstacle Arrays Frustrate Transport of EphA2 – Ephrin-A1 Clusters in Cancer Cell Lines

    PubMed Central

    Lohmüller, Theobald; Xu, Qian

    2013-01-01

    Juxtacrine signaling interactions between the EphA2 receptor tyrosine kinase and its ephrin-A1 ligand contribute to healthy tissue maintenance and misregulation of this system is observed in at least 40% of human breast cancer. Hybrid live cell – supported membrane experiments, in which membrane-linked ephrin-A1 displayed in supported membranes interacts with EphA2 in living cells, have revealed large scale clustering of EphA2:ephrin-A1 complexes as well as their lateral transport across the cell surface during triggering. Here, we utilize 100nm spaced hexagonally ordered arrays of gold nanodots embedded within supported membranes to present defined obstacles to the movement and assembly of EphA2 clusters. By functionalizing both the supported membrane and the nanodots with ephrin-A1, we perform a type of affinity chromatography on EphA2 signaling clusters in live cell membranes. Analysis of ten different breast cancer cell lines reveals that EphA2 transport is most frustrated by nanodot arrays in the most diseased cell lines. These observations suggest that strong physical association among EphA2 receptors, as well as their assembly into larger clusters, correlates with and may contribute to the pathological misregulation of the EphA2:ephrin-A1 pathway in breast cancer. PMID:23668885

  18. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-GENERAL REQUIREMENTS FOR SHIPMENTS AND PACKAGINGS Class 7 (Radioactive) Materials § 173.435 Table of A1... Terabecquerels (TBq), (see § 171.10). c The quantity may be determined from a measurement of the rate of decay...

  19. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...-GENERAL REQUIREMENTS FOR SHIPMENTS AND PACKAGINGS Class 7 (Radioactive) Materials § 173.435 Table of A1... Terabecquerels (TBq), (see § 171.10). c The quantity may be determined from a measurement of the rate of decay...

  20. NblA1/A2-Dependent Homeostasis of Amino Acid Pools during Nitrogen Starvation in Synechocystis sp. PCC 6803

    PubMed Central

    Kiyota, Hiroshi; Hirai, Masami Yokota; Ikeuchi, Masahiko

    2014-01-01

    Nutrient balance is important for photosynthetic growth and biomass production in microalgae. Here, we investigated and compared metabolic responses of amino acid pools to nitrogen and sulfur starvation in a unicellular model cyanobacterium, Synechocystis sp. PCC 6803, and its mutant nblA1/A2. It is known that NblA1/A2-dependent and -independent breakdown of abundant photosynthetic phycobiliproteins and other cellular proteins supply nutrients to the organism. However, the contribution of the NblA1/A2-dependent nutrient supply to amino acid pool homeostasis has not been studied. Our study demonstrates that changes in the pool size of many amino acids during nitrogen starvation can be categorized as NblA1/A2-dependent (Gln, Glu, glutathione, Gly, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr and Val) and NblA1/A2-independent (Ala, Asn, Lys, and Trp). We also report unique changes in amino acid pool sizes during sulfur starvation in wild type and the mutant and found a generally marked increase in the Lys pool in cyanobacteria during nutrient starvation. In conclusion, the NblA1/A2-dependent protein turnover contributes to the maintenance of many amino acid pools during nitrogen starvation. PMID:24983765

  1. Generalization of rectangular element stiffness matrix and thermal load vector associated with a(0) + a(1)x + a(2)y + a(3)xy type interpolation rule

    NASA Technical Reports Server (NTRS)

    Ray, Sujit K.; Utku, Senol; Wada, Ben K.

    1986-01-01

    The stiffness-matrix formulation for the rectangular finite element described by Melosh (1963) and Weaver and Johnston (1984) is generalized to orthotropic materials with material axes not necessarily coincident with the x and y axes; i.e., the condition d(13) = d(23) = 0 is removed. Also included are explicit expressions for the element load vector associated with nonuniform temperature increase in the element. Applications to the analysis of thermal stresses in thin Si-crystal ribbons subjected to temperature changes with highly nonuniform lengthwise and transverse gradients (Utku et al., 1986) and to the simulation of the thermoviscoelastic behavior of growing Si ribbons (Utku and Ray, 1986) are indicated.

  2. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

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

  3. 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,...

  4. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

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

  5. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

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

  6. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

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

  7. Spatio-mechanical EphA2/ephrin-A1 Signaling in Cancer Cells

    NASA Astrophysics Data System (ADS)

    Xu, Qian

    2011-12-01

    Communication strategies in nature are an integral part to the survival of multi-cellular organisms. Cell membranes provide the chemical environment in which intercellular signaling begins. The vast complexity of this signaling requires that a relatively conserved set of chemical constituents be able to generate enormous signal diversity. Spatial sorting of signaling molecules within the membrane allows for this diversity. My research uses synthetic lipid membranes, solid-state nanostructures, and high-resolution imaging to study a potentially novel spatio-mechanical regulatory mechanism in the EphA2 signaling pathway. My hypothesis is that the multi-scale organization of the EphA2 receptor in the cell membrane regulates its biochemical function. This hypothesis is motivated by the idea that extracellular mechanical inputs have an important role in intracellular signaling cascades.

  8. Conversion of carotenoids into vitamins A(1) and A(2) in two species of freshwater fish.

    PubMed

    Gross, J; Budowski, P

    1966-12-01

    1. Examination of two zooplankton species predominating in fish ponds, Daphnia magna and Chironomus larvae, revealed the presence of alpha- and beta-carotene, echinenone, canthaxanthin and 3-hydroxy-4-oxo-beta-carotene in Daphnia, and beta-carotene and cryptoxanthin ester in Chironomus. No specific provitamins A(2) (containing a 3,4-dehydro-beta-ionone ring) were detected. 2. Guppies (Lebistes reticulatus) and platies (Xiphophorus variatus) were found to form vitamin A from beta-carotene and from its oxygen-containing derivatives isozeaxanthin, canthaxanthin and astaxanthin. Slight conversion into vitamin A(2) seemed to occur simultaneously. 3,4-Dehydro-3'-hydroxy-beta-carotene formed little vitamin A, and the latter was mainly of the A(2) type. Lutein was devoid of provitamin A properties. 3. In addition to vitamin A, beta-carotene was detected in fish receiving the 4-oxo- and 4-hydroxy-carotenoids. A reaction scheme for the conversion of carotenoids into retinal and and 3,4-dehydroretinal is presented. 4. It is concluded that natural 4-oxo derivatives of beta-carotene may play a significant role as vitamin A precursors for fish. PMID:16742455

  9. Conversion of carotenoids into vitamins A1 and A2 in two species of freshwater fish

    PubMed Central

    Gross, Jeana; Budowski, P.

    1966-01-01

    1. Examination of two zooplankton species predominating in fish ponds, Daphnia magna and Chironomus larvae, revealed the presence of α- and β-carotene, echinenone, canthaxanthin and 3-hydroxy-4-oxo-β-carotene in Daphnia, and β-carotene and cryptoxanthin ester in Chironomus. No specific provitamins A2 (containing a 3,4-dehydro-β-ionone ring) were detected. 2. Guppies (Lebistes reticulatus) and platies (Xiphophorus variatus) were found to form vitamin A from β-carotene and from its oxygen-containing derivatives isozeaxanthin, canthaxanthin and astaxanthin. Slight conversion into vitamin A2 seemed to occur simultaneously. 3,4-Dehydro-3′-hydroxy-β-carotene formed little vitamin A, and the latter was mainly of the A2 type. Lutein was devoid of provitamin A properties. 3. In addition to vitamin A, β-carotene was detected in fish receiving the 4-oxo- and 4-hydroxy-carotenoids. A reaction scheme for the conversion of carotenoids into retinal and and 3,4-dehydroretinal is presented. 4. It is concluded that natural 4-oxo derivatives of β-carotene may play a significant role as vitamin A precursors for fish. PMID:16742455

  10. A1 and A2, two novel haloarchaeal isolates from bore cores of ancient Alpine rock salt deposits

    NASA Astrophysics Data System (ADS)

    Gruber, C.; Pfaffenhuemer, M.; Weidler, G.; Radax, C.; Stan-Lotter, H.

    2003-04-01

    Previously several novel halophilic archaea, for instance Haloccocus salifodinae BIp and Halococcus dombrowskii, were isolated from Permo-Triassic rock salt (age 200 - 250 million years) in our laboratory. By using molecular methods we found evidence for the presence of numerous additional haloarchaeal taxa. We investigated freshly drilled salt cores from a depth of about 600 m below surface in the salt mine of Altaussee, Austria, which were dissolved immediately in sterile water. After plating the dissolved salts on high salt nutrient agar, we were able to isolate, following incubation for 3 months, two red pigmented colonies, which were designated A1 and A2 and cultivated for further investigation. A1 and A2 showed the same antibiotic susceptibility as Halobacterium salinarum DSM 3754 and Halobacterium sp. NRC-1, which were cultivated from surface waters. Additionally, the cell morphology of the new isolates was highly similar to both reference strains. According to 16S rRNA gene sequences, whole cell protein patterns following SDS polyacrylamide gel electrophoresis, and restriction digestion patterns of their DNA following pulsed field gel electrophoresis, the isolates A1 and A2 could not be distinguished. 16S rRNA gene sequences indicated that the closest relative of strains A1 and A2 was Halobacterium salinarum DSM 3754 (sequence similarity 97,1%). Our results suggest that the isolates A1 and A2 might constitute a new haloarchaeal species, entrapped in ancient rock salt.

  11. Adenosine A(1), A(2a), A(2b), and A(3) receptors in hematopoiesis. 1. Expression of receptor mRNA in four mouse hematopoietic precursor cells.

    PubMed

    Streitová, D; Sefc, L; Savvulidi, F; Pospísil, M; Holá, J; Hofer, M

    2010-01-01

    Four mouse bone marrow or thymus cell populations, namely granulopoietic/monocytopoietic, erythropoietic, B-lymphopoietic, and T-lymphopoietic precursor cells have been assayed by RT-PCR technique for the presence and relative amounts of adenosine A(1), A(2a), A(2b), and A(3) receptor mRNA. It has been found that (i) all four populations studied express all four adenosine receptor subtypes, (ii) the A(1), receptor is the least expressed in all populations studied, (iii) the A(3) receptor is markedly expressed in the populations of granulopoietic/monocytopoietic and erythropoietic cells, (iv) the A(2a) receptor is markedly expressed in the populations of B-lymphopoietic and T-lymphopoietic cells, and v) the A(2b) receptor does not predominate in any of the precursor cells studied. Our data offer a new possibility for the assessment of the readiness of these cells to respond, by receptor-mediated mechanisms, to adenosine or its analogs present in the tissues as a result of endogenous processes and/or following their administration. PMID:19249907

  12. Differences in adenosine A-1 and A-2 receptor density revealed by autoradiography in methylxanthine-sensitive and insensitive mice

    SciTech Connect

    Jarvis, M.F.; Williams, M.

    1988-07-01

    Two strains of inbred mice, CBA/J and SWR/J, have been identified which are, respectively, sensitive and insensitive to the behavioral and toxic effects of methylxanthines. Autoradiographic analyses of brain adenosine receptors were conducted with (/sup 3/H)CHA to label adenosine A-1 receptors and (/sup 3/H)NECA, in the presence of 50 nM CPA, to label adenosine A-2 receptors. For both mouse strains, adenosine A-1 receptors were most highly concentrated in the hippocampus and cerebellum whereas adenosine A-2 receptors were selectively localized in the striatum. CBA/J mice displayed a 30% greater density of adenosine A-1 receptors in the hippocampal CA-1 and CA-3 regions and in the cerebellum as compared to the SWR/J mice. The number of A-2 receptors (Bmax) was 40% greater in the striatum and olfactory tubercle of CBA/J as compared to SWR/J mice. No significant regional differences in A-1 or A-2 receptor affinities were observed between these inbred strains of mice. These results indicate that the differential sensitivity to methylxanthines between these mouse strains may reflect a genetically mediated difference in regional adenosine receptor densities.

  13. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of these standards can be inspected at the Federal... 47 Telecommunication 5 2010-10-01 2010-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System...

  14. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of these standards can be inspected at the Federal... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System...

  15. The occultation of beta Scorpii by Jupiter. VII - The angular diameters of beta Scorpii A1 and A2

    NASA Technical Reports Server (NTRS)

    Elliot, J. L.; Rages, K.; Veverka, J.

    1976-01-01

    A new technique for measuring angular diameters of stars, which makes use of stellar images formed by planetary atmospheres during occultations, is described. This method has been applied to light curves of the 1971 May 13 occultation of beta Sco by Jupiter, yielding the angular diameters of the two early B stars comprising the spectroscopic binary beta Sco A. An angular diameter of about .000422 arcsec for beta Sco A1 and about .000264 arcsec is found for beta Sco A2. These angular diameters are in good agreement with that obtained with the intensity interferometer for beta Sco, a star of nearly the same magnitude and spectral type as beta Sco A1. If the distance to beta Sco A were precisely known, beta Sco A1 and A2 would become fundamental standards of mass, luminosity, and radius for early B stars. Present constraints on the distance and methods by which it could be accurately determined are discussed.

  16. Variants of the CYP21A2 and CYP21A1P genes in congenital adrenal hyperplasia.

    PubMed

    Lee, Hsien-Hsiung

    2013-03-15

    More than 90% of congenital adrenal hyperplasia cases are caused by mutation of the CYP21A2 gene which converted from the CYP21A1P pseudogene. Sizes of the 3.7-kb TaqI-produced fragment that exists downstream of the TNXB gene, representing the CYP21A2, and the 3.2-kb TaqI-produced fragment that exists downstream of the XA gene, representing the CYP21A1P pseudogene, are used as size markers in the restriction fragment length polymorphism (RFLP) analysis. However, the size of and location for distinguishing these two genes might not be completely precise or reliable. Recent studies indicated that the 3.2-kb TaqI fragment may include multiple variants of chimeric CYP21A1P/CYP21A2 genes, a haplotype with dual mutations of IVS2-12A/C>G and 707-714del, and a functional CYP21A2 gene caused by small-scale conversions of the 5' end of the CYP21A1P sequence. In addition, a 3.7-kb TaqI fragment with more than 4 haplotypes of CYP21A2-like downstream of the TNXA gene and a 6.2-kb TaqI fragment of the CYP21A2 that results from a nucleotide mutation in the 3' end sequence were also identified. Accordingly, these structural variants reveal that traditional recognition of these two genes based on the TaqI fragment size analysis may lead to misinterpretation and increasingly interfere with the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. PMID:23313747

  17. The functions of the A1A2A3 domains in von Willebrand factor include multimerin 1 binding.

    PubMed

    Parker, D'Andra N; Tasneem, Subia; Farndale, Richard W; Bihan, Dominique; Sadler, J Evan; Sebastian, Silvie; de Groot, Philip G; Hayward, Catherine P M

    2016-07-01

    Multimerin 1 (MMRN1) is a massive, homopolymeric protein that is stored in platelets and endothelial cells for activation-induced release. In vitro, MMRN1 binds to the outer surfaces of activated platelets and endothelial cells, the extracellular matrix (including collagen) and von Willebrand factor (VWF) to support platelet adhesive functions. VWF associates with MMRN1 at high shear, not static conditions, suggesting that shear exposes cryptic sites within VWF that support MMRN1 binding. Modified ELISA and surface plasmon resonance were used to study the structural features of VWF that support MMRN1 binding, and determine the affinities for VWF-MMRN1 binding. High shear microfluidic platelet adhesion assays determined the functional consequences for VWF-MMRN1 binding. VWF binding to MMRN1 was enhanced by shear exposure and ristocetin, and required VWF A1A2A3 region, specifically the A1 and A3 domains. VWF A1A2A3 bound to MMRN1 with a physiologically relevant binding affinity (KD: 2.0 ± 0.4 nM), whereas the individual VWF A1 (KD: 39.3 ± 7.7 nM) and A3 domains (KD: 229 ± 114 nM) bound to MMRN1 with lower affinities. VWF A1A2A3 was also sufficient to support the adhesion of resting platelets to MMRN1 at high shear, by a mechanism dependent on VWF-GPIbα binding. Our study provides new information on the molecular basis of MMRN1 binding to VWF, and its role in supporting platelet adhesion at high shear. We propose that at sites of vessel injury, MMRN1 that is released following activation of platelets and endothelial cells, binds to VWF A1A2A3 region to support platelet adhesion at arterial shear rates. PMID:27052467

  18. A correlated ab initio study of the X2A1 and A2E states of MgCH3

    NASA Technical Reports Server (NTRS)

    Woon, D. E.

    1996-01-01

    The X2A1 and A2E states of the MgCH3 radical have been studied with correlation consistent basis sets and the coupled cluster method RCCSD(T) in order to compare with two recent experimental efforts [M. A. Anderson and L. M. Ziurys, Astrophys. J. 452, L157 (1995); R. Rubino, J. M. Williamson, and T. A. Miller, J. Chem. Phys. 103, 5964 (1995)]. The best computed values [RCCSD(T)/cc-pCVTZ] for the X2A1 state are (experimental results in parentheses): Ae = 160.433 GHz, Be = 10.948 GHz (B0 = 11.008 GHz), and Mue = 1.011 D. The Mg-CH3 bond is weak, 26.3 kcal/mol. Values for the A2E state are Ae = 154.648 GHz (A0 = 149.666 GHz), Be = 10.87 GHz (B0 = 10.932 GHz), and Mue = 1.022 D. The excitation energy (Te) for the A2E <-- X2A1 transition is 19 999 cm-1 (T00 = 20 030 cm-1). A brief discussion of bonding trends in Mg-containing radials is included.

  19. A1/A2-Diamino-Substituted Pillar[5]arene-Based Acid-Base-Responsive Host-Guest System.

    PubMed

    Hu, Wei-Bo; Hu, Wen-Jing; Zhao, Xiao-Li; Liu, Yahu A; Li, Jiu-Sheng; Jiang, Biao; Wen, Ke

    2016-05-01

    An acid-base-responsive supramolecular host-guest system based on a planarly chiral A1/A2-diamino-substituted pillar[5]arene (1)/imidazolium ion recognition motif was created. The pillar[4]arene[1]diaminobenzene 1 can bring an electron-deficient imidazolium cation into its cylindrically shaped cavity under neutral or basic conditions and release it under acidic conditions. PMID:27088317

  20. JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease.

    PubMed

    Atack, John R; Shook, Brian C; Rassnick, Stefanie; Jackson, Paul F; Rhodes, Kenneth; Drinkenburg, Wilhelmus H; Ahnaou, Abdallah; Te Riele, Paula; Langlois, Xavier; Hrupka, Brian; De Haes, Patrick; Hendrickx, Herman; Aerts, Nancy; Hens, Koen; Wellens, Annemie; Vermeire, Jef; Megens, Anton A H P

    2014-10-15

    Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD. PMID:25203719

  1. Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction

    PubMed Central

    Pu, Xiangyuan; Ren, Meixia; An, Weiwei; Zhang, Ruoxin; Yan, Shunying; Situ, Haiteng; He, Xinjie; Chen, Yequn; Tan, Xuerui; Xiao, Qingzhong; Tucker, Arthur T.; Caulfield, Mark J.; Ye, Shu

    2016-01-01

    Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD

  2. Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

    PubMed

    Yang, Wei; Ng, Fu Liang; Chan, Kenneth; Pu, Xiangyuan; Poston, Robin N; Ren, Meixia; An, Weiwei; Zhang, Ruoxin; Wu, Jingchun; Yan, Shunying; Situ, Haiteng; He, Xinjie; Chen, Yequn; Tan, Xuerui; Xiao, Qingzhong; Tucker, Arthur T; Caulfield, Mark J; Ye, Shu

    2016-07-01

    Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD

  3. Serum Levels of ApoA1 and ApoA2 Are Associated with Cognitive Status in Older Men

    PubMed Central

    Ma, Cheng; Li, Jin; Bao, Zhijun; Ruan, Qingwei; Yu, Zhuowei

    2015-01-01

    Background. Advancing age, chronic inflammation, oxidative damage, and disorders of lipid metabolism are positively linked to the late-life cognitive impairment. Serum biomarkers may be associated with the cognitive status in older men. Methods. 440 old male subjects with different cognitive functions were recruited to investigate probable serum markers. Pearson Chi-Squared test, univariate analysis, and multivariate logistic regression analysis were performed to evaluate biomarkers which may be associated with cognitive status. Results. Levels of fundus atherosclerosis (AS) (P < 0.001), age (P < 0.001), serum biomarkers peroxidase (POD) (P = 0.026) and interleukin-6 (IL-6) (P = 0.001), serum levels of high-density lipoprotein cholesterol (HDL-C) (P < 0.001), apolipoprotein A2 (ApoA2) (P = 0.001), and ApoC2 (P = 0.005) showed significant differences. Compared to group 3, ApoA1 in group 1 (OR = 1.30, 95% CI 1.01–1.67) and group 2 (OR = 1.47, 95% CI 1.11–1.94) were higher, while ApoA2 were lower (group 1: OR = 0.43, 95% CI 0.18–1.02; group 2: OR = 0.21, 95% CI 0.08–0.54) after adjusting for control variables. Conclusion. The results demonstrated that age, AS levels, POD, IL-6, HDL-C, ApoA2, and ApoC2 were significantly related to cognitive status. Moreover, ApoA1 and ApoA2 were independently associated with cognitive impairment and late-life dementia. PMID:26682220

  4. Sequence variants at CYP1A1–CYP1A2 and AHR associate with coffee consumption

    PubMed Central

    Sulem, Patrick; Gudbjartsson, Daniel F.; Geller, Frank; Prokopenko, Inga; Feenstra, Bjarke; Aben, Katja K.H.; Franke, Barbara; den Heijer, Martin; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Yanek, Lisa R.; Becker, Lewis C.; Boyd, Heather A.; Stacey, Simon N.; Walters, G. Bragi; Jonasdottir, Adalbjorg; Thorleifsson, Gudmar; Holm, Hilma; Gudjonsson, Sigurjon A.; Rafnar, Thorunn; Björnsdottir, Gyda; Becker, Diane M.; Melbye, Mads; Kong, Augustine; Tönjes, Anke; Thorgeirsson, Thorgeir; Thorsteinsdottir, Unnur; Kiemeney, Lambertus A.; Stefansson, Kari

    2011-01-01

    Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), the Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10−14) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10−11). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers. PMID:21357676

  5. Cyp27c1 Red-Shifts the Spectral Sensitivity of Photoreceptors by Converting Vitamin A1 into A2.

    PubMed

    Enright, Jennifer M; Toomey, Matthew B; Sato, Shin-ya; Temple, Shelby E; Allen, James R; Fujiwara, Rina; Kramlinger, Valerie M; Nagy, Leslie D; Johnson, Kevin M; Xiao, Yi; How, Martin J; Johnson, Stephen L; Roberts, Nicholas W; Kefalov, Vladimir J; Guengerich, F Peter; Corbo, Joseph C

    2015-12-01

    Some vertebrate species have evolved means of extending their visual sensitivity beyond the range of human vision. One mechanism of enhancing sensitivity to long-wavelength light is to replace the 11-cis retinal chromophore in photopigments with 11-cis 3,4-didehydroretinal. Despite over a century of research on this topic, the enzymatic basis of this perceptual switch remains unknown. Here, we show that a cytochrome P450 family member, Cyp27c1, mediates this switch by converting vitamin A1 (the precursor of 11-cis retinal) into vitamin A2 (the precursor of 11-cis 3,4-didehydroretinal). Knockout of cyp27c1 in zebrafish abrogates production of vitamin A2, eliminating the animal's ability to red-shift its photoreceptor spectral sensitivity and reducing its ability to see and respond to near-infrared light. Thus, the expression of a single enzyme mediates dynamic spectral tuning of the entire visual system by controlling the balance of vitamin A1 and A2 in the eye. PMID:26549260

  6. A1-, A2A- and A3-subtype adenosine receptors modulate intraocular pressure in the mouse

    PubMed Central

    Avila, Marcel Y; Stone, Richard A; Civan, Mortimer M

    2001-01-01

    Despite the potential importance of the mouse in studying the pharmacology of aqueous dynamics, measurement of intraocular pressure (IOP) in its very small eye has been problematic. Utilizing a novel servo-null electrophysiologic approach recently applied to the mouse, we have identified a diversity of adenosine-receptor mechanisms in modulating IOP in this species. We report the first evidence that A3 receptors increase IOP in any species, and verify in the mouse reports with larger mammals that A1 receptors lower and A2A receptors increase IOP. PMID:11564641

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

    PubMed Central

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

    2007-01-01

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

  8. Inhibitory effects of nontoxic protein volvatoxin A1 on pore-forming cardiotoxic protein volvatoxin A2 by interaction with amphipathic alpha-helix.

    PubMed

    Wu, Pei-Tzu; Lin, Su-Chang; Hsu, Chyong-Ing; Liaw, Yen-Chywan; Lin, Jung-Yaw

    2006-07-01

    Volvatoxin A2, a pore-forming cardiotoxic protein, was isolated from the edible mushroom Volvariella volvacea. Previous studies have demonstrated that volvatoxin A consists of volvatoxin A2 and volvatoxin A1, and the hemolytic activity of volvatoxin A2 is completely abolished by volvatoxin A1 at a volvatoxin A2/volvatoxin A1 molar ratio of 2. In this study, we investigated the molecular mechanism by which volvatoxin A1 inhibits the cytotoxicity of volvatoxin A2. Volvatoxin A1 by itself was found to be nontoxic, and furthermore, it inhibited the hemolytic and cytotoxic activities of volvatoxin A2 at molar ratios of 2 or lower. Interestingly, volvatoxin A1 contains 393 amino acid residues that closely resemble a tandem repeat of volvatoxin A2. Volvatoxin A1 contains two pairs of amphipathic alpha-helices but it lacks a heparin-binding site. This suggests that volvatoxin A1 may interact with volvatoxin A2 but not with the cell membrane. By using confocal microscopy, it was demonstrated that volvatoxin A1 could not bind to the cell membrane; however, volvatoxin A1 could inhibit binding of volvatoxin A2 to the cell membrane at a molar ratio of 2. Via peptide competition assay and in conjunction with pull-down and co-pull-down experiments, we demonstrated that volvatoxin A1 and volvatoxin A2 may form a complex. Our results suggest that this occurs via the interaction of one molecule of volvatoxin A1, which contains two amphipathic alpha-helices, with two molecules of volvatoxin A2, each of which contains one amphipathic alpha-helix. Taken together, the results of this study reveal a novel mechanism by which volvatoxin A1 regulates the cytotoxicity of volvatoxin A2 via direct interaction, and potentially provide an exciting new strategy for chemotherapy. PMID:16792702

  9. Dipyridamole attenuates ischemia reperfusion induced acute kidney injury through adenosinergic A1 and A2A receptor agonism in rats.

    PubMed

    Puri, Nikkita; Mohey, Vinita; Singh, Manjinder; Kaur, Tajpreet; Pathak, Devendra; Buttar, Harpal Singh; Singh, Amrit Pal

    2016-04-01

    Dipyridamole (DYP) is an anti-platelet agent with marked vasodilator, anti-oxidant, and anti-inflammatory activity. The present study investigated the role of adenosine receptors in DYP-mediated protection against ischemia reperfusion-induced acute kidney injury (AKI) in rats. The rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h. The renal damage induced by ischemia reperfusion injury (IRI) was assessed by measuring creatinine clearance, blood urea nitrogen, uric acid, plasma potassium, fractional excretion of sodium, and microproteinuria in rats. The oxidative stress in renal tissues was assessed by quantification of thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The hematoxylin-eosin staining was carried out to observe histopathological changes in renal tissues. DYP (10 and 30 mg/kg, intraperitoneal, i.p.) was administered 30 min before subjecting the rats to renal IRI. In separate groups, caffeine (50 mg/kg, i.p.), an adenosinergic A1 and A2A receptor antagonist was administered with and without DYP treatment before subjecting the rats to renal IRI. The ischemia reperfusion-induced AKI was demonstrated by significant changes in serum as well as urinary parameters, enhanced oxidative stress, and histopathological changes in renal tissues. The administration of DYP demonstrated protection against AKI. The prior treatment with caffeine abolished DYP-mediated reno-protection suggesting role of A1 and A2A adenosine receptors in DYP-mediated reno-protection in rats. It is concluded that adenosine receptors find their definite involvement in DYP-mediated anti-oxidative and reno-protective effect against ischemia reperfusion-induced AKI. PMID:26728617

  10. Study of proton conductivity of a 2D flexible MOF and a 1D coordination polymer at higher temperature.

    PubMed

    Sanda, Suresh; Biswas, Soumava; Konar, Sanjit

    2015-02-16

    We report the proton conduction properties of a 2D flexible MOF and a 1D coordination polymer having the molecular formulas {[Zn(C10H2O8)0.5(C10S2N2H8)]·5H2O]}n (1) and {[Zn(C10H2O8)0.5(C10S2N2H8)]·2H2O]}n (2), respectively. Compounds 1 and 2 show high conductivity values of 2.55 × 10(-7) and 4.39 × 10(-4) S cm(-1) at 80 °C and 95% RH. The conductivity value of compound 1 is in the range of those for previously reported flexible MOFs, and compound 2 shows the highest proton conductivity among the carboxylate-based 1D CPs. The dimensionality and the internal hydrogen bonding connectivity play a vital role in the resultant conductivity. Variable-temperature experiments of both compounds at high humidity reveal that the conductivity values increase with increasing temperature, whereas the variable humidity studies signify the influence of relative humidity on high-temperature proton conductivity. The time-dependent measurements for both compounds demonstrate their ability to retain conductivity up to 10 h. PMID:25594401

  11. Purification and characterization of pepsins A1 and A2 from the Antarctic rock cod Trematomus bernacchii

    PubMed Central

    Brier, Sébastien; Maria, Giovanna; Carginale, Vincenzo; Capasso, Antonio; Wu, Yan; Taylor, Robert M.; Borotto, Nicholas B.; Capasso, Clemente; Engen, John R.

    2008-01-01

    SUMMARY The Antarctic notothenioid Trematomus bernacchii (rock cod) lives at a constant mean temperature of −1.9 °C. Gastric digestion under these conditions relies on the proteolytic activity of aspartic proteases such as pepsin. To understand the molecular mechanisms of Antarctic fish pepsins, T. bernacchii pepsins A1 and A2 were cloned, overexpressed in E. coli, purified and characterized with a number of biochemical and biophysical methods. The properties of these two Antarctic isoenzymes were compared to porcine pepsin and found to be unique in a number of ways. Fish pepsins were found to be more temperature sensitive, generally less active at lower pH and more sensitive to inhibition by pepstatin than the mesophilic counterpart. The specificity of Antarctic fish pepsins was similar but not identical to pig pepsin, likely owing to changes in the sequence of fish enzymes near the active site. Gene duplication of Antarctic rock cod pepsins is the likely mechanism for adaptation to the harsh temperature environment in which these enzymes must function. PMID:17976195

  12. In Vitro Interaction of the Housekeeping SecA1 with the Accessory SecA2 Protein of Mycobacterium tuberculosis

    PubMed Central

    Prabudiansyah, Irfan; Kusters, Ilja; Driessen, Arnold J. M.

    2015-01-01

    The majority of proteins that are secreted across the bacterial cytoplasmic membrane leave the cell via the Sec pathway, which in its minimal form consists of the dimeric ATP-driven motor protein SecA that associates with the protein-conducting membrane pore SecYEG. Some Gram-positive bacteria contain two homologues of SecA, termed SecA1 and SecA2. SecA1 is the essential housekeeping protein, whereas SecA2 is not essential but is involved in the translocation of a subset of proteins, including various virulence factors. Some SecA2 containing bacteria also harbor a homologous SecY2 protein that may form a separate translocase. Interestingly, mycobacteria contain only one SecY protein and thus both SecA1 and SecA2 are required to interact with SecYEG, either individually or together as a heterodimer. In order to address whether SecA1 and SecA2 cooperate during secretion of SecA2 dependent proteins, we examined the oligomeric state of SecA1 and SecA2 of Mycobacterium tuberculosis and their interactions with SecA2 and the cognate SecA1, respectively. We conclude that both SecA1 and SecA2 individually form homodimers in solution but when both proteins are present simultaneously, they form dissociable heterodimers. PMID:26047312

  13. Differential Roles for "Nr4a1" and "Nr4a2" in Object Location vs. Object Recognition Long-Term Memory

    ERIC Educational Resources Information Center

    McNulty, Susan E.; Barrett, Ruth M.; Vogel-Ciernia, Annie; Malvaez, Melissa; Hernandez, Nicole; Davatolhagh, M. Felicia; Matheos, Dina P.; Schiffman, Aaron; Wood, Marcelo A.

    2012-01-01

    "Nr4a1" and "Nr4a2" are transcription factors and immediate early genes belonging to the nuclear receptor Nr4a family. In this study, we examine their role in long-term memory formation for object location and object recognition. Using siRNA to block expression of either "Nr4a1" or "Nr4a2", we found that "Nr4a2" is necessary for both long-term…

  14. Biological and Structural Characterization of Glycosylation on Ephrin-A1, a Preferred Ligand for EphA2 Receptor Tyrosine Kinase*

    PubMed Central

    Ferluga, Sara; Hantgan, Roy; Goldgur, Yehuda; Himanen, Juha P.; Nikolov, Dimitar B.; Debinski, Waldemar

    2013-01-01

    The EphA2 receptor tyrosine kinase is overexpressed in a number of malignancies and is activated by ephrin ligands, most commonly by ephrin-A1. The crystal structure of the ligand-receptor complex revealed a glycosylation on the Asn-26 of ephrin-A1. Here we report for the first time the significance of the glycosylation in the biology of EphA2 and ephrin-A1. Ephrin-A1 was enzymatically deglycosylated, and its activity was evaluated in several assays using glioblastoma (GBM) cells and recombinant EphA2. We found that deglycosylated ephrin-A1 does not efficiently induce EphA2 receptor internalization and degradation, and does not activate the downstream signaling pathways involved in cell migration and proliferation. Data obtained by surface plasmon resonance confirms that deglycosylated ephrin-A1 does not bind EphA2 with high affinity. Mutations in the glycosylation site on ephrin-A1 result in protein aggregation and mislocalization. Analysis of Eph/ephrin crystal structures reveals an interaction between the ligand's carbohydrates and two residues of EphA2: Asp-78 and Lys-136. These findings suggest that the glycosylation on ephrin-A1 plays a critical role in the binding and activation of the EphA2 receptor. PMID:23661698

  15. Preferred Binding Orientations of Phenacetin in CYP1A1 and CYP1A2 Are Associated with Isoform-Selective Metabolism

    PubMed Central

    Huang, Qingbiao; Deshmukh, Rahul S.; Ericksen, Spencer S.; Tu, Youbin

    2012-01-01

    Human cytochromes P450 1A1 and 1A2 play important roles in drug metabolism and chemical carcinogenesis. Although these two enzymes share high sequence identity, they display different substrate specificities and inhibitor susceptibilities. In the present studies, we investigated the structural basis for these differences with phenacetin as a probe using a number of complementary approaches, such as enzyme kinetics, stoichiometric assays, NMR, and molecular modeling. Kinetic and stoichiometric analyses revealed that substrate specificity (kcat/Km) of CYP1A2 was approximately 18-fold greater than that of CYP1A1, as expected. Moreover, despite higher H2O2 production, the coupling efficiency of reducing equivalents to acetaminophen formation in CYP1A2 was tighter than that in CYP1A1. CYP1A1, in contrast to CYP1A2, displayed much higher uncoupling, producing more water. The subsequent NMR longitudinal (T1) relaxation studies with the substrate phenacetin and its product acetaminophen showed that both compounds displayed similar binding orientations within the active site of CYP1A1 and CYP1A2. However, the distance between the OCH2 protons of the ethoxy group (site of phenacetin O-deethylation) and the heme iron was 1.5 Å shorter in CYP1A2 than in CYP1A1. The NMR findings are thus consistent with our kinetic and stoichiometric results, providing a likely molecular basis for more efficient metabolism of phenacetin by CYP1A2. PMID:22949628

  16. Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder.

    PubMed

    Kinch, Amelie; Sundström, Christer; Tufveson, Gunnar; Glimelius, Ingrid

    2016-10-01

    The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection. PMID:27104753

  17. RT-PCR detection of CYP1A1, 1A2, and 2E1 mRNAs in rat nasal tissue

    SciTech Connect

    Reddy, S.L.; Kim, S.G.; States, J.C.; Dahl, A.R.; Hotchkiss, J.; Novak, R.F. Lovelace Biomedical and Environmental Research Inst., Albuquerque, NM )

    1991-03-15

    The expression of P450 in nasal tissue is of considerable importance given the exposure of these tissues to xenobiotics and the role of P450s in xenobiotic metabolism. CYP1A1, 1A2 and 2E1 mRNA expression was examined in olfactory tissue of rats exposed to 5 ppm pyridine 6 h daily for 4 d. RT-PCR was performed on poly(A){sup +} RNA using gene specific primers selected from published rat liver 1A1, 1A2 and 2E1 cDNAs. RT-PCR products derived from nasal mRNAs were detected and co-migrated with liver 1A1, 1A2 and 2W1 Rt-PCR products. Identical restriction patterns were obtained from HinfI and HpaII digests of nasal and liver 1A1 RT-PCR products; restriction digest patterns of nasal and liver 1A2 RT-PCR products were also identical. Southern analyses of nasal RT-PCR products, using liver 1A1 and 12 DNA probes, showed a single band suggesting considerable homology between nasal and liver 1A1 and 1A2 fragments. Cloning and sequencing of nasal 1A1, 1A2 and 2E1 RT-PCR products will confirm the identity of these gene products. These results show that 1A1, 1A2 and 2E1 mRNAs are expressed in rat olfactory tissue and suggest that the fragments examined share homology with those expressed in liver.

  18. A structural comparison of Listeria monocytogenes protein chaperones PrsA1 and PrsA2 reveals molecular features required for virulence.

    PubMed

    Cahoon, Laty A; Freitag, Nancy E; Prehna, Gerd

    2016-07-01

    Listeria monocytogenes is a Gram-positive environmental bacterium that lives within soil but transitions into a pathogen upon contact with a mammalian host. The transition of L. monocytogenes from soil dweller to cytosolic pathogen is dependent upon secreted virulence factors that mediate cell invasion and intracellular growth. PrsA1 and PrsA2 are secreted bacterial lipoprotein chaperones that contribute to the folding of proteins translocated across the bacterial membrane; PrsA2 is required for L. monocytogenes virulence, whereas the function of PrsA1 remains to be determined. We have solved an X-ray crystal structure of PrsA1 and have used this model to guide comparison structure-based mutagenesis studies with PrsA2. Targeted mutagenesis of PrsA2 demonstrates that oligomerization of PrsA2 as well as molecular features of the foldase domain are required for protein secretion and virulence, whereas a functional role was uncovered for PrsA1 in bacterial resistance to alcohol. Interestingly, PrsA2 membrane localization is not required for all PrsA2-dependent activities, suggesting that the lipoprotein retains function when released from the bacterial cell. PrsA chaperones are thus multifaceted proteins with distinct domains adapted to accommodate the functional needs of a diverse array of secreted substrates. PMID:27007641

  19. Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer

    PubMed Central

    Chen, Chi-Yuan; Jan, Chia-Ing; Pi, Wen-Chieh; Wang, Wen-Lung; Yang, Pan-Chyr; Wang, Tong-Hong; Karni, Rotem; Wang, Tzu-Chien V.

    2016-01-01

    The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis. PMID:26919236

  20. Promoters of the CATG-Specific Methyltransferase Gene hpyIM Differ between iceA1 and iceA2 Helicobacter pylori Strains

    PubMed Central

    Xu, Qing; Blaser, Martin J.

    2001-01-01

    Helicobacter pylori strains can be divided into two groups, based on the presence of two unrelated genes, iceA1 and iceA2, that occupy the same genomic locus. hpyIM, located immediately downstream of either gene, encodes a functional CATG-specific methyltransferase. Despite the strong conservation of the hpyIM open reading frame (ORF) among all H. pylori strains, the sequences upstream of the ORF in iceA1 and iceA2 strains are substantially different. To explore the roles of these upstream sequences in hpyIM regulation, promoter analysis of hpyIM was performed. Both deletion mutation and primer extension analyses demonstrate that the hpyIM promoters differ between H. pylori strains 60190 (iceA1) and J188 (iceA2). In strain 60190, hpyIM has two promoters, Pa or PI, which may function independently, whereas only one hpyIM promoter, Pc, was found in strain J188. The XylE assay showed that the hpyIM transcription level was much higher in strain 60190 than in strain J188, indicating that regulation of hpyIM transcription differs between the H. pylori iceA1 strain (60190) and iceA2 strains (J188). Since the iceA1 and iceA2 sequences are highly conserved within iceA1 or iceA2 strains, we conclude that promoters of the CATG-specific methylase gene hpyIM differ between iceA1 and iceA2 strains, which leads to differences in regulation of hpyIM transcription. PMID:11395450

  1. Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer.

    PubMed

    Chen, Chi-Yuan; Jan, Chia-Ing; Pi, Wen-Chieh; Wang, Wen-Lung; Yang, Pan-Chyr; Wang, Tong-Hong; Karni, Rotem; Wang, Tzu-Chien V

    2016-03-29

    The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis. PMID:26919236

  2. Amino-substituted 1,8-naphthyridines and pyrido[2,3-d]pyrimidines: new compounds with affinity for A1- and A2-adenosine receptors.

    PubMed

    Müller, C E; Grahner, B; Heber, D

    1994-12-01

    Two novel classes of adenosine receptor (AR) antagonists, 4-amino-1,8-naphthyridines and 5-aminopyrido[2,3-d]pyrimidines, have been identified and investigated in radioligand binding assays. The compounds exhibit affinities for A1 and A2a AR of rat brain in the micromolar range. 1,8-Naphthyridines are non-selective, or somewhat selective for either A1- or A2 AR. Pyrido[2,3-d]pyrimidines are several-fold selective for A1 AR, the most potent and selective compound being 5-n-butylamino-1,3-dimethyl-1,2,3,4-tetrahydropyrido-[2,3-d]pyr imi dine-2,4-dione (12) with a Ki value of 1.8 microM at A1 AR and greater than 10-fold A1-selectivity. PMID:7838877

  3. Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus)

    PubMed Central

    Feng, Ruijuan; Fang, Lingling; Cheng, Yunying; He, Xue; Jiang, Wentao; Dong, Ranran; Shi, Hongjuan; Jiang, Dongneng; Sun, Lina; Wang, Deshou

    2015-01-01

    Meiosis is a process unique to the differentiation of germ cells. Retinoic acid (RA) is the key factor controlling the sex-specific timing of meiotic initiation in tetrapods; however, the role of RA in meiotic initiation in teleosts has remained unclear. In this study, the genes encoding RA synthase aldh1a2, and catabolic enzyme cyp26a1 were isolated from Nile tilapia (Oreochromis niloticus), a species without stra8. The expression of aldh1a2 was up-regulated and expression of cyp26a1 was down-regulated before the meiotic initiation in ovaries and in testes. Treatment with RA synthase inhibitor or disruption of Aldh1a2 by CRISPR/Cas9 resulted in delayed meiotic initiation, with simultaneous down-regulation of cyp26a1 and up-regulation of sycp3. By contrast, treatment with an inhibitor of RA catabolic enzyme and disruption of cyp26a1 resulted in earlier meiotic initiation, with increased expression of aldh1a2 and sycp3. Additionally, treatment of XY fish with estrogen (E2) and XX fish with fadrozole led to sex reversal and reversion of meiotic initiation. These results indicate that RA is indispensable for meiotic initiation in teleosts via a stra8 independent signaling pathway where both aldh1a2 and cyp26a1 are critical. In contrast to mammals, E2 is a major regulator of sex determination and meiotic initiation in teleosts. PMID:25976364

  4. Spatial Organization of EphA2 at the Cell-Cell Interface Modulates Trans-Endocytosis of EphrinA1

    PubMed Central

    Greene, Adrienne C.; Lord, Samuel J.; Tian, Aiwei; Rhodes, Christopher; Kai, Hiroyuki; Groves, Jay T.

    2014-01-01

    EphA2 is a receptor tyrosine kinase (RTK) that is sensitive to spatial and mechanical aspects of the cell’s microenvironment. Misregulation of EphA2 occurs in many aggressive cancers. Although its juxtacrine signaling geometry (EphA2’s cognate ligand ephrinA1 is expressed on the surface of an apposing cell) provides a mechanism by which the receptor may experience extracellular forces, this also renders the system challenging to decode. By depositing living cells on synthetic supported lipid membranes displaying ephrinA1, we have reconstituted key features of the juxtacrine EphA2-ephrinA1 signaling system while maintaining the ability to perturb the spatial and mechanical properties of the membrane-cell interface with precision. In addition, we developed a trans-endocytosis assay to monitor internalization of ephrinA1 from a supported membrane into the apposing cell using a quantitative three-dimensional fluorescence microscopy assay. Using this experimental platform to mimic a cell-cell junction, we found that the signaling complex is not efficiently internalized when lateral reorganization at the membrane-cell contact sites is physically hindered. This suggests that EphA2-ephrinA1 trans-endocytosis is sensitive to the mechanical properties of a cell’s microenvironment and may have implications in physical aspects of tumor biology. PMID:24853748

  5. Vavilosides A1/A2-B1/B2, new furostane glycosides from the bulbs of Allium vavilovii with cytotoxic activity.

    PubMed

    Zolfaghari, Behzad; Sadeghi, Masoud; Troiano, Raffaele; Lanzotti, Virginia

    2013-04-01

    A phytochemical analysis of the bulbs of Allium vavilovii M. Pop. & Vved. was attained for the first time extensively, affording to the isolation of four new furostanol saponins, named vavilosides A1/A2-B1/B2 (1a/b-2a/2b), as two couple of isomers in equilibrium, together with ascalonicoside A1/A2 (3a/3b) and 22-O-methyl ascalonicoside A1/A2 (4a/4b), previously isolated from shallot, Allium ascalonicum. High concentrations of kaempferol, kaempferide, and kaempferol 4(I)-glucoside were also isolated. The chemical structures of the new compounds, established through a combination of extensive nuclear magnetic resonance, mass spectrometry and chemical analyses, were identified as (25R)-furost-5(6)-en-1β,3β,22α,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-galactopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside A1), (25R)-furost-5(6)-en-1β,3β,22β,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-galactopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside A2), (25R)-furost-5(6)-en-1β,3β,22α,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-xylopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside B1), (25R)-furost-5(6)-en-1β,3β,22β,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-d-xylopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside B2). The isolated saponins showed cytotoxic activity on J-774, murine monocyte/macrophage, and WEHI-164, murine fibrosarcoma, cell lines with the following rank: vaviloside B1/B2>ascalonicoside A1/A2>vaviloside A1/A2. PMID:23415085

  6. Molecular comparison of Slc11a1 and Slc11a2 genes of swamp- and riverine-type water buffaloes.

    PubMed

    Padiernos, R B C; Mingala, C N

    2016-06-01

    Solute-linked carrier 11a and 11a2 (Slc) have been associated with disease resistance and/or susceptibility across animal species. These genes have an important mechanism in the regulation against intracellular infection. This study analysed the genetic characteristic of Slc 11a and 11a2 in swamp-type and riverine-type water buffaloes to understand their immunological distinction. Characterization of Slc11a1 and Slc11a2 genes from swamp- and riverine-type water buffaloes was carried out by molecular cloning, sequencing and phylogenetic analysis. The cloned cDNA of Slc11a1 and Slc11a2 contained an open reading frame of 1647 and 1723 nucleotides, encoding 549 and 574 amino acids, respectively. Nucleotide sequence homology of both Slc11a1 and Slc11a2 had 99% in swamp and riverine type, which gives almost identical polypeptide. However, Slc11a1 and Slc11a2 have substitutions of 5 and 1 amino acid residues, correspondingly. These substitutions suggest as a potential gene markers for resistance and/or susceptibility to intracellular infection. Furthermore, phylogenetic analysis confirmed the degree of relationship between the bubaline species and justifies the distinctness of each breed by the bootstrap value generated. PMID:27091413

  7. Triple-Singlet Mixing in Si_3: the 1^3A_{1}^{''} - {a}{^3}A{^{'}_2} Transition

    NASA Astrophysics Data System (ADS)

    Zhang, Ruohan; Steimle, Timothy C.

    2013-06-01

    The electronic spectrum of the triplet states of the D_{3h} isomer of Si_3 recorded using both mass selected REMPI and LIF spectroscopy was recently reported. In that same study the dispersed laser induced fluorescence (DLIF) spectra resulting from excitation of various bands in the visible range were recorded. The DLIF spectra exhibited a progression with a 505 cm^{-1} spacing, which was assign to the breathing mode of the D_{3h}, equilateral triangle, Si_{3} molecule. In addition, and quite unexpectedly, the DLIF spectra exhibited a progression having a spacing of 173 cm^{-1}. This progression was tentatively assigned to transition involving the bending mode of the ^1A_1 state of the C_{2v} isomer. A possible explanation for the observation of transitions in the singlet manifold is that upon laser excitation in the D_{3h} triplet manifold there is rapid intersystem crossing to the singlet manifold followed by fluorescence to the ground state of C_{2v} isomer. Here we address the issue of possible intersystem crossing by recording the excitation on DLIF spectra in the present of a static magnetic field. Magnetic fields are known to enhance the singlet-triple mixing. Si_{3} was produced using a supersonic pulsed discharge source (900 V, 20 μs, 6kΩ) with a 1% SiH_{4} in argon mixture. Magnetic fields of approximately 500 and 950 Gauss were applied. We will report the interpretation of the magnetic field induced changes to the LIF and DLIF spectra and the implications for the singlet-triple mixing process. N. J. Reilly, X. Zhuang, V. Gupta, R. Nagarajan, R. C. Fortenberry, J. P. Maier, T. C. Steimle, J. F. Stanton, M. C. McCarthy; {J. Chem. Phys., {136(19)}, 194307, (2004). V. I. Makarov, I. V. Khmelinskii; {Advances in Chemical Phisics, {Volume 118}, 45-98, (2001). thanks

  8. Transcription of Oxidative Stress Genes Is Directly Activated by SpxA1 and, to a Lesser Extent, by SpxA2 in Streptococcus mutans

    PubMed Central

    Kajfasz, Jessica K.; Rivera-Ramos, Isamar; Scott-Anne, Kathleen; Gregoire, Stacy; Abranches, Jacqueline

    2015-01-01

    ABSTRACT The SpxA1 and SpxA2 (formerly SpxA and SpxB) transcriptional regulators of Streptococcus mutans are members of a highly conserved family of proteins found in Firmicutes, and they were previously shown to activate oxidative stress responses. In this study, we showed that SpxA1 exerts substantial positive regulatory influence over oxidative stress genes following exposure to H2O2, while SpxA2 appears to have a secondary regulatory role. In vitro transcription (IVT) assays using purified SpxA1 and/or SpxA2 showed that SpxA1 and, less often, SpxA2 directly activate transcription of some of the major oxidative stress genes. Addition of equimolar concentrations of SpxA1 and SpxA2 to the IVT reactions neither enhanced transcription of the tested genes nor disrupted the dominant role of SpxA1. Substitution of a conserved glycine residue (G52) present in both Spx proteins by arginine (SpxG52R) resulted in strains that phenocopied the Δspx strains. Moreover, addition of purified SpxA1G52R completely failed to activate transcription of ahpC, sodA, and tpx, further confirming that the G52 residue is critical for Spx functionality. IMPORTANCE Streptococcus mutans is a pathogen associated with the formation of dental caries in humans. Within the oral cavity, S. mutans routinely encounters oxidative stress. Our previous data revealed that two regulatory proteins, SpxA1 and SpxA2 (formerly SpxA and SpxB), bear high homology to the Spx regulator that has been characterized as a critical activator of oxidative stress genes in Bacillus subtilis. In this report, we prove that Spx proteins of S. mutans directly activate transcription of genes involved in the oxidative stress response, though SpxA1 appears to have a more dominant role than SpxA2. Therefore, the Spx regulators play a critical role in the ability of S. mutans to thrive within the oral cavity. PMID:25897032

  9. ABA renewal involves enhancements in both GluA2-lacking AMPA receptor activity and GluA1 phosphorylation in the lateral amygdala.

    PubMed

    Park, Kyungjoon; Song, Beomjong; Kim, Jeongyeon; Hong, Ingie; Song, Sangho; Lee, Junuk; Park, Sungmo; Kim, Jihye; An, Bobae; Lee, Hyun Woo; Lee, Seungbok; Kim, Hyun; Lee, Justin C; Lee, Sukwon; Choi, Sukwoo

    2014-01-01

    Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the

  10. Bidirectional signalling between EphA2 and ephrinA1 increases tubular cell attachment, laminin secretion and modulates erythropoietin expression after renal hypoxic injury.

    PubMed

    Rodriguez, Stéphane; Rudloff, Stefan; Koenig, Katrin Franziska; Karthik, Swapna; Hoogewijs, David; Huynh-Do, Uyen

    2016-08-01

    Acute kidney injury (AKI) is common in hospitalized patients and has a poor prognosis, the severity of AKI being linked to progression to chronic kidney disease. This stresses the need to search for protective mechanisms during the acute phase. We investigated kidney repair after hypoxic injury using a rat model of renal artery branch ligation, which led to an oxygen gradient vertical to the corticomedullary axis. Three distinct zones were observed: tubular necrosis, infarction border zone and preserved normal tissue. EphA2 is a receptor tyrosine kinase with pivotal roles in cell architecture, migration and survival, upon juxtacrine contact with its membrane-bound ligand EphrinA1. Following hypoxia, EphA2 was up-regulated in cortical and medullary tubular cells, while EphrinA1 was up-regulated in interstitial cells adjacent to peritubular capillaries. Moreover, erythropoietin (EPO) messenger RNA (mRNA) was strongly expressed in the border zone of infarcted kidney within the first 6 h. To gain more insight into the biological impact of EphA2 and EphrinA1 up-regulation, we activated the signalling pathways in vitro using recombinant EphrinA1/Fc or EphA2/Fc proteins. Stimulation of EphA2 forward signalling in the proximal tubular cell line HK2 increased cell attachment and laminin secretion at the baso-lateral side. Conversely, activation of reverse signalling through EphrinA1 expressed by Hep3B cells promoted EPO production at both the transcriptional and protein level. Strikingly, in co-culture experiments, juxtacrine contact between EphA2 expressing MDCK and EphrinA1 expressing Hep3B was sufficient to induce a significant up-regulation of EPO mRNA production in the latter cells, even in the absence of hypoxic conditions. The synergistic effects of EphA2 and hypoxia led to a 15-20-fold increase of EPO expression. Collectively, our results suggest an important role of EphA2/EphrinA1 signalling in kidney repair after hypoxic injury through stimulation of (i) tubular

  11. PapA1 and PapA2 are acyltransferases essential for the biosynthesis of the Mycobacterium tuberculosis virulence factor Sulfolipid-1

    PubMed Central

    Kumar, Pawan; Schelle, Michael W.; Jain, Madhulika; Lin, Fiona L.; Petzold, Christopher J.; Leavell, Michael D.; Leary, Julie A.; Cox, Jeffery S.; Bertozzi, Carolyn R.

    2007-01-01

    Mycobacterium tuberculosis produces numerous exotic lipids that have been implicated as virulence determinants. One such glycolipid, Sulfolipid-1 (SL-1), consists of a trehalose-2-sulfate (T2S) core acylated with four lipid moieties. A diacylated intermediate in SL-1 biosynthesis, SL1278, has been shown to activate the adaptive immune response in human patients. Although several proteins involved in SL-1 biosynthesis have been identified, the enzymes that acylate the T2S core to form SL1278 and SL-1, and the biosynthetic order of these acylation reactions, are unknown. Here we demonstrate that PapA2 and PapA1 are responsible for the sequential acylation of T2S to form SL1278 and are essential for SL-1 biosynthesis. In vitro, recombinant PapA2 converts T2S to 2′-palmitoyl T2S, and PapA1 further elaborates this newly identified SL-1 intermediate to an analog of SL1278. Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. Finally, the ΔpapA2 and ΔpapA1 mutants were screened for virulence defects in a mouse model of infection. The loss of SL-1 (and SL1278) did not appear to affect bacterial replication or trafficking, suggesting that the functions of SL-1 are specific to human infection. PMID:17592143

  12. 75 FR 28188 - Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-20

    ... 7, 2010 (75 FR 910), we published a final rule AD, FR Doc, E9-30471, in the Federal Register. That... (GE) CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1 turbofan engines. The GE alert service bulletin...

  13. Differential expression of CYP1A1 and CYP1A2 genes in H4IIE rat hepatoma cells exposed to TCDD and PAHs.

    PubMed

    Kaisarevic, Sonja; Dakic, Vanja; Hrubik, Jelena; Glisic, Branka; Lübcke-von Varel, Urte; Pogrmic-Majkic, Kristina; Fa, Svetlana; Teodorovic, Ivana; Brack, Werner; Kovacevic, Radmila

    2015-01-01

    Rat hepatoma cells H4IIE were treated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs) (dibenz(a,h)anthracene, benzo(a)pyrene, benz(a)anthracene, chrysene), low-concentration mixtures of PAHs and TCDD, and environmental mixtures contaminated by PAHs and their derivatives. Expression of the gene battery comprising cytochrome P450 Cyp1a1, Cyp1a2, Cyp1b1, and glutathione-s-transferase Gsta2 and Gstp was investigated using quantitative real time polymerase chain reaction (qRT-PCR) analysis. The results revealed that TCDD induce Cyp1a1>Cyp1a2>Cyp1b1, while PAHs and PAH-containing environmental mixtures induce Cyp1a2>Cyp1a1>Cyp1b1 gene expression pattern. While low-concentration mixtures elicited a more pronounced response in comparison to single treatments, the typical gene expression patterns were not observed. In all samples, Gsta2 was predominantly expressed relative to Gstp. These findings indicate that differential Cyp1a1 and Cyp1a2 expression in the H4IIE cells might be used for detection of PAHs in highly contaminated environmental mixtures, but not in low-concentration mixtures of these compounds. PMID:25555259

  14. PapA1 and PapA2 are acyltransferases essential for the biosynthesis of the Mycobacterium tuberculosis virulence factor sulfolipid-1.

    PubMed

    Kumar, Pawan; Schelle, Michael W; Jain, Madhulika; Lin, Fiona L; Petzold, Christopher J; Leavell, Michael D; Leary, Julie A; Cox, Jeffery S; Bertozzi, Carolyn R

    2007-07-01

    Mycobacterium tuberculosis produces numerous exotic lipids that have been implicated as virulence determinants. One such glycolipid, Sulfolipid-1 (SL-1), consists of a trehalose-2-sulfate (T2S) core acylated with four lipid moieties. A diacylated intermediate in SL-1 biosynthesis, SL(1278), has been shown to activate the adaptive immune response in human patients. Although several proteins involved in SL-1 biosynthesis have been identified, the enzymes that acylate the T2S core to form SL(1278) and SL-1, and the biosynthetic order of these acylation reactions, are unknown. Here we demonstrate that PapA2 and PapA1 are responsible for the sequential acylation of T2S to form SL(1278) and are essential for SL-1 biosynthesis. In vitro, recombinant PapA2 converts T2S to 2'-palmitoyl T2S, and PapA1 further elaborates this newly identified SL-1 intermediate to an analog of SL(1278). Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. Finally, the Delta papA2 and Delta papA1 mutants were screened for virulence defects in a mouse model of infection. The loss of SL-1 (and SL(1278)) did not appear to affect bacterial replication or trafficking, suggesting that the functions of SL-1 are specific to human infection. PMID:17592143

  15. Strategy for prenatal diagnosis of osteogenesis imperfecta by linkage analysis to the type I collagen loci COL1A1 and COL1A2.

    PubMed

    Benušienė, E; Kučinskas, V

    2000-01-01

    To improve prenatal diagnosis of osteogenesis imperfecta (OI) in Lithuania, possibilities of indirect molecular genetic diagnosis were investigated in 11 families with dominant OI. Segregation of polymorphic DNA markers closely linked to COL1A1 and COL1A2 genes with OI phenotype was investigated. Polymorphic DNA markers applied were individual haplotypes constructed using a set of restriction enzyme sites within or close to the genes. Comparison of phenotypic features with the concordant collagen locus showed that in four pedigrees with OI Sillence type I segregated with COL1A1, while two pedigrees with OI Sillence type I and OI type IV segregated with COL1A2. Out of six remaining pedigrees with OI Sillence type I, three were concordant at both loci, two pedigrees were discordant at the locus COL1A2 and non-informative at the locus COL1A1 and one pedigree was concordant at the locus COL1A1 and non-informative at the locus COL1A2. Informativity of DNA markers applied was also investigated in the Lithuanian OI families. The frequencies of six restriction enzyme site dimorphisms in type I collagen loci were estimated and polymorphism information content (PIC) values were calculated for each restriction site and for a combination of three sites. COL1A1 locus dimorphisms A/MspI, B/RsaI and F/MnlI, showed PIC values of 0.327, 0.191 and 0.366, respectively, giving a combined PIC of 0.656 at the locus, while COL1A2 locus dimorphisms C/EcoRI, D/MspI and E/RsaI RFLPs had PIC values of 0.357, 0.168 and 0.331, respectively, giving a combined PIC of 0.655 at the locus. PMID:11208313

  16. Induction of cytochromes P450 1A1 and 1A2 by tanshinones in human HepG2 hepatoma cell line

    SciTech Connect

    Zhang Rong; Sun Jianguo; Ma Liping; Wu Xiaolan; Pan Guoyu; Hao Haiping; Zhou Fang; Jiye, A; Liu Changhui; Ai Hua; Shang Lili; Gao Haiyan; Peng Ying; Wan Ping; Wu Hui; Wang Guangji

    2011-04-01

    Diterpenoid tanshinones including tanshinone IIA (TIIA), cryptotanshinone (CTS), tanshinone I (TI) and dihydrotanshinone I (DHTI) are the major bioactive components from Danshen. The major aim of our present study was to investigate the induction potential of these four main components of tanshinones (TIIA, CTS, TI, and DHTI) on the expression of CYP1A1 and CYP1A2 in HepG2 cells. Our results showed that all of these four tanshinones caused a significant time- and concentration-dependent increase in the amount of CYP1A1/2 expression in HepG2 cells. These induction effects were further characterized through transcriptional regulation: the induction of CYP1A1/2 mRNA level by tanshinones was completely blocked by the transcription inhibitor actinomycin D; the expression of CYP1A1/2 heterogeneous nuclear RNA was induced by tanshinone treatment; and CYP1A1 mRNA stability was not influenced by these tanshinones. Interestingly, tanshinones plus B[a]P produced additive/synergistic effect on CYP1A1/2 induction. In addition, the tanshinone-induced CYP1A1/2 expression was abolished by the aryl hydrocarbon receptor (AhR) antagonist resveratrol, suggesting an AhR dependent transcription mechanism. In the reporter gene assay, while TI and DHTI significantly induced AhR-dependent luciferase activity, TIIA and CTS failed to induce this activity. Collectively, the tanshinones could induce CYP1A1 and CYP1A2 expression through transcriptional activation mechanism and exert differential effects on activating AhR in HepG2 cells. Our findings suggest that rational administration of tanshinones should be considered with respect to their effect on AhR and CYP1A1/2 expression.

  17. Modulation of CYP1A1 and CYP1A2 hepatic enzymes after oral administration of Chios mastic gum to male Wistar rats.

    PubMed

    Katsanou, Efrosini S; Kyriakopoulou, Katerina; Emmanouil, Christina; Fokialakis, Nikolas; Skaltsounis, Alexios-Leandros; Machera, Kyriaki

    2014-01-01

    Chios mastic gum (CMG), a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE), at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well-known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD). The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE. PMID:24950217

  18. A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form

    PubMed Central

    Concolino, Paola; Mello, Enrica; Minucci, Angelo; Giardina, Emiliano; Zuppi, Cecilia; Toscano, Vincenzo; Capoluongo, Ettore

    2009-01-01

    Background More than 90% of Congenital Adrenal Hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. In this region, a 30 kb deletion produces a non functional chimeric gene with its 5' and 3' ends corresponding to CYP21A1P pseudogene and CYP21A2, respectively. To date, five different CYP21A1P/CYP21A2 chimeric genes have been found and characterized in recent studies. In this paper, we describe a new CYP21A1P/CYP21A2 chimera (CH-6) found in an Italian CAH patient. Methods Southern blot analysis and CYP21A2 sequencing were performed on the patient. In addition, in order to isolate the new CH-6 chimeric gene, two different strategies were used. Results The CYP21A2 sequencing analysis showed that the patient was homozygote for the g.655C/A>G mutation and heterozygote for the p.P30L missense mutation. In addition, the promoter sequence revealed the presence, in heterozygosis, of 13 SNPs generally produced by microconversion events between gene and pseudogene. Southern blot analysis showed that the woman was heterozygote for the classic 30-kb deletion producing a new CYP21A1P/CYP21A2 chimeric gene (CH-6). The hybrid junction site was located between the end of intron 2 pseudogene, after the g.656C/A>G mutation, and the beginning of exon 3, before the 8 bp deletion. Consequently, CH-6 carries three mutations: the weak pseudogene promoter region, the p.P30L and the g.655C/A>G splice mutation. Conclusion We describe a new CYP21A1P/CYP21A2 chimera (CH-6), associated with the HLA-B15, DR13 haplotype, in a young Italian CAH patient. PMID:19624807

  19. Copy number and haplotype variation at the VRN-A1 and central FR-A2 loci are associated with frost tolerance in hexaploid wheat

    PubMed Central

    Zhu, Jie; Pearce, Stephen; Burke, Adrienne; See, Deven Robert; Skinner, Daniel Z.; Dubcovsky, Jorge; Campbell, Kimberly Garland

    2016-01-01

    Frost tolerance is critical for wheat survival during cold winters. Natural variation for this trait is mainly associated with allelic differences at the VERNALIZATION 1 (VRN1) and FROST RESISTANCE 2 (FR2) loci. VRN1 regulates the transition between vegetative and reproductive stages and FR2, a locus including several tandemly duplicated C-REPEAT BINDING FACTOR (CBF) transcription factors, regulates the expression of Cold regulated genes. We identified sequence and copy number variation at these two loci among winter and spring wheat varieties and characterized their association with frost tolerance. We identified two FR-A2 haplotypes – ‘FR-A2-S’ and ‘FR-A2-T’ – distinguished by two insertion/deletions and ten single nucleotide polymorphisms within the CBF-A12 and CBF-A15 genes. Increased copy number of CBF-A14 was frequently associated with the FR-A2-T haplotypes and with higher CBF14 transcript levels in response to cold. Factorial ANOVAs revealed significant interactions between VRN1 and FR-A2 for frost tolerance in both winter and spring panels suggesting a crosstalk between vernalization and cold acclimation pathways. The model including these two loci and their interaction explained 32.0 and 20.7% of the variation in frost tolerance in the winter and spring panels, respectively. The interaction was validated in a winter wheat F4:5 population segregating for both genes. Increased VRN-A1 copy number was associated with improved frost tolerance among varieties carrying the FR-A2-T allele but not among those carrying the FR-A2-S allele. These results suggest that selection of varieties carrying the FR-A2-T allele and three copies of the recessive vrn-A1 allele would be a good strategy to improve frost tolerance in wheat. PMID:24626953

  20. Adenosine A(1), A(2a), A(2b), and A(3) receptors in hematopoiesis. 2. Expression of receptor mRNA in resting and lipopolysaccharide-activated mouse RAW 264.7 macrophages.

    PubMed

    Streitová, D; Hofer, M; Holá, J; Vacek, A; Pospísil, M

    2010-01-01

    Expression of mRNA for adenosine receptor subtypes A(1), A(2a), A(2b), and A(3) in normal and lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages has been investigated using the method of quantitative real-time polymerase chain reaction. The results have shown a very low, unquantifiable expression of adenosine A(1) receptor mRNA in both normal and LPS-activated macrophages. The other three adenosine receptor mRNAs have been found to be expressed at various but always quantifiable levels. Activation of the macrophages by LPS induced upregulation of the expression of adenosine receptor A(2a) and A(2b) mRNA, whereas the expression of adenosine receptor A(3) mRNA was downregulated. Unstimulated macrophages exhibited a high expression of the A(2b) adenosine receptor mRNA. The findings are discussed from the point of view of the antiinflammatory and hematopoiesis-stimulating roles of the adenosine receptor signaling. PMID:19249906

  1. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Performance Verification Report: EOS AMSU-A1 and AMSU-A2 Receiver Assemblies

    NASA Technical Reports Server (NTRS)

    Ma, Y.

    1995-01-01

    The AMSU-A receiver subsystem comprises two separated receiver assemblies; AMSU-A1 and AMSU-A2 (P/N 1356441-1). The AMSU-A1 receiver contains 13 channels and the AMSU-A2 receiver 2 channels. The AMSU-A1 receiver assembly is further divided into two parts; AMSU-A1-1 (P/N 1356429-1) and AMSU-A1-2 (P/N 1356409-1), which contain 9 and 4 channels, respectively. The receiver assemblies are highlighted and illustrate the functional block diagrams of the AMSU-A1 and AMSU-A2 systems. The AMSU-A receiver subsystem stands in between the antenna and signal processing subsystems of the AMSU-A instrument and comprises the RF and IF components from isolators to attenuators. It receives the RF signals from the antenna subsystem, down-converts the RF signals to IF signals, amplifies and defines the IF signals to proper power level and frequency bandwidth as specified for each channel, and inputs the IF signals to the signal processing subsystem. This test report presents the test data of the EOS AMSU-A Flight Model No. 1 (FM-1) receiver subsystem. The tests are performed per the Acceptance Test Procedure for the AMSU-A Receiver Subsystem, AE-26002/6A. The functional performance tests are conducted either at the component or subsystem level. While the component-level tests are performed over the entire operating temperature range predicted by thermal analysis, the subsystem-level tests are conducted at ambient temperature only.

  2. Vitamin-D receptor agonist calcitriol reduces calcification in vitro through selective upregulation of SLC20A2 but not SLC20A1 or XPR1

    PubMed Central

    Keasey, M. P.; Lemos, R. R.; Hagg, T.; Oliveira, J. R. M.

    2016-01-01

    Vitamin D deficiency (hypovitaminosis D) causes osteomalacia and poor long bone mineralization. In apparent contrast, hypovitaminosis D has been reported in patients with primary brain calcifications (“Fahr’s disease”). We evaluated the expression of two phosphate transporters which we have found to be associated with primary brain calcification (SLC20A2, whose promoter has a predicted vitamin D receptor binding site, and XPR1), and one unassociated (SLC20A1), in an in vitro model of calcification. Expression of all three genes was significantly decreased in calcifying human bone osteosarcoma (SaOs-2) cells. Further, we confirmed that vitamin D (calcitriol) reduced calcification as measured by Alizarin Red staining. Cells incubated with calcitriol under calcifying conditions specifically maintained expression of the phosphate transporter SLC20A2 at higher levels relative to controls, by RT-qPCR. Neither SLC20A1 nor XPR1 were affected by calcitriol treatment and remained suppressed. Critically, knockdown of SLC20A2 gene and protein with CRISPR technology in SaOs2 cells significantly ablated vitamin D mediated inhibition of calcification. This study elucidates the mechanistic importance of SLC20A2 in suppressing the calcification process. It also suggests that vitamin D might be used to regulate SLC20A2 gene expression, as well as reduce brain calcification which occurs in Fahr’s disease and normal aging. PMID:27184385

  3. Theoretical Studies of Observable Transitions to Recoupled Pair Bonded States of Sulfur Halide Compounds: SF/SCl (X^2{Π}{→}A^2{Σ}^-), SF_2/SCl_2 (X^1A_1{→}1^1B_1, X^1A_1{→}1^1A_2), and SFCl (X^1A'{→}A^1A{'{'}})

    NASA Astrophysics Data System (ADS)

    Leiding, Jeff; Woon, David E.; Dunning, Thom H.; , Jr.

    2011-06-01

    In previous studies regarding the nature of hypervalent behavior, we identified low-lying excited states of SF(a^4{Σ}^-), SCl(a^4{Σ}^-), SF_2(a^3B_1,b^3A_2), SFCl(a^3A{'{'}}) and SCl_2(a^3B_1) that involve recoupled pair bonding (rpb), where the electrons of the S 3p^2 pair are made available to form bonds. While the transitions from the ground states to the quartet states of SF/SCl and the triplet states of SF_2/SFCl/SCl_2 are spin-forbidden, each of these excited states have analogs with formally spin- and dipole-allowed transitions (except ^1A_2). We performed high level MRCI+Q/aug-cc-pV(Q+d)Z calculations in order to characterize the electronic spectra, spectroscopic constants, and bonding of these species, and made comparisons to available experimental data. We found that excitation into the experimentally known and dipole-forbidden singlet rpb state, SCl_2(B^1A_2), can explain the well-known photodissociation behavior of SCl_2 used to produce SCl(X^2{Π}) radicals in the laboratory. Finally, we have also found a possible system of bond-stretch isomers on the SFCl(A^1A{'{'}}) potential energy surface that is analogous to the behavior on the triplet surface reported in our previous study. Howe, J. D.; Ashfold, M. N. R.; Morgan, R. A.;Western, C. M.; Buma, W. J.; Milan, J. B. and de Lang, C. A. J. Chem. Soc. Faraday Trans. 1995, 91, 773. Leiding, J.; Woon, D. E., and Dunning, T. H., Jr. J. Phys. Chem. A 2011, 115, 329.

  4. CYP1A1 and CYP1A2 expression: comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines.

    PubMed

    Uno, Shigeyuki; Endo, Kaori; Ishida, Yuji; Tateno, Chise; Makishima, Makoto; Yoshizato, Katsutoshi; Nebert, Daniel W

    2009-05-15

    Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how "human-like" can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1_CYP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+)_severe-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs. PMID:19285097

  5. CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines

    SciTech Connect

    Uno, Shigeyuki; Endo, Kaori; Ishida, Yuji; Tateno, Chise; Makishima, Makoto; Yoshizato, Katsutoshi; Nebert, Daniel W.

    2009-05-15

    Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1{sub C}YP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+){sub s}evere-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

  6. Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction.

    PubMed

    Tofovic, Stevan P; Salah, Eman M; Smits, Glenn J; Whalley, Eric T; Ticho, Barry; Deykin, Aaron; Jackson, Edwin K

    2016-02-01

    Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with metabolic syndrome. The combined A1/A2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF1 rats (n = 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF1 rats (n = 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 ± 550; BG9928 group, 2900 ± 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 ± 179; BG9928 group, 196 ± 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/day: control group, 1702 ± 263; BG9928 group, 1076 ± 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A1/A2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A1/A2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias. PMID:26585572

  7. A Novel DHPLC-Based Procedure for the Analysis of COL1A1 and COL1A2 Mutations in Osteogenesis Imperfecta

    PubMed Central

    Fuccio, Antonella; Iorio, Mariangela; Amato, Felice; Elce, Ausilia; Ingino, Rosaria; Filocamo, Mirella; Castaldo, Giuseppe; Salvatore, Francesco; Tomaiuolo, Rossella

    2011-01-01

    Approximately 90% of patients with osteogenesis imperfecta (OI) exhibit dominant COL1A1 or COL1A2 mutations; however, molecular analysis is difficult because these genes span 51 and 52 exons, respectively. We devised a PCR-denaturing high-performance liquid chromatography (DHPLC) procedure to analyze the COL1A1 or COL1A2 coding regions and validated it using 130 DNA samples from individuals without OI, 25 DNA samples from two cells to investigate the procedure's potential for preimplantation diagnosis, and DNA samples from 10 patients with OI. Three novel intronic variants in vitro were expressed using a minigene assay to assess their effects on splicing. The procedure is rapid, inexpensive, and reproducible. Analysis of samples from individuals without OI revealed six novel and some known polymorphisms useful for linkage diagnosis because of high heterozygosity. Analysis of two-cell samples confirmed the known genotype in 24 of 25 experiments; DNA failed to amplify in only one case. No incidence of allele dropout was recorded. DHPLC revealed six novel mutations, three of which were intronic, in all patients with OI, and these results were confirmed by means of COL1A1 and COL1A2 direct sequencing. Expression of intronic mutations demonstrated that variant 804 + 2_804 + 3delTG in intron 11 disrupts normal splicing, thereby leading to formation of two alternative products. Variants c.3046-4_3046-5dupCT (COL1A1) and c.891 + 77A>T (COL1A2) did not affect splicing. The described DHPLC protocol combined with the minigene assay may contribute to molecular diagnosis in OI. Moreover, this protocol will aid in counseling about prenatal and preimplantation diagnosis. PMID:21884818

  8. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively.

    PubMed Central

    Cronstein, B N; Daguma, L; Nichols, D; Hutchison, A J; Williams, M

    1990-01-01

    Occupancy of specific receptors on neutrophils by adenosine or its analogues diminishes the stimulated release of toxic oxygen metabolites from neutrophils, while paradoxically promoting chemotaxis. We now report evidence that two distinct adenosine receptors are found on neutrophils (presumably the A1 and A2 receptors of other cell types). These adenosine receptors modulate chemotaxis and O2- generation, respectively. N6-Cyclopentyladenosine (CPA), a selective A1 agonist, promoted neutrophil chemotaxis to the chemoattractant FMLP as well as or better than 5'N-ethylcarboxamidoadenosine (NECA). In contrast, CPA did not inhibit O2- generation stimulated by FMLP. Pertussis toxin completely abolished promotion of chemotaxis by CPA but enhanced inhibition by NECA of O2- generation. Disruption of microtubules by colchicine or vinblastine also abrogated the enhancement by NECA of chemotaxis whereas these agents did not markedly interfere with inhibition by NECA of O2- generation. FMLP receptors, once they have bound ligand, shift to a high affinity state and become associated with the cytoskeleton. NECA significantly increased association of [3H]FMLP with cytoskeletal preparations as it inhibited O2-. Disruption of microtubules did not prevent NECA from increasing association of [3H]FMLP with cytoskeletal preparations. Additionally, CPA (A1 agonist) did not increase binding of [3H]FMLP to the cytoskeleton as well as NECA (A2 agonist). These studies indicate that occupancy of one class of adenosine receptors (A1) promotes chemotaxis by a mechanism requiring intact microtubules and G proteins whereas engagement of a second class of receptors (A2) inhibits O2- generation. Signalling via A2 receptors is independent of microtubules, insensitive to pertussis toxin and is associated with binding of [3H]FMLP to cytoskeletal preparations. PMID:2156895

  9. Downregulation of let‑7b promotes COL1A1 and COL1A2 expression in dermis and skin fibroblasts during heat wound repair.

    PubMed

    Liu, Jinyan; Luo, Chengqun; Yin, Zhaoqi; Li, Ping; Wang, Shaohua; Chen, Jia; He, Quanyong; Zhou, Jianda

    2016-03-01

    MicroRNAs (miRs), a class of non‑coding RNAs 18‑25 nucleotides in length, generally serve suppressive role in the regulation of gene expression via directly binding to the 3'‑untranslated region (UTR) of their target mRNA. Previous studies have identified several miRs to be involved in thermal injury repair. However, the role of miR let‑7b during the recovery of thermal injury, in addition to the underlying mechanisms, has not previously been studied. In the present study, the expression of let‑7b was observed to be significantly increased in skin tissue shortly following thermal injury, however, gradually reduced during the recovery of thermal injury. Notably, similar findings were observed in heat‑denatured skin fibroblasts. Furthermore, collagen, type I, alpha 1 (COL1A1) and collagen, type I, alpha 2 (COL1A2), which are associated with the synthesis of type I collagen, were identified as two targets of let‑7b in skin fibroblasts. The overexpression of let‑7b was observed to upregulate the protein expression levels of COL1A1 and COL1A2, while knockdown of let‑7b reduced the levels of COL1A1 and COL1A2 in skin fibroblasts. Furthermore, COL1A1 and COL1A2 were significantly downregulated shortly following thermal injury, while gradually upregulated during healing, in heat‑damaged skin tissue and skin fibroblasts, with the expression profiles opposite to that of let‑7b. Taken together, this suggests that the downregulation of let‑7b in heat‑damaged dermis promotes the synthesis of type I collagen and thus aids in burn wound repair. PMID:26861712

  10. Expression of calcitonin gene-related peptide, adenosine A2a receptor and adenosine A1 receptor in experiment rat migraine models

    PubMed Central

    LU, WENXIAN; LI, BIN; CHEN, JINBO; SU, YIPENG; DONG, XIAOMENG; SU, XINYANG; GAO, LIXIANG

    2016-01-01

    A migraine is a disabling neurovascular disorder characterized by a unilateral throbbing headache that lasts from 4 to 72 h. The headache is often accompanied by nausea, vomiting, phonophobia and photophobia, and may be worsened by physical exercise. The trigeminovascular system (TVS) is speculated to have an important role in migraines, although the pathophysiology of this disorder remains to be elucidated. Trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis (TNC) are important components of the TVS. Several clinical cases have provided evidence for the involvement of the brainstem in migraine initiation. Electrical stimulation of the trigeminal ganglion (ESTG) in rats can activate TVS during a migraine attack. Calcitonin gene-related peptide (CGRP) is an important vasoactive compound produced following TVS activation. Numerous studies have revealed that adenosine and its receptors have an important role in pain transmission and regulation process. However, only a few studies have examined whether adenosine A2a receptor (A2aR) and adenosine A1 receptor (A1R) are involved in migraine and nociceptive pathways. In the present study, CGRP, A2aR and A1R expression levels were detected in the TG and TNC of ESTG models through reverse transcription-quantitative polymerase chain reaction and western blot analysis. Tianshu capsule (TSC), a type of Chinese medicine, was also used in the ESTG rat models to examine its influence on the three proteins. Results demonstrated that CGRP, A2aR and A1R mediated pain transmission and the regulation process during migraine and the expression of the three proteins was regulated by TSC. PMID:26998280

  11. Isolation of two cytochrome P450 cDNAs, CYP1A1 and CYP1A2, from harp seal (Phoca groenlandica) and grey seal (Halichoerus grypus).

    PubMed

    Tilley, Rachel E; Kemp, Graham D; Teramitsu, Ikuko; Hall, Ailsa J

    2002-06-01

    Two cytochrome P450 (CYP), CYP1A1 and CYP1A2, cDNA sequences have been isolated and cloned from harp seal (Phoca groenlandica) and grey seal (Halichoerus grypus). EROD, a model substrate for CYP1A, and heterologous antibodies have been employed as a biomarker in marine mammals, however the CYP1A sequences have not been characterised in these two seal species. mRNA was used as the template in RT-PCR, rather than DNA as this indicates transcription of the CYP1A gene in these seal species exposed to environmental contaminants. Harp and grey seal CYP1A1 amino acid sequences exhibited >99% identity and the CYP1A2 sequences were >98% identical. Phylogenetic analyses of the two seal species with other mammalian, and avian CYP1A sequences, showed the CYP1A1 and CYP1A2 sequences clustered with corresponding sequences in other mammalian species. The closest sequences to the seal CYP1As was dog CYP1A. The CYP1A sequence information presented in this study has provided the necessary data for the future production of species-specific probes for the use as biomarkers of environmental contaminant exposure. PMID:12106895

  12. Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells.

    PubMed

    Joiakim, Aby; Mathieu, Patricia A; Shelp, Catherine; Boerner, Julie; Reiners, John J

    2016-05-01

    CYP1A1andCYP1A2are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e., phosphorylated) forms of extracellular regulated kinases (ERKs) and the epidermal growth factor receptor (EGFR). Shifting to serum/EGF-deficient medium also enhanced TCDD-mediated induction of cytochrome P450 (CYP)1A1 Treatment of cells cultured in complete medium with the EGFR inhibitors gefitinib (Iressa), AG1478, and CI-1033 resulted in concentration-dependent reductions of active EGFR and ERKs, and increased CYP1A1 mRNA content ∼3- to 18-fold above basal level. EGFR inhibitors synergized with TCDD and resulted in transient CYP1A1 and CYP1A2 mRNA accumulations ∼8-fold greater (maximum at 5 hours) than that achieved with only TCDD. AG1478, gefitinib, and TCDD individually induced small increases (∼1.2- to 2.5-fold) in CYP1A1 protein content but did not cause additive or synergistic accumulations of CYP1A1 protein when used in combination. The mitogen-activated protein kinase kinase inhibitor PD184352 inhibited ERK and EGFR activation in a concentration-dependent fashion without causing CYP1A1 mRNA accumulation. However, cotreatment with PD184352 potentiated TCDD-mediatedCYP1A1induction. TCDD-mediated induction ofCYP1A1in MCF7-TETon-EGFR cells, a MCF7 variant in which EGFR expression can be controlled, was not affected by the activity status of EGFR or ERKs. Hence, EGFR signaling mutes both basal and ligand-induced expression of two aryl hydrocarbon receptor-responsive P450s in MCF10A cultures. However, these effects are cell context-dependent. Furthermore, CYP1A1 mRNA and protein abundance are not closely coupled in MCF10A cultures. PMID:26953171

  13. The effect of knockout of sulfotransferases 1a1 and 1d1 and of transgenic human sulfotransferases 1A1/1A2 on the formation of DNA adducts from furfuryl alcohol in mouse models.

    PubMed

    Sachse, Benjamin; Meinl, Walter; Glatt, Hansruedi; Monien, Bernhard H

    2014-10-01

    Furfuryl alcohol is a rodent carcinogen present in numerous foodstuffs. Sulfotransferases (SULTs) convert furfuryl alcohol into the DNA reactive and mutagenic 2-sulfoxymethylfuran. Sensitive techniques for the isotope-dilution ultra performance liquid chromatography-tandem mass spectrometry quantification of resulting DNA adducts, e.g. N (2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N (2)-MF-dG), were developed. To better understand the contribution of specific SULT forms to the genotoxicity of furfuryl alcohol in vivo, we studied the tissue distribution of N (2)-MF-dG in different mouse models. Earlier mutagenicity studies with Salmonella typhimurium strains expressing different human and murine SULT forms indicated that human SULT1A1 and murine Sult1a1 and 1d1 catalyze furfuryl alcohol sulfo conjugation most effectively. Here, we used three mouse lines to study the bioactivation of furfuryl alcohol by murine SULTs, FVB/N wild-type (wt) mice and two genetically modified models lacking either murine Sult1a1 or Sult1d1. The animals received a single dose of furfuryl alcohol, and the levels of the DNA adducts were determined in liver, kidney, lung, colon and small intestine. The effect of Sult1d1 gene disruption on the genotoxicity of furfuryl alcohol was moderate and limited to kidney and small intestine. In contrast, the absence of functional Sult1a1 had a massive influence on the adduct levels, which were lowered by 33-73% in all tissues of the female Sult1a1 null mice compared with the wt animals. The detection of high N (2)-MF-dG levels in a humanized mouse line expressing hSULT1A1/1A2 instead of endogeneous Sult1a1 and Sult1d1 supports the hypothesis that furfuryl alcohol is converted to the mutagenic 2-sulfoxymethylfuran also in humans. PMID:25053625

  14. Development of Flavone Propargyl Ethers as Potent and Selective Inhibitors of Cytochrome P450 Enzymes 1A1 and 1A2

    PubMed Central

    Sridhar, Jayalakshmi; Ellis, Jamie; Dupart, Patrick; Liu, Jiawang; Stevens, Cheryl L.; Foroozesh, Maryam

    2014-01-01

    Naturally occurring flavonoids are known to be metabolized by several cytochrome P450 enzymes including P450s 1A1, 1A2, 1B1, 2C9, 3A4, and 3A5. In general flavonoids can act as substrates, inducers, and/or inhibitors of P450 enzymes. The position of the substituents on the flavone backbone has been shown to impact the biological activity against P450 enzymes. To explore the effect of a propargyl ether substitution on flavones and flavanones, 2′-flavone propargyl ether (2′-PF), 3′-flavone propargyl ether (3′-PF), 4′-flavone propargyl ether (4′-PF), 5-flavone propargyl ether (5-PF), 6-flavone propargyl ether (6-PF), 7-flavone propargyl ether (7-PF), 6-flavanone propargyl ether (6-PFN), and 7-flavanone propargyl ether (7-PFN) were synthesized. All of the newly synthesized compounds and the parent hydroxy flavones were tested for both direct inhibition and mechanism-based inhibition of cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1. The flavone propargyl ether derivatives were found to be more potent inhibitors of P450s 1A1 and 1A2. None of the flavones and flavanones in our study showed any inhibition of P450 2A6. Only 2′-PF and 6-PFN inhibited P450 2B1. 3′-PF showed direct inhibition of P450 1A1 with the highest observed potency of 0.02 μM, in addition to its ability to cause mechanism-based inhibition with KI and kinactivation values of 0.24 μM and 0.09 min−1 for this enzyme. 7-Hydroxy flavone also exhibited mechanism-based inhibition of P450 1A1 with KI and kinactivation values of 2.43 μM and 0.115 min−1. Docking studies and QSAR studies on P450 enzymes 1A1 and 1A2 were performed which revealed important insights into the nature of binding of these molecules and provided us with good QSAR models that can be used to design new flavone derivatives. PMID:23506553

  15. Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations

    PubMed Central

    2013-01-01

    Background Classic Ehlers–Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect. Methods This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the COL5A1 gene and, if no mutation was detected, COL5A2 analysis. In the negative patients the presence of large genomic rearrangements in COL5A1 was investigated using MLPA, and positive results were confirmed via SNP-array analysis. Results We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, COL5A1 or COL5A2 mutations were detected. Twenty-one mutations were in the COL5A1 gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel COL5A2 splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the COL1A1 gene was identified in one patient with vascular-like cEDS. Conclusions Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical

  16. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.

    PubMed

    Sykes, B; Ogilvie, D; Wordsworth, P; Wallis, G; Mathew, C; Beighton, P; Nicholls, A; Pope, F M; Thompson, E; Tsipouras, P

    1990-02-01

    The segregation of COL1A1 and COL1A2, the two genes which encode the chains of type I collagen, was analyzed in 38 dominant osteogenesis imperfecta (OI) pedigrees by using polymorphic markers within or close to the genes. This was done in order to estimate the consistency of linkage of OI genes to these two loci. None of the 38 pedigrees showed evidence of recombination between the OI gene and both collagen loci, suggesting that the frequency of unlinked loci in the population must be low. From these results, approximate 95% confidence limits for the proportion of families linked to the type I collagen genes can be set between .91 and 1.00. This is high enough to base prenatal diagnosis of dominantly inherited OI on linkage to these genes even in families which are too small for the linkage to be independently confirmed to high levels of significance. When phenotypic features were compared with the concordant collagen locus, all eight pedigrees with Sillence OI type IV segregated with COL1A2. On the other hand, Sillence OI type I segregated with both COL1A1 (17 pedigrees) and COL1A2 (7 pedigrees). The concordant locus was uncertain in the remaining six OI type I pedigrees. Of several other features, the presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature. PMID:1967900

  17. Dual blockade of the A1 and A2A adenosine receptor prevents amyloid beta toxicity in neuroblastoma cells exposed to aluminum chloride.

    PubMed

    Giunta, Salvatore; Andriolo, Violetta; Castorina, Alessandro

    2014-09-01

    In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl3) enhanced the neurotoxicity of the amyloid beta(25-35) fragment (Abeta(25-35)) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A2A adenosine receptors (A2AR), although it also inhibits A1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta(25-35)+AlCl3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta(25-35)+AlCl3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A1R and A2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl3 treatment exacerbated Abeta(25-35) toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta(25-35) only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta(25-35)+AlCl3-induced damage, suggesting that A1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A1R inhibition in the setting of combined Abeta(25-35)+AlCl3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum. PMID:25058312

  18. Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo

    PubMed Central

    Dračínská, Helena; Bárta, František; Levová, Kateřina; Hudecová, Alena; Moserová, Michaela; Schmeiser, Heinz H.; Kopka, Klaus; Frei, Eva; Arlt, Volker M.; Stiborová, Marie

    2016-01-01

    Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H:quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the 32P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts. PMID:26845733

  19. Identification, characterization and genetic mapping of TLR7, TLR8a1 and TLR8a2 genes in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Palti, Yniv; Gahr, Scott A; Purcell, Maureen K; Hadidi, Sima; Rexroad, Caird E; Wiens, Gregory D

    2010-02-01

    Induction of the innate immune pathways is critical for early anti-viral defense but there is limited understanding of how teleost fish recognize viral molecules and activate these pathways. In mammals, Toll-like receptors (TLR) 7 and 8 bind single-stranded RNA of viral origin and are activated by synthetic anti-viral imidazoquinoline compounds. Herein, we identify and describe the rainbow trout (Oncorhynchus mykiss) TLR7 and TLR8 gene orthologs and their mRNA expression. Two TLR7/8 loci were identified from a rainbow trout bacterial artificial chromosome (BAC) library using DNA fingerprinting and genetic linkage analyses. Direct sequencing of two representative BACs revealed intact omTLR7 and omTLR8a1 open reading frames (ORFs) located on chromosome 3 and a second locus on chromosome 22 that contains an omTLR8a2 ORF and a putative TLR7 pseudogene. We used the omTLR8a1/2 nomenclature for the two trout TLR8 genes as phylogenetic analysis revealed that they and all the other teleost TLR8 genes sequenced to date are similar to the zebrafish TLR8a, but are distinct from the zebrafish TLR8b. The duplicated trout loci exhibit conserved synteny with other fish genomes extending beyond the tandem of TLR7/8 genes. The trout TLR7 and 8a1/2 genes are composed of a single large exon similar to all other described TLR7/8 genes. The omTLR7 ORF is predicted to encode a 1049 amino acid (aa) protein with 84% similarity to the Fugu TLR7 and a conserved pattern of predicted leucine-rich repeats (LRR). The omTLR8a1 and omTLR8a2 are predicted to encode 1035- and 1034-aa proteins, respectively, and have 86% similarity to each other. omTLR8a1 is likely the ortholog of the only Atlantic salmon TLR8 gene described to date as they have 95% aa sequence similarity. The tissue expression profiles of omTLR7, omTLR8a1 and omTLR8a2 in healthy trout were highest in spleen tissue followed by anterior and then posterior kidney tissues. Rainbow trout anterior kidney leukocytes produced elevated

  20. Identification, characterization and genetic mapping of TLR7, TLR8a1 and TLR8a2 genes in rainbow trout (Oncorhynchus mykiss)

    USGS Publications Warehouse

    Palti, Yniv; Gahr, Scott A.; Purcell, Maureen K.; Hadidi, Sima; Rexroad, Caird E., III; Wiens, Gregory A.

    2010-01-01

    Induction of the innate immune pathways is critical for early anti-viral defense but there is limited understanding of how teleost fish recognize viral molecules and activate these pathways. In mammals, Toll-like receptors (TLR) 7 and 8 bind single-stranded RNA of viral origin and are activated by synthetic anti-viral imidazoquinoline compounds. Herein, we identify and describe the rainbow trout (Oncorhynchus mykiss) TLR7 and TLR8 gene orthologs and their mRNA expression. Two TLR7/8 loci were identified from a rainbow trout bacterial artificial chromosome (BAC) library using DNA fingerprinting and genetic linkage analyses. Direct sequencing of two representative BACs revealed intact omTLR7 and omTLR8a1 open reading frames (ORFs) located on chromosome 3 and a second locus on chromosome 22 that contains an omTLR8a2 ORF and a putative TLR7 pseudogene. We used the omTLR8a1/2 nomenclature for the two trout TLR8 genes as phylogenetic analysis revealed that they and all the other teleost TLR8 genes sequenced to date are similar to the zebrafish TLR8a, but are distinct from the zebrafish TLR8b. The duplicated trout loci exhibit conserved synteny with other fish genomes extending beyond the tandem of TLR7/8 genes. The trout TLR7 and 8a1/2 genes are composed of a single large exon similar to all other described TLR7/8 genes. The omTLR7 ORF is predicted to encode a 1049 amino acid (aa) protein with 84% similarity to the Fugu TLR7 and a conserved pattern of predicted leucine-rich repeats (LRR). The omTLR8a1 and omTLR8a2 are predicted to encode 1035- and 1034-aa proteins, respectively, and have 86% similarity to each other. omTLR8a1 is likely the ortholog of the only Atlantic salmon TLR8 gene described to date as they have 95% aa sequence similarity. The tissue expression profiles of omTLR7, omTLR8a1 and omTLR8a2 in healthy trout were highest in spleen tissue followed by anterior and then posterior kidney tissues. Rainbow trout anterior kidney leukocytes produced elevated

  1. Modulation of dopamine-mediated facilitation at the neuromuscular junction of Wistar rats: A role for adenosine A1/A2A receptors and P2 purinoceptors.

    PubMed

    Elnozahi, Neveen A; AlQot, Hadir E; Mohy El-Din, Mahmoud M; Bistawroos, Azza E; Abou Zeit-Har, Mohamed S

    2016-06-21

    This study aims to understand how dopamine and the neuromodulators, adenosine and adenosine triphosphate (ATP) modulate neuromuscular transmission. Adenosine and ATP are well-recognized for their regulatory effects on dopamine in the central nervous system. However, if similar interactions occur at the neuromuscular junction is unknown. We hypothesize that the activation of adenosine A1/A2A and/or P2 purinoceptors may influence the action of dopamine on neuromuscular transmission. Using the rat phrenic nerve hemi-diaphragm, we assessed the influence of dopamine, adenosine and ATP on the height of nerve-evoked muscle twitches. We investigated how the selective blockade of adenosine A1 receptors (2.5nM DPCPX), adenosine A2A receptors (50nM CSC) and P2 purinoceptors (100μM suramin) modified the effects of dopamine. Dopamine alone increased indirect muscle contractions while adenosine and ATP either enhanced or depressed nerve-evoked muscle twitches in a concentration-dependent manner. The facilitatory effects of 256μM dopamine were significantly reduced to 29.62±2.79% or 53.69±5.45% in the presence of DPCPX or CSC, respectively, relative to 70.03±1.57% with dopamine alone. Alternatively, the action of 256μM dopamine was potentiated from 70.03±1.57, in the absence of suramin, to 86.83±4.36%, in the presence of suramin. It can be concluded that the activation of adenosine A1 and A2A receptors and P2 purinoceptors potentially play a central role in the regulation of dopamine effects at the neuromuscular junction. Clinically this study offers new insights for the indirect manipulation of neuromuscular transmission for the treatment of disorders characterized by motor dysfunction. PMID:27060487

  2. Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart

    PubMed Central

    Lee, Yong-Cheol; Jung, Jiyoon; Park, Sang-Jin

    2016-01-01

    The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs) and adenosine receptors (ADRs) in remifentanil preconditioning (R-Pre) and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP), velocity of contraction (+dP/dtmax), and coronary flow (CF) were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax, and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia). These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross-talk. PMID:26773185

  3. Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart.

    PubMed

    Lee, Yong-Cheol; Jung, Jiyoon; Park, Sang-Jin

    2016-01-01

    The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs) and adenosine receptors (ADRs) in remifentanil preconditioning (R-Pre) and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP),velocity of contraction (+dP/dtmax), and coronary flow (CF) were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax,and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia). These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross-talk. PMID:26773185

  4. Hypervelocity Impact (HVI). Volume 2; WLE Small-Scale Fiberglass Panel Flat Multi-Layer Targets A-1, A-2, and B-1

    NASA Technical Reports Server (NTRS)

    Gorman, Michael R.; Ziola, Steven M.

    2007-01-01

    During 2003 and 2004, the Johnson Space Center's White Sands Testing Facility in Las Cruces, New Mexico conducted hypervelocity impact tests on the space shuttle wing leading edge. Hypervelocity impact tests were conducted to determine if Micro-Meteoroid/Orbital Debris impacts could be reliably detected and located using simple passive ultrasonic methods. The objective of Targets A-1, A-2, and B-2 was to study hypervelocity impacts through multi-layered panels simulating Whipple shields on spacecraft. Impact damage was detected using lightweight, low power instrumentation capable of being used in flight.

  5. Revised structures of gambiriins A1, A2, B1, and B2, chalcane-flavan dimers from gambir (Uncaria gambir extract).

    PubMed

    Taniguchi, Shoko; Kuroda, Kayo; Doi, Kou-ichi; Tanabe, Masahiro; Shibata, Takashi; Yoshida, Takashi; Hatano, Tsutomu

    2007-02-01

    Gambir, the aqueous extract from Uncaria gambir (Rubiaceae), has been used as an astringent medicine in Asian countries. Investigation of the constituents in the extract led to the isolation of four chalcane-flavan dimers, gambiriin A1 (6), A2 (7), B1 (8), and B2 (9), in addition to (+)-catechin (1), (+)-epicatechin (2), and dimeric proanthocyanidins, procyanidin B1 (3), procyanidin B3 (4), and gambiriin C (5). The spectroscopic and chemical data obtained in the present study indicated that their previously proposed structures 6a, 7a, 8a, and 9a should be revised to 6, 7, 8, and 9, respectively. PMID:17268100

  6. Postsynaptic VAMP/Synaptobrevin Facilitates Differential Vesicle Trafficking of GluA1 and GluA2 AMPA Receptor Subunits

    PubMed Central

    Hussain, Suleman; Davanger, Svend

    2015-01-01

    Vertebrate organisms adapt to a continuously changing environment by regulating the strength of synaptic connections between brain cells. Excitatory synapses are believed to increase their strength by vesicular insertion of transmitter glutamate receptors into the postsynaptic plasma membrane. These vesicles, however, have never been demonstrated or characterized. For the first time, we show the presence of small vesicles in postsynaptic spines, often closely adjacent to the plasma membrane and PSD (postsynaptic density). We demonstrate that they harbor vesicle-associated membrane protein 2 (VAMP2/synaptobrevin-2) and glutamate receptor subunit 1 (GluA1). Disrupting VAMP2 by tetanus toxin treatment reduces the concentration of GluA1 in the postsynaptic plasma membrane. GluA1/VAMP2-containing vesicles, but not GluA2/VAMP2-vesicles, are concentrated in postsynaptic spines relative to dendrites. Our results indicate that small postsynaptic vesicles containing GluA1 are inserted directly into the spine plasma membrane through a VAMP2-dependent mechanism. PMID:26488171

  7. Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice

    PubMed Central

    Alshahrani, Saeed; Almutairi, Mohammed Mashari; Kursan, Shams; Dias-Junior, Eduardo; Almiahuob, Mohamed Mahmoud; Aguilar-Bryan, Lydia; Di Fulvio, Mauricio

    2015-01-01

    The products of the Slc12a1 and Slc12a2 genes, commonly known as Na+-dependent K+2Cl− co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl−]i) in pancreatic β-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl− transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele of Slc12a2 exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15–30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence of Slc12a2 associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl− uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a single Slc12a2 allele may protect β-cells from failure due to increased homeostatic expression of Slc12a1. PMID:26400961

  8. Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice.

    PubMed

    Alshahrani, Saeed; Almutairi, Mohammed Mashari; Kursan, Shams; Dias-Junior, Eduardo; Almiahuob, Mohamed Mahmoud; Aguilar-Bryan, Lydia; Di Fulvio, Mauricio

    2015-12-01

    The products of the Slc12a1 and Slc12a2 genes, commonly known as Na(+)-dependent K(+)2Cl(-) co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl(-)]i) in pancreatic β-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl(-) transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele of Slc12a2 exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15-30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence of Slc12a2 associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl(-) uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a single Slc12a2 allele may protect β-cells from failure due to increased homeostatic expression of Slc12a1. PMID:26400961

  9. The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis

    PubMed Central

    Floyd, Christopher N.; Ellis, Benjamin H.; Ferro, Albert

    2014-01-01

    Background The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke. Methods Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models. Findings A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03–1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05–1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71–1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34–2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14–2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34–2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74–1.33; p = 0.950). Egger's regression test suggested a low probability of publication bias for all analyses (p>0.05). Conclusions The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin

  10. Applications of stable V79-derived cell lines expressing rat cytochromes P4501A1, 1A2, and 2B1.

    PubMed

    Doehmer, J; Wölfel, C; Dogra, S; Doehmer, C; Seidel, A; Platt, K L; Oesch, F; Glatt, H R

    1992-01-01

    1. Chinese hamster V79-derived cell lines, stably expressing cytochromes P4501A1, 1A2, and 2B1 activities, were constructed by genetic engineering in continuation of our work to establish a battery of V79 derived cell lines designed to study the metabolism of xenobiotics. 2. Cell lines XEM1 and XEM2, expressing cytochrome P4501A1, were capable of the O-dealkylation of 7-ethoxycoumarin and the hydroxylation of benzo[a]pyrene. 3. Cell lines XEMd.MZ and XEMd.NH, expressing P4501A2, were shown to hydroxylate 17 beta-estradiol and 2-aminofluorene. 4. Cell line SD1, expressing cytochrome P4502B1, was able to hydroxylate testosterone stereo- and regio-specifically at the 16 alpha and 16 beta positions. 5. Cell lines were validated in mutagenicity, cytotoxicity, and metabolism studies employing benzo[a]pyrene, trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, cyclophosphamide, ifosfamide, and picene. 6. Construction of metabolically-competent V79-derived cell lines be recombinant DNA technology will be a fundamental improvement for the evaluation of the cytotoxic, genotoxic and pharmacological properties of a chemical. PMID:1441600

  11. Two families with Leber's hereditary optic neuropathy carrying G11778A and T14502C mutations with haplogroup H2a2a1 in mitochondrial DNA.

    PubMed

    Qiao, Chen; Wei, Tanwei; Hu, Bo; Peng, Chunyan; Qiu, Xueping; Wei, Li; Yan, Ming

    2015-08-01

    The mitochondrial haplogroup has been reported to affect the clinical expression of Leber's hereditary optic neuropathy (LHON). The present study aimed to investigate the interaction between mutations and the haplogroup of mitochondrial DNA (mtDNA) in families. Two unrelated families with LHON were enrolled in the study, and clinical, genetic and molecular characterizations were determined in the affected and unaffected family members. Polymerase chain reaction direct sequencing was performed using 24 pairs of overlapping primers for whole mtDNA to screen for mutations and haplogroup. Bioinformatics analysis was performed to evaluate the pathogenic effect of these mtDNA mutations and the haplogroup. The G11778A mutation was identified in the two families. In addition, the members of family 2 exhibited the T14502C mutation and those in family 1 exhibited the T3394C and T14502C mutations, which were regarded as secondary mutations. The penetrance of visual loss in families 1 and 2 were 30.8 and 33.3%, respectively. In addition, the two families were found to be in the H2a2a1 haplogroup. In this limited sample size, it was demonstrated that the H2a2a1 haplogroup had a possible protective effect against LHON. Additional modifying factors, including environmental factors, lifestyle, estrogen levels and nuclear genes may also be important in LHON. PMID:25936877

  12. Gene sequences for cytochromes p450 1A1 and 1A2: the need for biomarker development in sea otters (Enhydra lutris).

    PubMed

    Hook, Sharon E; Cobb, Michael E; Oris, James T; Anderson, Jack W

    2008-11-01

    There has been recent public concern regarding the impacts of environmental pollution on populations of otters. Population level impacts have been seen with otter (Lutra lutra) populations in Europe due to polychlorinated biphenyls, and with some segments of the Prince William Sound, AK, sea otter (Enhydra lutris) population following the Exxon Valdez oil spill. Despite public interest in these animals and their ecological significance, there are few tools that allow for the study of otter's response to contaminant exposure. Cytochrome p450 1A (CYP1A) performs the first step in metabolizing many xenobiotics, including many polychlorinated biphenyls and polycyclic aromatic hydrocarbons. CYP1A induction is a frequently used biomarker of exposure to these compounds. Despite the potential importance of this gene in ecological risk assessment, the complete coding sequence has not been published for any otter species. This study's objective was to isolate the gene for CYP1A1 and CYP1A2 in sea otters using a series of PCR-based approaches. The coding sequences from CYP1A1 and CYP1A2 from sea otters were identified and published in GenBank. Both CYP1A sequences are homologous to those obtained from marine mammals and other carnivores. These sequences will be useful as tools for researchers assessing contaminant exposure in mustelid populations. PMID:18761099

  13. In Situ Proteolysis for Crystallization of Membrane Bound Cytochrome P450 17A1 and 17A2 Proteins from Zebrafish.

    PubMed

    Lei, Li; Egli, Martin

    2016-01-01

    Fish and human cytochrome P450 (P450) 17A1 catalyze both steroid 17α-hydroxylation and 17α,20-lyase reactions. Fish P450 17A2 catalyzes only 17α-hydroxylation. Both enzymes are microsomal-type P450s, integral membrane proteins that bind to the membrane through their N-terminal hydrophobic segment, the signal anchor sequence. The presence of this N-terminal region renders expression of full-length proteins challenging or impossible. For some proteins, variable truncation of the signal anchor sequence precludes expression or results in poor expression levels. To crystallize P450 17A1 and 17A2 in order to gain insight into their different activities, we used an alternative N-terminal sequence to boost expression together with in situ proteolysis. Key features of our approach to identify crystallizable P450 fragments were the use of an N-terminal leader sequence, a screen composed of 12 proteases to establish optimal cleavage, variations of protease concentration in combination with an SDS-PAGE assay, and analysis of the resulting fragments using Edman sequencing. Described in this unit are protocols for vector preparation, expression, purification, and in situ proteolytic crystallization of two membrane-bound P450 proteins. © 2016 by John Wiley & Sons, Inc. PMID:27038268

  14. Shear stress–induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region

    PubMed Central

    Chen, Junmei; Gallagher, Ryan; Zheng, Ying; Chung, Dominic W.

    2011-01-01

    VWF is required for platelet adhesion to sites of vessel injury, a process vital for both hemostasis and thrombosis. Enhanced VWF secretion and oxidative stress are both hallmarks of inflammation. We recently showed that the neutrophil oxidant hypochlorous acid (HOCl) inhibits VWF proteolysis by ADAMTS13 by oxidizing VWF methionine 1606 (M1606) in the A2 domain. M1606 was readily oxidized in a substrate peptide, but required urea in multimeric plasma VWF. In the present study, we examined whether shear stress enhances VWF oxidation. With an HOCl-generating system containing myeloperoxidase (MPO) and H2O2, we found that shear stress accelerated M1606 oxidation, with 56% becoming oxidized within 1 hour. Seven other methionine residues in the VWF A1A2A3 region (containing the sites for platelet and collagen binding and ADAMTS13 cleavage) were variably oxidized, one completely. Oxidized methionines accumulated preferentially in the largest VWF multimers. HOCl-oxidized VWF was hyperfunctional, agglutinating platelets at ristocetin concentrations that induced minimal agglutination using unoxidized VWF and binding more of the nanobody AU/VWFa-11, which detects a gain-of-function conformation of the A1 domain. These findings suggest that neutrophil oxidants will both render newly secreted VWF uncleavable and alter the largest plasma VWF forms such that they become hyperfunctional and resistant to proteolysis by ADAMTS13. PMID:21917758

  15. A D-π-A1-π-A2 push-pull small molecule donor for solution processed bulk heterojunction organic solar cells.

    PubMed

    Gautam, Prabhat; Misra, Rajneesh; Biswas, Subhayan; Sharma, Ganesh D

    2016-05-18

    Herein, benzothiadiazole (BTD), as an acceptor A1, has been used as a backbone to link triphenylamine (TPA) as donor and naphthalimide (NPI) as acceptor (A2) moieties through ethylene linkers to design a small molecule. The donor-π-acceptor-π-acceptor (D-π-A1-π-A2) type small molecule denoted as was synthesized. In order to use it as an electron donor for solution processed bulk heterojunction small molecule solar cells its photonic and electronic properties were explored. The small molecule organic solar cells based on the optimized blend of with PC71BM processed in chloroform showed a power conversion efficiency (PCE) of 2.21%, which was significantly improved up to 6.67%, when a two-step annealing (TSA) treated blend was used as an active layer. The increase in the PCE was due to the enhancement in both Jsc and FF. The improvement in Jsc was related to the enhancement in the light harvesting efficiency of a TSA treated active layer relative to the as-cast layer, which is reflected in a better IPCE and better charge collection. The TSA treatment also leads to better nanoscale morphology for exciton dissociation into free charge carriers and improved crystallinity for balanced charge transport. PMID:27149659

  16. A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1

    PubMed Central

    Geissler, Rene; Simkin, Alfred; Floss, Doreen; Patel, Ravi; Fogarty, Elizabeth A.; Scheller, Jürgen; Grimson, Andrew

    2016-01-01

    3′-untranslated regions (UTRs) specify post-transcriptional fates of mammalian messenger RNAs (mRNAs), yet knowledge of the underlying sequences and mechanisms is largely incomplete. Here, we identify two related novel 3′ UTR motifs in mammals that specify transcript degradation. These motifs are interchangeable and active only within 3′ UTRs, where they are often preferentially conserved; furthermore, they are found in hundreds of transcripts, many encoding regulatory proteins. We found that degradation occurs via mRNA deadenylation, mediated by the CCR4–NOT complex. We purified trans factors that recognize the motifs and identified heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2/B1, which are required for transcript degradation, acting in a previously unknown manner. We used RNA sequencing (RNA-seq) to confirm hnRNP A1 and A2/B1 motif-dependent roles genome-wide, profiling cells depleted of these factors singly and in combination. Interestingly, the motifs are most active within the distal portion of 3′ UTRs, suggesting that their role in gene regulation can be modulated by alternative processing, resulting in shorter 3′ UTRs. PMID:27151978

  17. Involvement of Peripheral Adenosine A2 Receptors in Adenosine A1 Receptor–Mediated Recovery of Respiratory Motor Function After Upper Cervical Spinal Cord Hemisection

    PubMed Central

    James, Elysia; Nantwi, Kwaku D

    2006-01-01

    Background/Objective: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated through central adenosine A1 receptor antagonism to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although respiration is modulated by central and peripheral mechanisms, putative involvement of peripheral adenosine A2 receptors in functional recovery in our model is untested. The objective of this study was to assess the effects of peripherally located adenosine A2 receptors on recovery of respiratory function after cervical (C2) spinal cord hemisection. Methods: Respiratory activity was electrophysiologically assessed (under standardized recording conditions) in C2-hemisected adult rats with the carotid bodies intact (H-CBI; n =12) or excised (H-CBE; n =12). Animals were administered the adenosine A2 receptor agonist, CGS-21680, followed by the A1 receptor antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX), or administered DPCPX alone. Recovered respiratory activity, characterized as drug-induced activity in the previously quiescent left phrenic nerve of C2-hemisected animals in H-CBI and H-CBE rats, was compared. Recovered respiratory activity was calculated by dividing drug-induced activity in the left phrenic nerve by activity in the right phrenic nerve. Results: Administration of CGS-21680 before DPCPX (n = 6) in H-CBI rats induced a significantly greater recovery (58.5 ± 3.6%) than when DPCPX (42.6 ± 4.6%) was administered (n = 6) alone. In H-CBE rats, prior administration of CGS-21680 (n = 6) did not enhance recovery over that induced by DPCPX (n = 6) alone. Recovery in H-CBE rats amounted to 39.7 ± 3.7% and 38.4 + 4.2%, respectively. Conclusions: Our results suggest that adenosine A2 receptors located in the carotid bodies can enhance the magnitude of adenosine A1 receptor–mediated recovery of respiratory function after C2 hemisection

  18. Purification and characterization of chimeric human IgA1 and IgA2 expressed in COS and Chinese hamster ovary cells.

    PubMed

    Morton, H C; Atkin, J D; Owens, R J; Woof, J M

    1993-11-01

    Ag-specific chimeric human IgA molecules, of the two human subclasses, IgA1 and IgA2, have been expressed in two mammalian cell systems. Analysis of the secreted IgA molecules, purified in milligram quantities from stable Chinese hamster ovary transfectants by Ag affinity chromatography, has allowed a direct comparison of the biologic properties of the two subclasses. HPLC gel filtration analysis revealed that in both subclasses, the IgA molecules associate predominantly into dimers. The monomer units are presumed to interact noncovalently, inasmuch as no dimers are evident when the antibodies are subjected to SDS-PAGE. The recombinant antibodies are glycosylated, inasmuch as a lectin blotting procedure revealed that the H chains of both subclasses are recognized by Con A. When subjected to digestion by preparations of IgA1-specific proteases secreted by two pathogenic streptococcal strains, Streptococcus sanguis and Streptococcus oralis, the recombinant IgA molecules behave just as their natural equivalents. Thus, only the chimeric IgA1 molecule is cleaved, with the IgA2 remaining intact. In terms of interaction with natural effector molecules, both recombinant IgA isotypes were shown to interact with Fc alpha receptors on calcitriol-stimulated HL-60 cells with similar affinity, but neither antibody was found to interact with human C1q. The expression system described readily permits manipulation of the human IgA genes, which should lead to a fuller molecular understanding of how this important antibody mediates its function. PMID:8409433

  19. Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody-inhibited β-adrenergic mucin secretion response

    PubMed Central

    Pereira, M M C; Lloyd Mills, C; Dormer, R L; McPherson, M A

    1998-01-01

    The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated β-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β-adrenergic response and whether excessive cyclic AMP rise is required.CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured.The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion.DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion.CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism.DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not.Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis. PMID:9831904

  20. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

    PubMed Central

    Amin, N; Byrne, E; Johnson, J; Chenevix-Trench, G; Walter, S; Nolte, I M; Vink, J M; Rawal, R; Mangino, M; Teumer, A; Keers, J C; Verwoert, G; Baumeister, S; Biffar, R; Petersmann, A; Dahmen, N; Doering, A; Isaacs, A; Broer, L; Wray, N R; Montgomery, G W; Levy, D; Psaty, B M; Gudnason, V; Chakravarti, A; Sulem, P; Gudbjartsson, D F; Kiemeney, L A; Thorsteinsdottir, U; Stefansson, K; van Rooij, F J A; Aulchenko, Y S; Hottenga, J J; Rivadeneira, F R; Hofman, A; Uitterlinden, A G; Hammond, C J; Shin, S-Y; Ikram, A; Witteman, J C M; Janssens, A C J W; Snieder, H; Tiemeier, H; Wolfenbuttel, B H R; Oostra, B A; Heath, A C; Wichmann, E; Spector, T D; Grabe, H J; Boomsma, D I; Martin, N G; van Duijn, C M

    2012-01-01

    Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10−11 and 2.7 × 10−11), which were also in strong linkage disequilibrium (r2=0.7) with each other, lie in the 23-kb long commonly shared 5′ flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10−09) near NRCAM—a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10−09)—an SNP associated with blood pressure—in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10−05) and Parkinson's disease pathways (P-value=3.6 × 10−05). PMID:21876539

  1. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    PubMed

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type. PMID:26927310

  2. Ischaemia and reperfusion injury of rat liver increases expression of glutathione S-transferase A1/A2 in zone 3 of the hepatic lobule.

    PubMed Central

    Branum, G D; Selim, N; Liu, X; Whalen, R; Boyer, T D

    1998-01-01

    Effects of ischaemia-reperfusion injury (I/R) of liver on expression of rat glutathione S-transferase (rGST) isoenzymes that metabolize products of oxidative stress were examined. Rats underwent lobar liver ischaemia for 30 min followed by reperfusion. In ischaemic lobes, rGSTA1/A2 transcript levels increased significantly 12 h after I/R (2.94-fold) and protein levels increased significantly at 24 h (1.45-fold); increased transcript levels were also observed in nonischaemic lobes (1.78-fold). Superoxide dismutase prevented I/R and the increases in transcript and protein levels in ischaemic and non-ischaemic lobes. By in-situ hybridization, increases in transcript levels at 6 h were present in zones 2 and 3 of the ischaemic lobes and peaked at 12 h (2.5-fold zone 2, 4.5-fold zone 3). Significant increases in transcript levels also were observed at 24 h in zones 2 (2.0-fold) and 3 (2.9-fold) of non-ischaemic lobes. Nuclear run-off assays showed a 1.8-fold increase in rGSTA1/A2 transcription rates in ischaemic lobes at 3 h. We conclude that I/R causes increased rGSTA1/A2 expression in the zone of the hepatic lobule most susceptible to oxidative injury and that this expression may be an important defence against injury. PMID:9461493

  3. Comparative ability of various PCBs, PCDFs, and TCDD to induce cytochrome P450 1A1 and 1A2 activity following 4 weeks of treatment (short communication)

    SciTech Connect

    De Vito, M.J.; Maier, W.E.; Diliberto, J.J.; Birnbaum, L.S.

    1993-01-01

    The toxic equivalency factors (TEF) have been proposed for dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls (PCBs). The proposed TEFs, which are presently being evaluated in the authors' laboratory are currently used to estimate the potential health risk associated with exposure to complex mixtures containing these chemicals. Hepatic cytochrome P-450 1A1 and 1A2 activities were determined for all chemicals tested and compared to those from TCDD treated mice. These initial studies indicate that the interim TEFs for the dibenzofurans adequately predict the relative induction potency for these compounds. However, the TEFs proposed for the dioxin-like PCBs overestimate the potency of these compounds by factors of 10-10,000. The present study indicates that more experimental data is required before TEFs for PCBs are used in regulatory decision making.

  4. Pharmacokinetic and pharmacodynamic consequences of inhibition of terazosin metabolism via CYP3A1 and/or 3A2 by DA-8159, an erectogenic, in rats

    PubMed Central

    Oh, E Y; Bae, S K; Kwon, J W; You, M; Lee, D C; Lee, M G

    2007-01-01

    Background and purpose: Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting alpha blocker). Therefore, this study was performed with DA-8159 (a long acting PDE 5 inhibitor) and terazosin in rats to find whether or not pharmacokinetic and pharmacodynamic interactions between the two drugs were observed. Experimental approach: Pharmacokinetic and pharmacodynamic (changes in blood pressure) interactions between DA-8159 and terazosin were evaluated after simultaneous i.v. and p.o. administration of DA-8159 (30 mg kg−1) and terazosin (5 mg kg−1) to male Sprague–Dawley rats. Key results: After simultaneous i.v. and p.o. administration of terazosin and DA-8159, the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of terazosin became significantly greater (57.4 and 75.4% increase for i.v. and p.o. administration, respectively) than those of without DA-8159. The blood pressure dropping effect was considerable after simultaneous p.o. administration of DA-8159 and terazosin compared with each drug alone. Conclusions and implications: The significantly greater AUC of terazosin after both simultaneous i.v. and p.o. administration of both drugs could be due to the hepatic (both i.v. and p.o.) and intestinal (p.o.) inhibition of the metabolism of terazosin via CYP3A1 and/or 3A2 by DA-8159, since both DA-8159 and terazosin are metabolized via CYP3A1 and/or 3A2 in rats. The blood pressure lowering effect after simultaneous p.o. administration of both drugs could be due to significant increase in plasma concentrations of terazosin. PMID:17351661

  5. Annexin A1 reduces inflammatory reaction and tissue damage through inhibition of phospholipase A2 activation in adult rats following spinal cord injury.

    PubMed

    Liu, Nai-Kui; Zhang, Yi Ping; Han, Shu; Pei, Jiong; Xu, Lisa Y; Lu, Pei-Hua; Shields, Christopher B; Xu, Xiao-Ming

    2007-10-01

    Annexin A1 (ANXA1) has been suggested to be a mediator of the anti-inflammatory actions of glucocorticoids and more recently an endogenous neuroprotective agent. In the present study, we investigated the anti-inflammatory and neuroprotective effects of ANXA1 in a model of contusive spinal cord injury (SCI). Here we report that injections of ANXA1 (Ac 2-26) into the acutely injured spinal cord at 2 concentrations (5 and 20 microg) inhibited SCI-induced increases in phospholipase A2 and myeloperoxidase activities. In addition, ANXA1 administration reduced the expression of interleukin-1beta and activated caspase-3 at 24 hours, and glial fibrillary acidic protein at 4 weeks postinjury. Furthermore, ANXA1 administration significantly reversed phospholipase A2-induced spinal cord neuronal death in vitro and reduced tissue damage and increased white matter sparing in vivo, compared to the vehicle-treated controls. Fluorogold retrograde tracing showed that ANXA1 administration protected axons of long descending pathways at 6 weeks post-SCI. ANXA1 administration also significantly increased the number of animals that responded to transcranial magnetic motor-evoked potentials. However, no measurable behavioral improvement was found after these treatments. These results, particularly the improvements obtained in tissue sparing and electrophysiologic measures, suggest a neuroprotective effect of ANXA1. PMID:17917587

  6. Cloning and structural analysis of two highly divergent IgA isotypes, IgA1 and IgA2 from the duck billed platypus, Ornithorhynchus anatinus.

    PubMed

    Vernersson, M; Belov, K; Aveskogh, M; Hellman, L

    2010-01-01

    To trace the emergence of modern IgA isotypes during vertebrate evolution we have studied the immunoglobulin repertoire of a model monotreme, the platypus. Two highly divergent IgA-like isotypes (IgA1 and IgA2) were identified and their primary structures were determined from full-length cDNAs. A comparative analysis of the amino acid sequences for IgA from various animal species showed that the two platypus IgA isotypes form a branch clearly separated from their eutherian (placental) counterparts. However, they still conform to the general structure of eutherian IgA, with a hinge region and three constant domains. This indicates that the deletion of the second domain and the formation of a hinge region in IgA did occur very early during mammalian evolution, more than 166 million years ago. The two IgA isotypes in platypus differ in primary structure and appear to have arisen from a very early gene duplication, possibly preceding the metatherian eutherian split. Interestingly, one of these isotypes, IgA1, appears to be expressed in only the platypus, but is present in the echidna based on Southern blot analysis. The platypus may require a more effective mucosal immunity, with two highly divergent IgA forms, than the terrestrial echidna, due to its lifestyle, where it is exposed to pathogens both on land and in the water. PMID:19913303

  7. Formation of DNA adducts in wild-type and transgenic mice expressing human sulfotransferases 1A1 and 1A2 after oral exposure to furfuryl alcohol

    PubMed Central

    Høie, Anja Hortemo; Monien, Bernhard Hans; Sakhi, Amrit Kaur; Glatt, Hansruedi; Hjertholm, Hege; Husøy, Trine

    2015-01-01

    Furfuryl alcohol (FFA) is present in many heat-treated foods as a result of its formation via dehydration of pentoses. It is also used legally as a flavouring agent. In an inhalation study conducted in the National Toxicology Program, FFA showed some evidence of carcinogenic activity in rats and mice. FFA was generally negative in conventional genotoxicity assays, which suggests that it may be a non-genotoxic carcinogen. However, it was recently found that FFA is mutagenic in Salmonella strains expressing appropriate sulfotransferases (SULTs), such as human or mouse SULT1A1. The same DNA adducts that were formed by FFA in these strains, mainly N 2-((furan-2-yl)methyl)-2′-deoxyguanosine (N 2-MF-dG), were also detected in tissues of FFA-exposed mice and even in human lung specimens. In the present study, a single oral dose of FFA (250mg/kg body weight) or saline was administered to FVB/N mice and transgenic mice expressing human SULT1A1/1A2 on the FVB/N background. The transgenic mice were used, since human and mouse SULT1A1 substantially differ in substrate specificity and tissue distribution. DNA adducts were studied in liver, kidney, proximal and distal small intestine as well as colon, using isotope-dilution ultra performance liquid chromatography (UPLC–MS/MS). Surprisingly, low levels of adducts that may represent N 2-MF-dG were detected even in tissues of untreated mice. FFA exposure enhanced the adduct levels in colon and liver, but not in the remaining investigated tissues of wild-type (wt) mice. The situation was similar in transgenic mice, except that N 2-MF-dG levels were also strongly enhanced in the proximal small intestine. These different results between wt and transgenic mice may be attributed to the fact that human SULT1A1, but not the orthologous mouse enzyme, is strongly expressed in the small intestine. PMID:25904584

  8. A 1 + 1' resonance-enhanced multiphoton ionization scheme for rotationally state-selective detection of formaldehyde via the à (1)A2 ← X[combining tilde] (1)A1 transition.

    PubMed

    Park, G Barratt; Krüger, Bastian C; Meyer, Sven; Wodtke, Alec M; Schäfer, Tim

    2016-08-10

    The formaldehyde molecule is an important model system for understanding dynamical processes in small polyatomic molecules. However, prior to this work, there have been no reports of a resonance-enhanced multiphoton ionization (REMPI) detection scheme for formaldehyde suitable for rovibrationally state-selective detection in molecular beam scattering experiments. Previously reported tunable REMPI schemes are either non-rotationally resolved, involve multiple resonant steps, or involve many-photon ionization steps. In the current work, we present a new 1 + 1' REMPI scheme for formaldehyde. The first photon is tunable and provides rotational resolution via the vibronically allowed à (1)A2 ← X[combining tilde] (1)A1 transition. Molecules are then directly ionized from the à state by one photon of 157 nm. The results indicate that the ionization cross section from the 4(1) vibrational level of the à state is independent of the rotational level used as intermediate, to within experimental uncertainty. The 1 + 1' REMPI intensities are therefore directly proportional to the à ← X[combining tilde] absorption intensities and can be used for quantitative measurement of X[combining tilde]-state population distributions. PMID:27461406

  9. COL1A1 and COL1A2 sequencing results in cohort of patients undergoing evaluation for potential child abuse.

    PubMed

    Zarate, Yuri A; Clingenpeel, Rachel; Sellars, Elizabeth A; Tang, Xinyu; Kaylor, Julie A; Bosanko, Katherine; Linam, Leann E; Byers, Peter H

    2016-07-01

    Child abuse is a major public health concern that can explain a proportion of fractures in children. Osteogenesis imperfecta (OI) is the most common inherited syndrome that predisposes to skeletal fractures. We conducted a retrospective analysis of data from clinical, laboratory, and radiographic information from children evaluated for child abuse in which molecular testing for COL1A1 and COL1A2 genes was conducted. A total of 43 patients underwent molecular testing for OI. Pathogenic variants predicted to result in a mild form of OI were found in two patients (5%), both clinically suspected to have this diagnosis. None of the cases in whom OI molecular testing was ordered when maltreatment concerns were thought to be more likely (0/35) were identified to have pathogenic variants. After reviewing each individual case, the final diagnosis was child abuse for 34 cases (77%), and additional radiographic and laboratory studies did not identify any with inherited metabolic predisposition to fracture or rickets. We conclude that routine testing for OI in the setting of child abuse when no other suggestive clinical findings are present has a low yield. A careful review of the medical history and a detailed clinical evaluation help identify those at risk for genetic alterations. © 2016 Wiley Periodicals, Inc. PMID:27090748

  10. DNA adducts induced by food mutagen PhIP in a mouse model expressing human sulfotransferases 1A1 and 1A2.

    PubMed

    Høie, Anja Hortemo; Monien, Bernhard Hans; Glatt, Hansruedi; Hjertholm, Hege; Husøy, Trine

    2016-04-25

    Food processing contaminant 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) has previously been shown to induce formation of DNA adducts in vivo. In a previous study the adduct levels were found to increase in a mouse model expressing human (h) sulfotransferases (SULTs) 1A1 and 1A2 after PhIP exposure, detected by (32)P-postlabelling. Isotope dilution ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) is emerging as the method of choice for selective and reproducible detection of known DNA adducts. In the present study we investigated the level and distribution of PhIP induced DNA adducts in male FVB mice 9-11 weeks of age with hSULT mice or wild-type mice (wt) using UPLC-MS/MS. Mice received a single administration of 75 mg/kg bw PhIP by oral gavage, and DNA was analysed 3h after exposure. C8-(2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine- N(2)-yl)-2'-deoxyguanosine (C8-PhIP-dG) adduct levels are significantly higher in PhIP exposed hSULT mice compared with PhIP exposed wt mice. The liver was the least affected organ in wild-type mice, whereas it was the most affected organ in hSULT mice with a 14-fold higher adduct level. PMID:26940682

  11. Identification and Quantification of Fumonisin A1, A2, and A3 in Corn by High-Resolution Liquid Chromatography-Orbitrap Mass Spectrometry

    PubMed Central

    Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Harayama, Koichi; Toriba, Akira; Hayakawa, Kazuichi

    2015-01-01

    Three compounds, hypothesized as fumonisin A1 (FA1), fumonisin A2 (FA2), and fumonisin A3 (FA3), were detected in a corn sample contaminated with mycotoxins by high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS). One of them has been identified as FA1 synthesized by the acetylation of fumonisin B1 (FB1), and established a method for its quantification. Herein, we identified the two remaining compounds as FA2 and FA3, which were acetylated fumonisin B2 (FB2) and fumonisin B3 (FB3), respectively. Moreover, we examined a method for the simultaneous analysis of FA1, FA2, FA3, FB1, FB2, and FB3. The corn samples were prepared by extraction using a QuEChERS kit and purification using a multifunctional cartridge. The linearity, recovery, repeatability, limit of detection, and limit of quantification of the method were >0.99, 82.9%–104.6%, 3.7%–9.5%, 0.02–0.60 μg/kg, and 0.05–1.98 μg/kg, respectively. The simultaneous analysis of the six fumonisins revealed that FA1, FA2, and FA3 were present in all corn samples contaminated with FB1, FB2, and FB3. The results suggested that corn marketed for consumption can be considered as being contaminated with both the fumonisin B-series and with fumonisin A-series. This report presents the first identification and quantification of FA1, FA2, and FA3 in corn samples. PMID:25690692

  12. Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a

    PubMed Central

    Carlsen, Thomas H.R.; Pedersen, Jannie; Prentoe, Jannick C.; Giang, Erick; Keck, Zhen-Yong; Mikkelsen, Lotte S.; Law, Mansun; Foung, Steven K. H.; Bukh, Jens

    2015-01-01

    Human monoclonal antibodies (HMAbs) with neutralizing capabilities constitute potential immune-based treatments or prophylaxis against hepatitis C virus (HCV). However, lack of cell culture-derived HCV (HCVcc) harboring authentic envelope proteins (E1/E2) has hindered neutralization investigations across genotypes, subtypes, and isolates. We investigated the breadth of neutralization of 10 HMAbs with therapeutic potential against a panel of 16 JFH1-based HCVcc expressing patient-derived Core-NS2 from genotypes 1a (strains H77, TN, and DH6), 1b (J4, DH1, and DH5), 2a (J6, JFH1, and T9), 2b (J8, DH8, and DH10), 2c (S83), and 3a (S52, DBN, and DH11). Virus stocks used for in vitro neutralization analysis contained authentic E1/E2, with the exception of full-length JFH1 that acquired the N417S substitution in E2. The 50% inhibition concentration (IC50) for each HMAb against the HCVcc panel was determined by dose-response neutralization assays in Huh7.5 cells with antibody concentrations ranging from 0.0012 to 100 μg/ml. Interestingly, IC50-values against the different HCVcc’s exhibited large variations among the HMAbs, and only three HMAbs (HC-1AM, HC84.24, and AR4A) neutralized all 16 HCVcc recombinants. Furthermore, the IC50-values for a given HMAb varied greatly with the HCVcc strain, which supports the use of a diverse virus panel. In cooperation analyses, HMAbs HC84.24, AR3A, and, especially HC84.26, demonstrated synergistic effects towards the majority of the HCVcc’s when combined individually with AR4A. Conclusion: Through a neutralization analysis of 10 clinically relevant HMAbs against 16 JFH1-based Core-NS2 recombinants from genotypes 1a, 1b, 2a, 2b, 2c, and 3a, we identified at least 3 HMAbs with potent and broad neutralization potential. The neutralization synergism obtained when pooling the most potent HMAbs could have significant implications for developing novel strategies to treat and control HCV. PMID:25043937

  13. The Localization of Cytochrome P450s CYP1A1 and CYP1A2 into Different Lipid Microdomains Is Governed by Their N-terminal and Internal Protein Regions.

    PubMed

    Park, Ji Won; Reed, James R; Backes, Wayne L

    2015-12-01

    In cellular membranes, different lipid species are heterogeneously distributed forming domains with different characteristics. Ordered domains are tightly packed with cholesterol, sphingomyelin, and saturated fatty acids, whereas disordered domains contain high levels of unsaturated fatty acids. Our laboratory has shown that membrane heterogeneity affects the organization of cytochrome P450s and their cognate redox partner, the cytochrome P450 reductase (CPR). Despite the high degree of sequence similarity, CYP1A1 was found to localize to disordered regions, whereas CYP1A2 resided in ordered domains. We hypothesized that regions of amino acid sequence variability may contain signal motifs that direct CYP1A proteins into ordered or disordered domains. Thus, chimeric constructs of CYP1A1 and CYP1A2 were created, and their localization was tested in HEK293T cells. CYP1A2, containing the N-terminal regions from CYP1A1, no longer localized in ordered domains, whereas the N terminus of CYP1A2 partially directed CYP1A1 into ordered regions. In addition, intact CYP1A2 containing a 206-302-residue peptide segment of CYP1A1 had less affinity to bind to ordered microdomains. After expression, the catalytic activity of CYP1A2 was higher than that of the CYP1A1-CYP1A2 chimera containing the N-terminal end of CYP1A1 with subsaturating CPR concentrations, but it was approximately equal with excess CPR suggesting that the localization of the CYP1A enzyme in ordered domains favored its interaction with CPR. These data demonstrate that both the N-terminal end and an internal region of CYP1A2 play roles in targeting CYP1A2 to ordered domains, and domain localization may influence P450 function under conditions that resemble those found in vivo. PMID:26468279

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2016-01-01

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

  16. 75 FR 910 - Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-07

    ...-07R1, Amendment 39-15179 (72 FR 49183, August 28, 2007) and AD 2007-05-16, Amendment 39-14977 (72 FR... FR 17799). That action proposed to require: Replacing certain fan disks installed on regional jets... instructions related to operators who fly a regional jet (RJ) with the CF34-3A1 engine as a business jet...

  17. Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2.

    PubMed

    Bauer-Marinovic, Morana; Taugner, Felicitas; Florian, Simone; Glatt, Hansruedi

    2012-05-01

    5-Sulphooxymethylfurfural (SMF), an electrophilic metabolite of the abundant Maillard product 5-hydroxymethylfurfural (HMF), was intraperitoneally administered to FVB/N mice. At a dosage of 250 mg/kg, most animals died after 5-11 days due to massive damage to proximal tubules. At lower dosages, administered repeatedly, tubules also were the major target of toxicity, with regeneration and atypical hyperplasia occurring at later periods. Additionally, hepatotoxic effects and serositis of peritoneal tissues were observed. SMF is a minor metabolite of HMF in conventional mice, but HMF is an excellent substrate for a major sulphotransferase (hSULT1A1) in humans. Parental FVB/N mice and FVB/N-hSULT1A1/2 mice, carrying multiple copies of the hSULT1A1/2 gene cluster, were exposed to HMF in drinking water (0, 134 and 536 mg/kg body mass/day) for 12 weeks. Nephrotoxic effects and enhanced proliferation of hepatocytes were only detected at the high dosage. They were mild and, surprisingly, unaffected by hSULT1A1/2 expression. Thus, SMF was a potent nephrotoxicant when administered as a bolus, but did not reach levels sufficient to produce serious toxicity when generated from HMF administered continuously via drinking water. This was even the case in transgenic mice expressing clearly higher HMF sulphation activity in liver and kidney than humans. PMID:22349055

  18. EphrinA1-EphA2 Signal Induces Compaction and Polarization of Madin-Darby Canine Kidney Cells by Inactivating Ezrin through Negative Regulation of RhoA*

    PubMed Central

    Wakayama, Yuki; Miura, Koichi; Sabe, Hisataka; Mochizuki, Naoki

    2011-01-01

    The epithelial cells exhibit either a columnar or a flat shape dependent on extracellular stimuli or the cell-cell adhesion. Membrane-anchored ephrinA stimulates EphA receptor tyrosine kinases as a ligand in a cell-cell contact-dependent manner. The mechanism through which ephrinA1/EphA2 signal regulates the cell morphology remains elusive. We demonstrate here that ephrinA1/EphA2 signal induces compaction and enhanced polarization (columnar change) of Madin-Darby canine kidney epithelial cells by regulating Ezrin, a linker that connects plasma membrane and actin cytoskeleton. Activation of EphA2 resulted in RhoA inactivation through p190RhoGAP-A and subsequent dephosphorylation of Ezrin on Thr-567 phosphorylated by Rho kinase. Consistently, the cells expressing an active mutant of Ezrin in which Thr-567 was replaced with Asp did not change their shape in response to ephrinA1. Furthermore, depletion of Ezrin led to compaction and enhanced polarization without ephrinA1 stimulation, suggesting the role for active Ezrin in keeping the flat cell shape. Ezrin localized to apical domain irrespective of ephrinA1 stimulation, whereas phosphorylated Ezrin on the apical domain was reduced by ephrinA1 stimulation. Collectively, ephrinA1/EphA2 signal negatively regulates Ezrin and promotes the alteration of cell shape, from flat to columnar shape. PMID:21979959

  19. Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors.

    PubMed

    Squarcialupi, Lucia; Falsini, Matteo; Catarzi, Daniela; Varano, Flavia; Betti, Marco; Varani, Katia; Vincenzi, Fabrizio; Dal Ben, Diego; Lambertucci, Catia; Volpini, Rosaria; Colotta, Vittoria

    2016-06-15

    A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1-31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22-31) displayed nanomolar affinity for the hA2A AR (Ki=3.62-57nM) and slightly lower for the hA1 ARs, thus showing different degrees (3-22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki=3.62nM and 18nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki=5.26nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs. PMID:27161878

  20. Regulation of the AbrA1/A2 Two-Component System in Streptomyces coelicolor and the Potential of Its Deletion Strain as a Heterologous Host for Antibiotic Production

    PubMed Central

    Rico, Sergio; Yepes, Ana; Rodríguez, Héctor; Santamaría, Jorge; Antoraz, Sergio; Krause, Eva M.; Díaz, Margarita; Santamaría, Ramón I.

    2014-01-01

    The Two-Component System (TCS) AbrA1/A2 from Streptomyces coelicolor M145 is a negative regulator of antibiotic production and morphological differentiation. In this work we show that it is able to auto-regulate its expression, exerting a positive induction of its own operon promoter, and that its activation is dependent on the presence of iron. The overexpression of the abrA2 response regulator (RR) gene in the mutant ΔabrA1/A2 results in a toxic phenotype. The reason is an excess of phosphorylated AbrA2, as shown by phosphoablative and phosphomimetic AbrA2 mutants. Therefore, non-cognate histidine kinases (HKs) or small phospho-donors may be responsible for AbrA2 phosphorylation in vivo. The results suggest that in the parent strain S. coelicolor M145 the correct amount of phosphorylated AbrA2 is adjusted through the phosphorylation-dephosphorylation activity rate of the HK AbrA1. Furthermore, the ABC transporter system, which is part of the four-gene operon comprising AbrA1/A2, is necessary to de-repress antibiotic production in the TCS null mutant. Finally, in order to test the possible biotechnological applications of the ΔabrA1/A2 strain, we demonstrate that the production of the antitumoral antibiotic oviedomycin is duplicated in this strain as compared with the production obtained in the wild type, showing that this strain is a good host for heterologous antibiotic production. Thus, this genetically modified strain could be interesting for the biotechnology industry. PMID:25303210

  1. Solution structure determination of monomeric human IgA2 by X-ray and neutron scattering, analytical ultracentrifugation and constrained modelling: a comparison with monomeric human IgA1.

    PubMed

    Furtado, Patricia B; Whitty, Patrick W; Robertson, Alexis; Eaton, Julian T; Almogren, Adel; Kerr, Michael A; Woof, Jenny M; Perkins, Stephen J

    2004-05-14

    Immunoglobulin A (IgA), the most abundant human immunoglobulin, mediates immune protection at mucosal surfaces as well as in plasma. It exists as two subclasses IgA1 and IgA2, and IgA2 is found in at least two allotypic forms, IgA2m(1) or IgA2m(2). Compared to IgA1, IgA2 has a much shorter hinge region, which joins the two Fab and one Fc fragments. In order to assess its solution structure, monomeric recombinant IgA2m(1) was studied by X-ray and neutron scattering. Its Guinier X-ray radius of gyration R(G) is 5.18 nm and its neutron R(G) is 5.03 nm, both of which are significantly smaller than those for monomeric IgA1 at 6.1-6.2 nm. The distance distribution function P(r)for IgA2m(1) showed a broad peak with a subpeak and gave a maximum dimension of 17 nm, in contrast to the P(r) curve for IgA1, which showed two distinct peaks and a maximum dimension of 21 nm. The sedimentation coefficients of IgA1 and IgA2m(1) were 6.2S and 6.4S, respectively. These data show that the solution structure of IgA2m(1) is significantly more compact than IgA1. The complete monomeric IgA2m(1) structure was modelled using molecular dynamics to generate random IgA2 hinge structures, to which homology models for the Fab and Fc fragments were connected to generate 10,000 full models. A total of 104 compact best-fit IgA2m(1) models gave good curve fits. These best-fit models were modified by linking the two Fab light chains with a disulphide bridge that is found in IgA2m(1), and subjecting these to energy refinement to optimise this linkage. The averaged solution structure of the arrangement of the Fab and Fc fragments in IgA2m(1) was found to be predominantly T-shaped and flexible, but also included Y-shaped structures. The IgA2 models show full steric access to the two FcalphaRI-binding sites at the Calpha2-Calpha3 interdomain region in the Fc fragment. Since previous scattering modelling had shown that IgA1 also possessed a flexible T-shaped solution structure, such a T-shape may be

  2. HTR-PROTEUS Pebble Bed Experimental Program Cores 1, 1A, 2, and 3: Hexagonal Close Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    John D. Bess; Barbara H. Dolphin; James W. Sterbentz; Luka Snoj; Igor Lengar; Oliver Köberl

    2012-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. Four benchmark experiments were evaluated in this report: Cores 1, 1A, 2, and 3. These core configurations represent the hexagonal close packing (HCP) configurations of the HTR-PROTEUS experiment with a moderator-to-fuel pebble ratio of 1:2. Core 1 represents the only configuration utilizing ZEBRA control rods. Cores 1A, 2, and 3 use withdrawable, hollow, stainless steel control rods. Cores 1 and 1A are similar except for the use of different control rods; Core 1A also has one less layer of pebbles (21 layers instead of 22). Core 2 retains the first 16 layers of pebbles from Cores 1 and 1A and has 16 layers of moderator pebbles stacked above the fueled layers. Core 3 retains the first 17 layers of pebbles but has polyethylene rods inserted between pebbles to simulate water ingress. The additional partial pebble layer (layer 18) for Core 3 was not included as it was used for core operations and not the reported critical configuration. Cores 1, 1A, 2, and 3 were determined to be acceptable benchmark experiments.

  3. HTR-PROTEUS Pebble Bed Experimental Program Cores 1, 1A, 2, and 3: Hexagonal Close Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    John D. Bess; Barbara H. Dolphin; James W. Sterbentz; Luka Snoj; Igor Lengar; Oliver Köberl

    2013-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. Four benchmark experiments were evaluated in this report: Cores 1, 1A, 2, and 3. These core configurations represent the hexagonal close packing (HCP) configurations of the HTR-PROTEUS experiment with a moderator-to-fuel pebble ratio of 1:2. Core 1 represents the only configuration utilizing ZEBRA control rods. Cores 1A, 2, and 3 use withdrawable, hollow, stainless steel control rods. Cores 1 and 1A are similar except for the use of different control rods; Core 1A also has one less layer of pebbles (21 layers instead of 22). Core 2 retains the first 16 layers of pebbles from Cores 1 and 1A and has 16 layers of moderator pebbles stacked above the fueled layers. Core 3 retains the first 17 layers of pebbles but has polyethylene rods inserted between pebbles to simulate water ingress. The additional partial pebble layer (layer 18) for Core 3 was not included as it was used for core operations and not the reported critical configuration. Cores 1, 1A, 2, and 3 were determined to be acceptable benchmark experiments.

  4. Earth Observing System/Advanced Microwave Sounding Unit-A (EOS/AMSU-A): Reliability prediction report for module A1 (channels 3 through 15) and module A2 (channels 1 and 2)

    NASA Technical Reports Server (NTRS)

    Geimer, W.

    1995-01-01

    This report documents the final reliability prediction performed on the Earth Observing System/Advanced Microwave Sounding Unit-A (EOS/AMSU-A). The A1 Module contains Channels 3 through 15, and is referred to herein as 'EOS/AMSU-A1'. The A2 Module contains Channels 1 and 2, and is referred herein as 'EOS/AMSU-A2'. The 'specified' figures were obtained from Aerojet Reports 8897-1 and 9116-1. The predicted reliability figure for the EOS/AMSU-A1 meets the specified value and provides a Mean Time Between Failures (MTBF) of 74,390 hours. The predicted reliability figure for the EOS/AMSU-A2 meets the specified value and provides a MTBF of 193,110 hours.

  5. 78 FR 56921 - South Bay Salt Pond Restoration Project, Phase 2 (Ponds R3, R4, R5, S5, A1, A2W, A8, A8S, A19...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-16

    ... Fish and Wildlife Service South Bay Salt Pond Restoration Project, Phase 2 (Ponds R3, R4, R5, S5, A1... restoration of ponds R3, R4, R5, S5, A1, A2W, A8, A8S, A19, A20, and A21 at the Don Edwards National Wildlife... 2 of the South Bay Salt Pond Restoration Project and consists of restoring and enhancing over...

  6. CYP1A1 and CYP1A2 expression levels are differentially regulated in three-dimensional spheroids of liver cancer cells compared to two-dimensional monolayer cultures.

    PubMed

    Terashima, Jun; Goto, Shinpei; Hattori, Hiroki; Hoshi, Sawaka; Ushirokawa, Midori; Kudo, Kenzo; Habano, Wataru; Ozawa, Shogo

    2015-12-01

    Compared to two-dimensional (2D) monolayer cultures, three-dimensional (3D) tumor cell culture models are thought to be structurally more similar to the in vivo tumor microenvironment. We investigated the regulation of the expression of genes encoding the drug-metabolizing enzymes CYP1A1 and CYP1A2 in 3D spheroids comprised of cells of the human hepatocellular carcinoma cell JHH1, Huh7, and HepG2. Expression of CYP1A1 and CYP1A2 in the spheroids was higher than that in 2D cultured cells. Expression of CYP1A1 and CYP1A2 is regulated by aryl hydrocarbon receptor (AhR) in 2D cultured cells. Knockdown of AhR in spheroids suppressed CYP1A1 expression; however, CYP1A2 expression levels remained unchanged. Moreover, we found that pregnane X receptor (PXR) likely regulated CYP1A2 expression in JHH1, HepG2, and Huh7 spheroids and that CYP1A1 expression in JHH1 and Huh7 3D spheroids is regulated not only by AhR but also by PXR. It is well known that gene expression levels are different between 3D spheroids and 2D monolayer cultured cells, and our results indicate that the regulation of gene expression also varies between the two culture conditions. Taken together, these results underlie a novel finding regarding the regulation of drug-metabolizing enzyme expression in liver cancer cells growing as 3D spheroids. PMID:26643992

  7. Sequencing and characterization of mixed function monooxygenase genes CYP1A1 and CYP1A2 of Mink (Mustela vison) to facilitate study of dioxin-like compounds

    SciTech Connect

    Zhang Xiaowei; Moore, Jeremy N.; Newsted, John L.; Hecker, Markus Zwiernik, Matthew J.; Jones, Paul D.; Bursian, Steven J.

    2009-02-01

    As part of an ongoing effort to understand aryl hydrocarbon receptor (AhR) mediated toxicity in mink, cDNAs encoding for CYP1A1 and the CYP1A2 mixed function monooxygenases were cloned and characterized. In addition, the effects of selected dibenzofurans on the expression of these genes and the presence of their respective proteins (P4501A) were investigated, and then correlated with the catalytic activities of these proteins as measured by ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) activities. The predicted protein sequences for CYP1A1 and CYP1A2 comprise 517 and 512 amino acid residues, respectively. The phylogenetic analysis of the mink CYP1As with protein sequences of other mammals revealed high sequence homology with sea otter, seals and the dog, with amino acid identities ranging from 89 to 95% for CYP1A1 and 81 to 93% for CYP1A2. Since exposure to both 2,3,7,8-Tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) resulted in dose-dependent increases of CYP1A1 mRNA, CYP1A2 mRNA and CYP1A protein levels an underlying AhR-mediated mechanism is suggested. The up-regulation of CYP1A mRNA in liver was more consistent to the sum adipose TEQ concentration than to the liver TEQ concentration in minks treated with TCDF or PeCDF. The result suggested that the hepatic-sequestered fraction of PeCDF was biologically inactive to the induction of CYP1A1 and CYP1A2.

  8. STAT5a promotes the transcription of mature mmu-miR-135a in 3T3-L1 cells by binding to both miR-135a-1 and miR-135a-2 promoter elements.

    PubMed

    Wei, Xiajie; Cheng, Xiaoyan; Peng, Yongdong; Zheng, Rong; Chai, Jin; Jiang, Siwen

    2016-08-01

    Despite extensive research on the role of miR-135a in biological processes, very little attention has been paid to the regulation of its transcription. We have previously reported that miR-135a suppresses 3T3-L1 preadipocyte differentiation and adipogenesis by directly targeting the adenomatous polyposis coli (APC) gene and activating the canonical Wnt/β-catenin signaling pathway, but the regulatory elements that regulate the expression of the two isoforms of miR-135a (miR-135a-1 and miR-135a-2) remain poorly understood. Here, by using deletion analysis, we predicted two binding sites (-874/-856 and -2020/-2002) for the transcription factor Signal Transducers and Activators of Transcription 5a (STAT5a) within the core promoters of miR-135a-1 and miR-135a-2 (-1128/-556 and -2264/-1773), and the subsequent site-directed mutagenesis indicated that the two STAT5a binding sites regulated the activity of the miR-135a-1 and miR-135a-2 promoters. The binding of STAT5a to the miR-135a-1/2 core promoters in vitro and in cell culture was identified by electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays. Overexpression and RNAi knockdown of STAT5a showed that the transcription factor regulated the endogenous miR-135a expression. Additionally, The expression time frame of STAT5a and APC indicated a potential negative feedback between them. In sum, the overall results from this study indicate that STAT5a regulates miR-135a transcription by binding to both miR-135a-1 and miR135a-2 promoter elements and the findings provide novel insights into the molecular regulatory mechanisms of miR-135a during adipogenesis. PMID:27276245

  9. Comparative Analysis of the Tyr-Kinases CapB1 and CapB2 Fused to Their Cognate Modulators CapA1 and CapA2 from Staphylococcus aureus

    PubMed Central

    Fleurie, Aurore; Béchet, Emmanuelle; Gueguen-Chaignon, Virginie; Freton, Céline; Aumont-Nicaise, Magali; Moréra, Solange; Grangeasse, Christophe; Nessler, Sylvie

    2013-01-01

    A particular class of tyrosine-kinases sharing no structural similarity with eukaryotic tyrosine-kinases has been evidenced in a large array of bacterial species. These bacterial tyrosine-kinases are able to autophosphorylate on a C-terminal tyrosine-rich motif. Their autophosphorylation has been shown to play a crucial role in the biosynthesis or export of capsular polysaccharide. The analysis of the first crystal structure of the staphylococcal tyrosine kinase CapB2 associated with the activating domain of the transmembrane modulator CapA1 had brought conclusive explanation for both the autophosphorylation and activation processes. In order to explain why CapA1 activates CapB2 more efficiently than its cognate transmembrane modulator CapA2, we solved the crystal structure of CapA2B2 and compared it with the previously published structure of CapA1B2. This structural analysis did not provide the expected clues about the activation discrepancy observed between the two modulators. Staphylococcus aureus also encodes for a CapB2 homologue named CapB1 displaying more than 70% sequence similarity and being surprisingly nearly unable to autophosphorylate. We solved the crystal structure of CapA1B1 and carefully compare it with the structure of CapA1B2. The active sites of both proteins are highly conserved and the biochemical characterization of mutant proteins engineered to test the importance of small structural discrepancies identified between the two structures did not explain the inactivity of CapB1. We thus tested if CapB1 could phosphorylate other protein substrates or hydrolyze ATP. However, no activity could be detected in our in vitro assays. Taken together, these data question about the biological role of the homologous protein pairs CapA1/CapB1 and CapA2/CapB2 and we discuss about several possible interpretations. PMID:24146800

  10. Ethanol and 4-methylpyrazole increase DNA adduct formation of furfuryl alcohol in FVB/N wild-type mice and in mice expressing human sulfotransferases 1A1/1A2.

    PubMed

    Sachse, Benjamin; Meinl, Walter; Glatt, Hansruedi; Monien, Bernhard H

    2016-03-01

    Furfuryl alcohol (FFA) is a carcinogenic food contaminant, which is formed by acid- and heat-catalyzed degradation of fructose and glucose. The activation by sulfotransferases (SULTs) yields a DNA reactive and mutagenic sulfate ester. The most prominent DNA adduct, N(2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N(2)-MF-dG), was detected in FFA-treated mice and also in human tissue samples. The dominant pathway of FFA detoxification is the oxidation via alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The activity of these enzymes may be greatly altered in the presence of inhibitors or competitive substrates. Here, we investigated the impact of ethanol and the ADH inhibitor 4-methylpyrazole (4MP) on the DNA adduct formation by FFA in wild-type and in humanized mice that were transgenic for human SULT1A1/1A2 and deficient in the mouse (m) Sult1a1 and Sult1d1 genes (h1A1/1A2/1a1(-)/1d1(-)). The administration of FFA alone led to hepatic adduct levels of 4.5 N(2)-MF-dG/10(8) nucleosides and 33.6 N(2)-MF-dG/10(8) nucleosides in male and female wild-type mice, respectively, and of 19.6 N(2)-MF-dG/10(8) nucleosides and 95.4 N(2)-MF-dG/10(8) nucleosides in male and female h1A1/1A2/1a1(-)/1d1(-) mice. The coadministration of 1.6g ethanol/kg body weight increased N(2)-MF-dG levels by 2.3-fold in male and by 1.7-fold in female wild-type mice and by 2.5-fold in male and by 1.5-fold in female h1A1/1A2/1a1(-)/1d1(-) mice. The coadministration of 100mg 4MP/kg body weight had a similar effect on the adduct levels. These findings indicate that modulators of the oxidative metabolism, e.g. the drug 4MP or consumption of alcoholic beverages, may increase the genotoxic effects of FFA also in humans. PMID:26775039

  11. Loss of Interdependent Binding by the FoxO1 and FoxA1/A2 Forkhead Transcription Factors Culminates in Perturbation of Active Chromatin Marks and Binding of Transcriptional Regulators at Insulin-sensitive Genes.

    PubMed

    Yalley, Akua; Schill, Daniel; Hatta, Mitsutoki; Johnson, Nicole; Cirillo, Lisa Ann

    2016-04-15

    FoxO1 binds to insulin response elements located in the promoters of insulin-like growth factor-binding protein 1 (IGFBP1) and glucose-6-phosphatase (G6Pase), activating their expression. Insulin-mediated phosphorylation of FoxO1 promotes cytoplasmic translocation, inhibiting FoxO1-mediated transactivation. We have previously demonstrated that FoxO1 opens and remodels chromatin assembled from the IGFBP1 promoter via a highly conserved winged helix motif. This finding, which established FoxO1 as a "pioneer" factor, suggested a model whereby FoxO1 chromatin remodeling at regulatory targets facilitates binding and recruitment of additional regulatory factors. However, the impact of FoxO1 phosphorylation on its ability to bind chromatin and the effect of FoxO1 loss on recruitment of neighboring transcription factors at its regulatory targets in liver chromatin is unknown. In this study, we demonstrate that an amino acid substitution that mimics insulin-mediated phosphorylation of a serine in the winged helix DNA binding motif curtails FoxO1 nucleosome binding. We also demonstrate that shRNA-mediated loss of FoxO1 binding to the IGFBP1 and G6Pase promoters in HepG2 cells significantly reduces binding of RNA polymerase II and the pioneer factors FoxA1/A2. Knockdown of FoxA1 similarly reduced binding of RNA polymerase II and FoxO1. Reduction in acetylation of histone H3 Lys-27 accompanies loss of FoxO1 and FoxA1/A2 binding. Interdependent binding of FoxO1 and FoxA1/A2 possibly entails cooperative binding because FoxO1 and FoxA1/A2 facilitate one another's binding to IGFPB1 promoter DNA. These results illustrate how transcription factors can nucleate transcriptional events in chromatin in response to signaling events and suggest a model for regulation of hepatic glucose metabolism through interdependent FoxO/FoxA binding. PMID:26929406

  12. Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients

    PubMed Central

    Guzmán, Fanny; Rosas, Fernando; Thomas, M. Carmen; López, Manuel Carlos; González, John Mario; Cuéllar, Adriana; Puerta, Concepción J.

    2016-01-01

    Background TcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide. Methodology/Principal Findings From 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN-γ, TNFα, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07–0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation. Conclusion/Significance These results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy. PMID:26974162

  13. Characterization of differences in substrate specificity among CYP1A1, CYP1A2 and CYP1B1: an integrated approach employing molecular docking and molecular dynamics simulations.

    PubMed

    Kesharwani, Siddharth S; Nandekar, Prajwal P; Pragyan, Preeti; Rathod, Vijay; Sangamwar, Abhay T

    2016-08-01

    Recent trends in new drug discovery of anticancer drugs have made oncologists more aware of the fact that the new drug discovery must target the developing mechanism of tumorigenesis to improve the therapeutic efficacy of antineoplastic drugs. The drugs designed are expected to have high affinity towards the novel targets selectively. Current research highlights overexpression of CYP450s, particularly cytochrome P450 1A1 (CYP1A1), in tumour cells, representing a novel target for anticancer therapy. However, the CYP1 family is identified as posing significant problems in selectivity of anticancer molecules towards CYP1A1. Three members have been identified in the human CYP1 family: CYP1A1, CYP1A2 and CYP1B1. Although sequences of the three isoform have high sequence identity, they have distinct substrate specificities. The understanding of macromolecular features that govern substrate specificity is required to understand the interplay between the protein function and dynamics, design novel antitumour compounds that could be specifically metabolized by only CYP1A1 to mediate their antitumour activity and elucidate the reasons for differences in substrate specificity profile among the three proteins. In the present study, we employed a combination of computational methodologies: molecular docking and molecular dynamics simulations. We utilized eight substrates for elucidating the difference in substrate specificity of the three isoforms. Lastly, we conclude that the substrate specificity of a particular substrate depends upon the type of the active site residues, the dynamic motions in the protein structure upon ligand binding and the physico-chemical characteristics of a particular ligand. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26916064

  14. Marker Assisted Transfer of Two Powdery Mildew Resistance Genes PmTb7A.1 and PmTb7A.2 from Triticum boeoticum (Boiss.) to Triticum aestivum (L.)

    PubMed Central

    Elkot, Ahmed Fawzy Abdelnaby; Chhuneja, Parveen; Kaur, Satinder; Saluja, Manny; Keller, Beat; Singh, Kuldeep

    2015-01-01

    Powdery mildew (PM), caused by Blumeria graminis f. sp. tritici, is one of the important wheat diseases, worldwide. Two PM resistance genes, designated as PmTb7A.1 and PmTb7A.2, were identified in T. boeoticum acc. pau5088 and mapped on chromosome 7AL approximately 48cM apart. Two resistance gene analogue (RGA)-STS markers Ta7AL-4556232 and 7AL-4426363 were identified to be linked to the PmTb7A.1 and PmTb7A.2, at a distance of 0.6cM and 6.0cM, respectively. In the present study, following marker assisted selection (MAS), the two genes were transferred to T. aestivum using T. durum as bridging species. As many as 12,317 florets of F1 of the cross T. durum /T. boeoticum were pollinated with T. aestivum lines PBW343-IL and PBW621 to produce 61 and 65 seeds, respectively, of three-way F1. The resulting F1s of the cross T. durum/T. boeoticum//T. aestivum were screened with marker flanking both the PM resistance genes PmTb7A.1 and PmTb7A.2 (foreground selection) and the selected plants were backcrossed to generate BC1F1. Marker assisted selection was carried both in BC1F1 and the BC2F1 generations. Introgression of alien chromatin in BC2F1 plants varied from 15.4 - 62.9 percent. Out of more than 110 BC2F1 plants showing introgression for markers linked to the two PM resistance genes, 40 agronomically desirable plants were selected for background selection for the carrier chromosome to identify the plants with minimum of the alien introgression. Cytological analysis showed that most plants have chromosome number ranging from 40-42. The BC2F2 plants homozygous for the two genes have been identified. These will be crossed to generate lines combining both the PM resistance genes but with minimal of the alien introgression. The PM resistance gene PmTb7A.1 maps in a region very close to Sr22, a stem rust resistance gene effective against the race Ug99. Analysis of selected plants with markers linked to Sr22 showed introgression of Sr22 from T. boeoticum in several BC2F1 plants

  15. Binding patterns of bovine seminal plasma proteins A1/A2, 30 kDa and osteopontin on ejaculated sperm before and after incubation with isthmic and ampullary oviductal fluid.

    PubMed

    Souza, Carlos Eduardo A; Moura, Arlindo A; Monaco, Elisa; Killian, Gary J

    2008-04-01

    Previous studies from our laboratory have reported empirical associations between bovine seminal plasma protein(s) (BSP) A1/A2 and 30 kDa and osteopontin (OPN) in accessory sex gland fluid and bull fertility. These BSP and OPN are believed to bind to sperm at ejaculation and to remain bound until sperm reach the oviduct. The objective of the present study was to evaluate the topographical distribution of BSP A1/A2, 30 kDa and OPN binding on: (1) bovine ejaculated sperm; (2) ejaculated sperm incubated with isthmic oviductal fluid (ODF); (3) ejaculated sperm+isthmic ODF incubated in ampullary ODF. From each of these media, aliquots of sperm for BSP and OPN were processed for immunocytochemistry and analysis by laser scanning confocal microscopy. Isthmic and ampullary ODF was collected from indwelling catheters and used as pools from three cows in the non-luteal phase of the estrous cycle. Anti-BSP A1/A2 was detected bound to the midpiece, post-equatorial and equatorial segments and acrosome of sperm after ejaculation and after incubation with isthmic and ampullary ODF. The BSP A1/A2 fluorescence was more concentrated on the midpiece and increased as acrosome-intact sperm came in contact with ODF. As compared with acrosome-intact sperm, non-intact acrosome intact sperm had 39 and 68% reductions of acrosome fluorescence and 36% and 90% increases of post-equatorial fluorescence after contact with isthmic and ampullary ODF (P<0.05). Anti-BSP 30 kDa was more intense on the midpiece than on post-equatorial, equatorial and acrosome regions of sperm after ejaculation and contact with ODF. However, equatorial fluorescence was 141% and 89% more intense and acrosome stainning was 80% and 76% less (P<0.05) in non-intact acrosome sperm than in acrosome intact cells, during all ODF incubations. Anti-OPN was identified on the acrosome of ejaculated sperm, but with less fluorescence (P<0.05) on the post-equatorial segment and midpiece. Incubation of sperm with isthmic ODF increased

  16. 32 CFR 809a.0 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 6 2012-07-01 2012-07-01 false Purpose. 809a.0 Section 809a.0 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE § 809a.0 Purpose. This part prescribes the...

  17. 32 CFR 809a.0 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 6 2014-07-01 2014-07-01 false Purpose. 809a.0 Section 809a.0 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION INSTALLATION ENTRY POLICY, CIVIL DISTURBANCE INTERVENTION AND DISASTER ASSISTANCE § 809a.0 Purpose. This part prescribes the...

  18. Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlorodibenzofuran.

    PubMed

    Budinsky, Robert A; LeCluyse, Edward L; Ferguson, Stephen S; Rowlands, J Craig; Simon, Ted

    2010-11-01

    The concentration dose response for aryl hydrocarbon receptor (AHR)-mediated CYP1A1 and CYP1A2 messenger RNA (mRNA) induction and enzyme activity was determined in primary cultures of rat and human hepatocytes for 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 2,3,7,8-tetrachlorodibenzofuran. Eleven different congener concentrations from 0.00001 to 100 nM were used, thus spanning seven orders of magnitude. The Hill model was used to obtain values of EC(x) and maximal response from the individual data sets. No-observed effect concentration values were derived using several statistical methods including Dunnett's test, the Welch-Aspin test, and step-down bilinear regression. Thresholds were estimated using baseline projection methods and a "hockey stick" fitting method. Human hepatocytes were less responsive and less sensitive with respect to CYP1A1 activity and mRNA induction than rats. On the other hand, the human CYP1A2 response was more robust than the response in rats but generally less sensitive. These data allow an evaluation of relative species sensitivities for developing interspecies toxicodynamic adjustment factors, for assessing AHR activation thresholds, and for evaluating relative congener potencies. Overall, these data support the position that humans are less sensitive than rats to these AHR-dependent end points and support the use of a data-derived adjustment factor of 1.0 or less for extrapolating between rats and humans. PMID:20705892

  19. Ac2-26 Mimetic Peptide of Annexin A1 Inhibits Local and Systemic Inflammatory Processes Induced by Bothrops moojeni Venom and the Lys-49 Phospholipase A2 in a Rat Model

    PubMed Central

    Carlos, Carla Patrícia; Ullah, Anwar; Arni, Raghuvir Krishnaswamy; Gil, Cristiane Damas; Oliani, Sonia Maria

    2015-01-01

    Annexin A1 (AnxA1) is an endogenous glucocorticoid regulated protein that modulates anti-inflammatory process and its therapeutic potential has recently been recognized in a range of systemic inflammatory disorders. The effect of the N-terminal peptide Ac2-26 of AnxA1 on the toxic activities of Bothrops moojeni crude venom (CV) and its myotoxin II (MjTX-II) were evaluated using a peritonitis rat model. Peritonitis was induced by the intraperitoneal injection of either CV or MjTX-II, a Lys-49 phospholipase A2. Fifteen minutes after the injection, the rats were treated with either Ac2-26 or PBS. Four hours later, the CV and MjTX-II-induced peritonitis were characterized by neutrophilia (in the peritoneal exudate, blood and mesentery) and increased number of mesenteric degranulated mast cells and macrophages. At 24 hours post-injection, the local inflammatory response was attenuated in the CV-induced peritonitis while the MjTX-II group exhibited neutrophilia (peritoneal exudates and blood). Ac2-26 treatment prevented the influx of neutrophils in MjTX-II–induced peritonitis and diminished the proportion of mesenteric degranulated mast cells and macrophages in CV-induced peritonitis. Additionally, CV and MjTX-II promoted increased levels of IL-1β and IL-6 in the peritoneal exudates which were significantly reduced after Ac2-26 treatment. At 4 and 24 hours, the endogenous expression of AnxA1 was upregulated in the mesenteric neutrophils (CV and MjTX-II groups) and mast cells (CV group). In the kidneys, CV and MjTX-II administrations were associated with an increased number of macrophages and morphological alterations in the juxtamedullary nephrons in proximal and distal tubules. Ac2-26 promoted significant recovery of the juxtamedullary structures, decreased the number of macrophages and diminished the AnxA1 in epithelial cells from distal tubules and renal capsules. Our results show that Ac2-26 treatment significantly attenuates local and systemic inflammatory

  20. Dimerization Is Not a Determining Factor for Functional High Affinity Human Plasminogen Binding by the Group A Streptococcal Virulence Factor PAM and Is Mediated by Specific Residues within the PAM a1a2 Domain*

    PubMed Central

    Bhattacharya, Sarbani; Liang, Zhong; Quek, Adam J.; Ploplis, Victoria A.; Law, Ruby; Castellino, Francis J.

    2014-01-01

    A emm53 subclass of Group A Streptococcus pyogenes (GAS) interacts tightly with human plasma plasminogen (hPg) and plasmin (hPm) via the kringle 2 (K2hPg) domain of hPg/hPm and the N-terminal a1a2 regions of a GAS coiled-coil M-like protein (PAM). Previous studies have shown that a monomeric PAM fragment, VEK30 (residues 97–125 + Tyr), interacted specifically with isolated K2hPg. However, the binding strength of VEK30 (KD = 56 nm) was ∼60-fold weaker than that of full-length dimeric PAM (KD = 1 nm). To assess whether this attenuated binding was due to the inability of VEK30 to dimerize, we defined the minimal length of PAM required to dimerize using a series of peptides with additional PAM residues placed at the NH2 and COOH termini of VEK30. VEK64 (PAM residues 83–145 + Tyr) was found to be the smallest peptide that adopted an α-helical dimer, and was bound to K2hPg with nearly the same affinity as PAM (KD = 1–2 nm). However, addition of two PAM residues (Arg126-His127) to the COOH terminus of VEK30 (VEK32) maintained a monomeric peptidic structure, but exhibited similar K2hPg binding affinity as full-length dimeric PAM. We identified five residues in a1a2 (Arg113, His114, Glu116, Arg126, His127), mutation of which reduced PAM binding affinity for K2hPg by ∼1000-fold. Replacement of these critical residues by Ala in the GAS genome resulted in reduced virulence, similar to the effects of inactivating the PAM gene entirely. We conclude that rather than dimerization of PAM, the five key residues in the binding domain of PAM are essential to mediate the high affinity interaction with hPg, leading to increased GAS virulence. PMID:24962580

  1. Dimerization is not a determining factor for functional high affinity human plasminogen binding by the group A streptococcal virulence factor PAM and is mediated by specific residues within the PAM a1a2 domain.

    PubMed

    Bhattacharya, Sarbani; Liang, Zhong; Quek, Adam J; Ploplis, Victoria A; Law, Ruby; Castellino, Francis J

    2014-08-01

    A emm53 subclass of Group A Streptococcus pyogenes (GAS) interacts tightly with human plasma plasminogen (hPg) and plasmin (hPm) via the kringle 2 (K2hPg) domain of hPg/hPm and the N-terminal a1a2 regions of a GAS coiled-coil M-like protein (PAM). Previous studies have shown that a monomeric PAM fragment, VEK30 (residues 97-125 + Tyr), interacted specifically with isolated K2hPg. However, the binding strength of VEK30 (KD = 56 nm) was ∼60-fold weaker than that of full-length dimeric PAM (KD = 1 nm). To assess whether this attenuated binding was due to the inability of VEK30 to dimerize, we defined the minimal length of PAM required to dimerize using a series of peptides with additional PAM residues placed at the NH2 and COOH termini of VEK30. VEK64 (PAM residues 83-145 + Tyr) was found to be the smallest peptide that adopted an α-helical dimer, and was bound to K2hPg with nearly the same affinity as PAM (KD = 1-2 nm). However, addition of two PAM residues (Arg(126)-His(127)) to the COOH terminus of VEK30 (VEK32) maintained a monomeric peptidic structure, but exhibited similar K2hPg binding affinity as full-length dimeric PAM. We identified five residues in a1a2 (Arg(113), His(114), Glu(116), Arg(126), His(127)), mutation of which reduced PAM binding affinity for K2hPg by ∼ 1000-fold. Replacement of these critical residues by Ala in the GAS genome resulted in reduced virulence, similar to the effects of inactivating the PAM gene entirely. We conclude that rather than dimerization of PAM, the five key residues in the binding domain of PAM are essential to mediate the high affinity interaction with hPg, leading to increased GAS virulence. PMID:24962580

  2. Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

    PubMed Central

    Koszałka, Patrycja; Gołuńska, Monika; Urban, Aleksandra; Stasiłojć, Grzegorz; Stanisławowski, Marcin; Majewski, Marceli; Składanowski, Andrzej C.; Bigda, Jacek

    2016-01-01

    CD73 (ecto-5'-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched. We have analyzed the role of high affinity adenosine receptors A1, A2A, and A3 in B16F10 melanoma progression using specific agonists (CCPA, CGS-21680 and IB-MECA, respectively). We limited endogenous extracellular adenosine background using CD73 knockout mice treated with CD73 chemical inhibitor, AOPCP (adenosine α,β-methylene 5’-diphosphate). Activation of any adenosine receptor significantly inhibited B16F10 melanoma growth but only at its early stage. At 14th day of growth, the decrease in tumor neovascularization and MAPK pathway activation induced by CD73 depletion was reversed by all agonists. Activation of A1AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A3AR activation increased both the microvessel density and expression of pro-angiogenic factors. All agonists induced significant increase in macrophage tumor infiltration, with IB-MECA being most effective. This effect was accompanied by substantial changes in cytokines regulating macrophage polarization between pro-inflammatory and pro-angiogenic phenotype. Our results demonstrate an evidence that each of the analyzed receptors has a specific role in the stimulation of tumor angiogenesis and confirm significantly more multifaceted role of adenosine in its regulation than was already observed. They also reveal previously unexplored consequences to extracellular adenosine signaling depletion in

  3. Magnetic field dependence of high-Tc interface superconductivity in L a1.55S r0.45Cu O4/L a2Cu O4 heterostructures

    NASA Astrophysics Data System (ADS)

    Gasparov, V. A.; Drigo, L.; Audouard, A.; He, Xi; Božović, I.

    2016-07-01

    Heterostructures made of a layer of a cuprate insulator L a2Cu O4 on the top of a layer of a nonsuperconducting cuprate metal L a1.55S r0.45Cu O4 show high-Tc interface superconductivity confined within a single Cu O2 plane. Given this extreme quasi-two-dimensional quantum confinement, it is of interest to find out how interface superconductivity behaves when exposed to an external magnetic field. With this motivation, we have performed contactless tunnel-diode-oscillator-based measurements in pulsed magnetic fields up to 56 T as well as measurements of the complex mutual inductance between a spiral coil and the film in static fields up to 3 T. Remarkably, we observe that interface superconductivity survives up to very high perpendicular fields, in excess of 40 T. In addition, the critical magnetic field Hm(T ) reveals an upward divergence with decreasing temperature, in line with vortex melting as in bulk superconducting cuprates.

  4. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies.

    PubMed

    Butterfield, Russell J; Foley, A Reghan; Dastgir, Jahannaz; Asman, Stephanie; Dunn, Diane M; Zou, Yaqun; Hu, Ying; Donkervoort, Sandra; Flanigan, Kevin M; Swoboda, Kathryn J; Winder, Thomas L; Weiss, Robert B; Bönnemann, Carsten G

    2013-11-01

    Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. PMID:24038877

  5. Genotoxicity of three food processing contaminants in transgenic mice expressing human sulfotransferases 1A1 and 1A2 as assessed by the in vivo alkaline single cell gel electrophoresis assay.

    PubMed

    Høie, Anja Hortemo; Svendsen, Camilla; Brunborg, Gunnar; Glatt, Hansruedi; Alexander, Jan; Meinl, Walter; Husøy, Trine

    2015-10-01

    The food processing contaminants 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 5-hydroxymethylfurfural (HMF) and 2,5 dimethylfuran (DMF) are potentially both mutagenic and carcinogenic in vitro and/or in vivo, although data on DMF is lacking. The PHIP metabolite N-hydroxy-PhIP and HMF are bioactivated by sulfotransferases (SULTs). The substrate specificity and tissue distribution of SULTs differs between species. A single oral dose of PhIP, HMF or DMF was administered to wild-type (wt) mice and mice expressing human SULT1A1/1A2 (hSULT mice). DNA damage was studied using the in vivo alkaline single cell gel electrophoresis (SCGE) assay. No effects were detected in wt mice. In the hSULT mice, PhIP and HMF exposure increased the levels of DNA damage in the liver and kidney, respectively. DMF was not found to be genotoxic. The observation of increased DNA damage in hSULT mice compared with wt mice supports the role of human SULTs in the bioactivation of N-hydroxy-PhIP and HMF in vivo. PMID:26270892

  6. Deletion of Amino Acid Transporter ASCT2 (SLC1A5) Reveals an Essential Role for Transporters SNAT1 (SLC38A1) and SNAT2 (SLC38A2) to Sustain Glutaminolysis in Cancer Cells.

    PubMed

    Bröer, Angelika; Rahimi, Farid; Bröer, Stefan

    2016-06-17

    Many cancer cells depend on glutamine as they use the glutaminolysis pathway to generate building blocks and energy for anabolic purposes. As a result, glutamine transporters are essential for cancer growth and are potential targets for cancer chemotherapy with ASCT2 (SLC1A5) being investigated most intensively. Here we show that HeLa epithelial cervical cancer cells and 143B osteosarcoma cells express a set of glutamine transporters including SNAT1 (SLC38A1), SNAT2 (SLC38A2), SNAT4 (SLC38A4), LAT1 (SLC7A5), and ASCT2 (SLC1A5). Net glutamine uptake did not depend on ASCT2 but required expression of SNAT1 and SNAT2. Deletion of ASCT2 did not reduce cell growth but caused an amino acid starvation response and up-regulation of SNAT1 to replace ASCT2 functionally. Silencing of GCN2 in the ASCT2(-/-) background reduced cell growth, showing that a combined targeted approach would inhibit growth of glutamine-dependent cancer cells. PMID:27129276

  7. Degradation of phycobilisomes in Synechocystis sp. PCC6803: evidence for essential formation of an NblA1/NblA2 heterodimer and its codegradation by A Clp protease complex.

    PubMed

    Baier, Antje; Winkler, Wiebke; Korte, Thomas; Lockau, Wolfgang; Karradt, Anne

    2014-04-25

    When cyanobacteria acclimate to nitrogen deficiency, they degrade their large (3-5-MDa), light-harvesting complexes, the phycobilisomes. This massive, yet specific, intracellular degradation of the pigmented phycobiliproteins causes a color change of cyanobacterial cultures from blue-green to yellow-green, a process referred to as chlorosis or bleaching. Phycobilisome degradation is induced by expression of the nblA gene, which encodes a protein of ~7 kDa. NblA most likely acts as an adaptor protein that guides a Clp protease to the phycobiliproteins, thereby initiating the degradation process. Most cyanobacteria and red algae possess just one nblA-homologous gene. As an exception, the widely used "model organism" Synechocystis sp. PCC6803 expresses two such genes, nblA16803 and nblA26803, both of whose products are required for phycobilisome degradation. Here, we demonstrate that the two NblA proteins heterodimerize in vitro and in vivo using pull-down assays and a Förster energy-transfer approach, respectively. We further show that the NblA proteins form a ternary complex with ClpC (the HSP100 chaperone partner of Clp proteases) and phycobiliproteins in vitro. This complex is susceptible to ATP-dependent degradation by a Clp protease, a finding that supports a proposed mechanism of the degradation process. Expression of the single nblA gene encoded by the genome of the N2-fixing, filamentous cyanobacterium Nostoc sp. PCC7120 in the nblA1/nblA2 mutant of Synechocystis sp. PCC6803 induced phycobilisome degradation, suggesting that the function of the NblA heterodimer of Synechocystis sp. PCC6803 is combined in the homodimeric protein of Nostoc sp. PCC7120. PMID:24610785

  8. Novel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2.

    PubMed

    Thymiakou, Efstathia; Kardassis, Dimitris

    2014-06-01

    ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene. PMID:24807696

  9. Large non-factorizable contributions in B → a 0 a 0 decays

    NASA Astrophysics Data System (ADS)

    Dou, Defa; Liu, Xin; Li, Jing-Wu; Xiao, Zhen-Jun

    2016-08-01

    We investigate three tree-dominated B\\to {a}0{a}0 decays for the first time in the perturbative QCD(pQCD) approach at leading order in the standard model, with a 0 standing for the light scalar {a}0(980) state, which is assumed as a meson based on the model of a conventional two-quark (q\\bar{q}) structure. All the topologies of the Feynman diagrams such as the non-factorizable spectator ones and the annihilation ones are calculated in the pQCD approach. It is of great interest to find that, in contrast to the known B\\to π π decays, the B\\to {a}0{a}0 decays are governed by the large non-factorizable contributions, which give rise to the large B\\to {a}0{a}0 decay rates in the order of {10}-6∼ {10}-5, although the a 0 meson has an extremely small vector decay constant {f}{a0}. Also observed are large direct CP-violating asymmetries around 15% and 30% for the {B}0\\to {a}00{a}00 and {a}0+{a}0- modes. These sizable predictions could be easily examined at the running Large Hadron Collider and the near future Super-B/Belle-II experiments. The future precision measurements combined with these pQCD predictions might be helpful to explore the complicated QCD dynamics and the inner structure of the light scalar a 0, as well as to complementarily constrain the unitary angle α.

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

    SciTech Connect

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

    2013-02-01

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

  11. An analysis of the methyl rotation dynamics in the S0 (X˜ 1A1) and T1 (ã 3A2) states of thioacetone, (CH3)2CS and (CD3)2CS from pyrolysis jet spectra

    NASA Astrophysics Data System (ADS)

    Moule, D. C.; Smeyers, Y. G.; Senent, M. L.; Clouthier, D. J.; Karolczak, J.; Judge, R. H.

    1991-09-01

    Jet-cooled, laser-induced phosphorescence excitation spectra (LIP) of thioacetone (CH3)2CS/(CD3)2CS have been recorded over the region 16 800-18 500 cm-1 using the pyrolysis jet spectroscopic technique. The responsible electronic transition, T1←S0, ã 3A`←X˜ 1A1, results from an n→π* electron promotion and gives rise to a pattern of vibronic bands that were attributed to activity of the methyl torsion and the sulphur out-of-plane wagging modes. The intensities of the torsional and wagging progressions in the excitation spectra were interpreted in terms of a C2v-Cs molecular distortion of the triplet molecule from its singlet ground state equilibrium structure. A complete unrestricted Hartree-Fock (UHF) ab initio molecular orbital (MO) structural optimization of the T1 state predicted that the sulphur was displaced by 27.36° from the molecular plane and the methyl groups were rotated by 10.93° in clockwise-counterclockwise directions. Restricted Hartree-Fock (RHF) calculations were used to generate the V(θ1,θ2) potential surface governing methyl rotation for the S0 state. This was incorporated into a two-dimensional Hamiltonian, symmetrized for the G36 point group and solved variationally for the torsional frequencies. The calculated frequencies of 159.97/118.94 for the ν17(b1) mode of S0 (CH3)2CS/(CD3)2CS were found to agree with the experimental values, 153.2/114.7 cm-1.

  12. 26 CFR 1.263A-0 - Outline of regulations under section 263A.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Outline of regulations under section 263A. 1.263A-0 Section 1.263A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Items Not Deductible § 1.263A-0 Outline of regulations under section 263A. This section lists the paragraphs...

  13. Proteomic analysis of trichloroethylene-induced alterations in expression, distribution, and interactions of SET/TAF-Iα and two SET/TAF-Iα-binding proteins, eEF1A1 and eEF1A2, in hepatic L-02 cells

    SciTech Connect

    Hong, Wen-Xu; Yang, Liang; Chen, Moutong; Yang, Xifei; Ren, Xiaohu; Fang, Shisong; Ye, Jinbo; Huang, Haiyan; Peng, Chaoqiong; Zhou, Li; Huang, Xinfeng; Yang, Fan; Wu, Desheng; Zhuang, Zhixiong; Liu, Jianjun

    2012-09-01

    Emerging evidence indicates that trichloroethylene (TCE) exposure causes severe hepatotoxicity. However, the mechanisms of TCE hepatotoxicity remain unclear. Recently, we reported that TCE exposure up-regulated the expression of the oncoprotein SET/TAF-Iα and SET knockdown attenuated TCE-induced cytotoxicity in hepatic L-02 cells. To decipher the function of SET/TAF-Iα and its contributions to TCE-induced hepatotoxicity, we employed a proteomic analysis of SET/TAF-Iα with tandem affinity purification to identify SET/TAF-Iα-binding proteins. We identified 42 novel Gene Ontology co-annotated SET/TAF-Iα-binding proteins. The identifications of two of these proteins (eEF1A1, elongation factor 1-alpha 1; eEF1A2, elongation factor 1-alpha 2) were confirmed by Western blot analysis and co-immunoprecipitation (Co-IP). Furthermore, we analyzed the effects of TCE on the expression, distribution and interactions of eEF1A1, eEF1A2 and SET in L-02 cells. Western blot analysis reveals a significant up-regulation of eEF1A1, eEF1A2 and two isoforms of SET, and immunocytochemical analysis reveals that eEF1A1 and SET is redistributed by TCE. SET is redistributed from the nucleus to the cytoplasm, while eFE1A1 is translocated from the cytoplasm to the nucleus. Moreover, we find by Co-IP that TCE exposure significantly increases the interaction of SET with eEF1A2. Our data not only provide insights into the physiological functions of SET/TAF-Iα and complement the SET interaction networks, but also demonstrate that TCE exposure induces alterations in the expression, distribution and interactions of SET and its binding partners. These alterations may constitute the mechanisms of TCE cytotoxicity. -- Highlights: ► Identify 62 SET/TAF-Iα-associated proteins in human L-02 cells ► Trichloroethylene (TCE) alters the interaction of SET with eEF1A1 and eEF1A2. ► TCE induces the translocation and up-regulation of SET. ► TCE induces the translocation and up-regulation of eEF1A.

  14. 26 CFR 1.6038A-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Table of contents. 1.6038A-0 Section 1.6038A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6038A-0 Table of contents. This section lists the captions that appear in the regulations...

  15. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Table of contents. 20.2056A-0 Section 20.2056A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-0 Table...

  16. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Table of contents. 20.2056A-0 Section 20.2056A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-0 Table...

  17. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Table of contents. 20.2056A-0 Section 20.2056A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-0 Table...

  18. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Table of contents. 20.2056A-0 Section 20.2056A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-0 Table...

  19. 26 CFR 20.2056A-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Table of contents. 20.2056A-0 Section 20.2056A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-0 Table...

  20. 26 CFR 1.6038A-0 - Table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) Material profit and loss statements. (4) Existing records test. (5) Significant industry segment test. (i... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Table of contents. 1.6038A-0 Section 1.6038A-0...) INCOME TAXES Information Returns § 1.6038A-0 Table of contents. This section lists the captions...

  1. 26 CFR 1.409A-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Table of contents. 1.409A-0 Section 1.409A-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-0 Table of contents. This section lists captions contained in...

  2. 26 CFR 1.468A-0T - Nuclear decommissioning costs; table of contents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 6 2010-04-01 2010-04-01 false Nuclear decommissioning costs; table of contents... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Taxable Year for Which Deductions Taken § 1.468A-0T Nuclear...) Definitions. (c) Special rules applicable to certain experimental nuclear facilities. § 1.468A-2TTreatment...

  3. Repeated dose toxicity and relative potency of 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for induction of CYP1A1, CYP1A2 and thymic atrophy in female Harlan Sprague-Dawley rats

    PubMed Central

    Hooth, Michelle J.; Nyska, Abraham; Fomby, Laurene M.; Vasconcelos, Daphne Y.; Vallant, Molly; DeVito, Michael J.; Walker, Nigel J.

    2012-01-01

    In this study we assessed the relative toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague-Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50000 and 500000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015-0.0072, for PCN 66 and 0.00029-0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO Toxic Equivalency Factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity. PMID:22813907

  4. 26 CFR 1.409A-0 - Table of contents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 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-0 Table of contents... or other international agreement. (ii) Plans with respect to certain other compensation. (iii)...

  5. Optical transition radiation interferometry for the A0 photoinjector

    SciTech Connect

    Kazakevich, G.; Edwards, H.; Fliller, R.; Nagaitsev, S.; Ruan, J.; Thurman-Keup, R.; /Fermilab

    2008-06-01

    Optical Transition Radiation Interferometry (OTRI) is a promising diagnostic technique and has been successfully developed and used for investigation of relativistic beams. For mid-energy accelerators the technique is traditionally based on thin polymer films (the first one is being transparent for visible light), which causes beam multiple scattering of about 1 mrad. A disadvantage of those films is unacceptable vacuum properties for photoinjectors and accelerators using superconducting cavities. We have studied the application of thin mica sheets for the OTRI diagnostics at the A0 Photoinjector in comparison with 2.5 {micro}m thick Mylar films. This diagnostic is also applicable for the ILCTA-NML accelerator test facility that is planned at Fermilab. This report discusses the experimental setups of the OTR interferometer for the A0 Photoinjector and presents comparisons of simulations and measurements obtained using Mylar and mica-based interferometers.

  6. Moist Heat Disinfection and Revisiting the A0 Concept.

    PubMed

    McCormick, Patrick J; Schoene, Michael J; Dehmler, Matthew A; McDonnell, Gerald

    2016-04-01

    Moist heat is employed in the medical device, pharmaceutical, and food processing industries to render products and goods safe for use and human consumption. Applications include its use to pasteurize a broad range of foods and beverages, the control of microbial contamination of blood products, and treatment of bone tissue transplants and vaccines. In the pharmaceutical industry, water heated to 65°C to 80°C is used to sanitize high-purity water systems. In healthcare, it has been employed for decades to disinfect patient care items ranging from bedpans to anesthesia equipment. There is a good understanding of the conditions necessary to achieve disinfection of microorganisms at temperatures ranging from 65°C to 100°C. Based on this information, the efficacy of moist heat processes at a range of exposure times and temperatures can be quantified based on mathematical models such as the A0 calculation. While the A0 concept is recognized within the European healthcare community, it has yet to be widely adopted within the United States. This article provides information regarding the A0 concept, a brief overview of the classification of thermal disinfection for use with healthcare applications within the United States, and recent data on reinvestigating the thermal disinfection of a selected panel of microorganisms and a mixed culture biofilm. PMID:27100072

  7. A1C test

    MedlinePlus

    HbA1C test; Glycated hemoglobin test; Glycosylated hemoglobin test; Hemoglobin glycosylated test; Glycohemoglobin test ... have recently eaten does not affect the A1C test, so you do not need to fast to ...

  8. A1C

    MedlinePlus

    A1C is a blood test for type 2 diabetes and prediabetes. It measures your average blood glucose, or blood sugar, level over the past 3 ... A1C alone or in combination with other diabetes tests to make a diagnosis. They also use the ...

  9. Intial synchroscan streak camera imaging at the A0 photoinjector

    SciTech Connect

    Lumpkin, A.H.; Ruan, J.; /Fermilab

    2008-04-01

    At the Fermilab A0 photoinjector facility, bunch-length measurements of the laser micropulse and the e-beam micropulse have been done in the past with a single-sweep module of the Hamamatsu C5680 streak camera with an intrinsic shot-to-shot trigger jitter of 10 to 20 ps. We have upgraded the camera system with the synchroscan module tuned to 81.25 MHz to provide synchronous summing capability with less than 1.5-ps FWHM trigger jitter and a phase-locked delay box to provide phase stability of {approx}1 ps over 10s of minutes. This allowed us to measure both the UV laser pulse train at 244 nm and the e-beam via optical transition radiation (OTR). Due to the low electron beam energies and OTR signals, we typically summed over 50 micropulses with 1 nC per micropulse. We also did electron beam bunch length vs. micropulse charge measurements to identify a significant e-beam micropulse elongation from 10 to 30 ps (FWHM) for charges from 1 to 4.6 nC. This effect is attributed to space-charge effects in the PC gun as reproduced by ASTRA calculations. Chromatic temporal dispersion effects in the optics were also characterized and will be reported.

  10. Experimental study of A0 Lamb wave tomography

    NASA Astrophysics Data System (ADS)

    Seher, Matthias; Huthwaite, Peter; Lowe, Michael; Cawley, Peter

    2015-03-01

    Corrosion damage in inaccessible regions presents a significant challenge to the petrochemical industry, and determining the remaining wall thickness is important to establish the remaining service life. Guided wave tomography is one solution and involves transmitting Lamb waves through the area of interest and using the received signals to reconstruct the remaining wall thickness. This avoids the need to access all points on the surface, making the technique well suited to inspection beneath supports. For this purpose a tomography system for pipe inspections is developed using low frequency A0 Lamb waves that are excited and detected with two arrays of electromagnetic acoustic transducers (EMATs). Two different defect depths are considered with different contrasts relative to the nominal wall thickness and in a first step, the repeatability of the measurements is demonstrated. Due to the limited view array configuration, the maximum depth of the reconstruction underestimates the true depth. In a second experimental study, the influence of a pipe clamp on the thickness reconstruction is considered, representing an inspection problem with restricted access. Preliminary results have shown that the maximum defect depth is further underestimated when compared to the thickness reconstructions without the clamp. However, it is possible to detect the defect underneath the clamp for all conducted experiments.

  11. Experimental study of A0 Lamb wave tomography

    SciTech Connect

    Seher, Matthias Huthwaite, Peter Lowe, Michael Cawley, Peter

    2015-03-31

    Corrosion damage in inaccessible regions presents a significant challenge to the petrochemical industry, and determining the remaining wall thickness is important to establish the remaining service life. Guided wave tomography is one solution and involves transmitting Lamb waves through the area of interest and using the received signals to reconstruct the remaining wall thickness. This avoids the need to access all points on the surface, making the technique well suited to inspection beneath supports. For this purpose a tomography system for pipe inspections is developed using low frequency A0 Lamb waves that are excited and detected with two arrays of electromagnetic acoustic transducers (EMATs). Two different defect depths are considered with different contrasts relative to the nominal wall thickness and in a first step, the repeatability of the measurements is demonstrated. Due to the limited view array configuration, the maximum depth of the reconstruction underestimates the true depth. In a second experimental study, the influence of a pipe clamp on the thickness reconstruction is considered, representing an inspection problem with restricted access. Preliminary results have shown that the maximum defect depth is further underestimated when compared to the thickness reconstructions without the clamp. However, it is possible to detect the defect underneath the clamp for all conducted experiments.

  12. A1C Test

    MedlinePlus

    ... to minimize the complications caused by chronically elevated glucose levels, such as progressive damage to body organs like the kidneys, eyes, cardiovascular system, and nerves. The A1c test result ...

  13. Sulfotransferase 4A1.

    PubMed

    Minchin, Rodney F; Lewis, Aaron; Mitchell, Deanne; Kadlubar, Fred F; McManus, Michael E

    2008-01-01

    In this review, we highlight the physical and enzymatic properties of the novel human sulfotransferase, SULT4A1. The gene is most highly expressed in selective regions of the brain, although work to date has failed to identify any specific endogenous substrate for the enzyme. SULT4A1 shares low homology with other human sulfotransferases. Nevertheless, it is highly conserved between species. Despite the low homology, it is structurally very similar to other cytosolic sulfotransferases with a conserved substrate binding domain, dimerization site and partial cofactor binding sites. However, the catalytic cavity is much smaller, and it has been suggested that the cofactor may not be accommodated within it. A recent link between variability in the 5'UTR of the SULT4A1 gene and schizophrenia has heightened interest in the endogenous function of the enzyme and its possible role in human disease. PMID:18248844

  14. A 0.23 pJ 11.05-bit ENOB 125-MS/s pipelined ADC in a 0.18 μm CMOS process

    NASA Astrophysics Data System (ADS)

    Yong, Wang; Jianyun, Zhang; Rui, Yin; Yuhang, Zhao; Wei, Zhang

    2015-05-01

    This paper describes a 12-bit 125-MS/s pipelined analog-to-digital converter (ADC) that is implemented in a 0.18 μm CMOS process. A gate-bootstrapping switch is used as the bottom-sampling switch in the first stage to enhance the sampling linearity. The measured differential and integral nonlinearities of the prototype are less than 0.79 least significant bit (LSB) and 0.86 LSB, respectively, at the full sampling rate. The ADC exhibits an effective number of bits (ENOB) of more than 11.05 bits at the input frequency of 10.5 MHz. The ADC also achieves a 10.5 bits ENOB with the Nyquist input frequency at the full sample rate. In addition, the ADC consumes 62 mW from a 1.9 V power supply and occupies 1.17 mm2, which includes an on-chip reference buffer. The figure-of-merit of this ADC is 0.23 pJ/step. Project supported by the Foundation of Shanghai Municipal Commission of Economy and Informatization (No. 130311).

  15. Pneumococcal IgA1 protease subverts specific protection by human IgA1.

    PubMed

    Janoff, E N; Rubins, J B; Fasching, C; Charboneau, D; Rahkola, J T; Plaut, A G; Weiser, J N

    2014-03-01

    Bacterial immunoglobulin A1 (IgA1) proteases may sabotage the protective effects of IgA. In vitro, both exogenous and endogenously produced IgA1 protease inhibited phagocytic killing of Streptococcus pneumoniae by capsule-specific IgA1 human monoclonal antibodies (hMAbs) but not IgA2. These IgA1 proteases cleaved and reduced binding of the the effector Fcα1 heavy chain but not the antigen-binding F(ab)/light chain to pneumococcal surfaces. In vivo, IgA1 protease-resistant IgA2, but not IgA1 protease-sensitive IgA1, supported 60% survival in mice infected with wild-type S. pneumoniae. IgA1 hMAbs protected mice against IgA1 protease-deficient but not -producing pneumococci. Parallel mouse sera with human IgA2 showed more efficient complement-mediated reductions in pneumococci with neutrophils than did IgA1, particularly with protease-producing organisms. After natural human pneumococcal bacteremia, purified serum IgG inhibited IgA1 protease activity in 7 of 11 patients (64%). These observations provide the first evidence in vivo that IgA1 protease can circumvent killing of S. pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate. PMID:23820749

  16. In vitro and in vivo evaluation of a 0.5% chlorhexidine gluconate teat dip.

    PubMed

    Boddie, R L; Watts, J L; Nickerson, S C

    1990-03-15

    The activity of a 0.5% chlorhexidine gluconate postmilking teat germicide in reducing the numbers of Staphylococcus aureus and Streptococcus agalactiae on the skin of excised teats from cows was determined. The product yielded logarithmic reductions of 4.09 and 4.10 against S aureus and Str agalactiae, respectively, compared with 3.80 and 3.81 reductions, using a 1% iodophor dip. Germicide tolerance to an organic load containing Serratia marcescens or Pseudomonas spp was also determined. Organisms were not recovered from the product 8 hours after introduction of a simulated organic load containing either species of bacteria. The germicide was further evaluated against S aureus and Str agalactiae, using experimental challenge-exposure procedures in a research dairy herd. Efficacy was 73.4% (P less than 0.001) against S aureus and 68.1% (P less than 0.005) against Str agalactiae. PMID:2179180

  17. Photo-cathode preparation system of the A0 photo-injector

    NASA Astrophysics Data System (ADS)

    Kuchnir, M.

    2002-08-01

    The A0 Photo-Injector is an electron accelerator located in the AZero high bay area of Fermilab. A pulsed laser system generates electron bunches by the photo-electric effect when hitting a photo-cathode in a 1.5-cell, 1.3 GHz RF gun. A 9-cell, 1.3 GHz superconducting resonant cavity then accelerates the electrons to 15 MeV. The 10 ps time resolved waveform of the laser pulses is transferred to the electron bunches. This report is focused on the first hardware component of this accelerator, the Photo-cathode Preparation System. The reason for its existence is in the nature of the photo-electric material film used: Cs2 > Te (Cesium Telluride), a very reactive compound that once coated on the cathode requires that it be transported and used in ultra high vacuum (UHV), i.e. < 10-9 Torr.

  18. Photo-cathode preparation system of the A0 photo-injector

    SciTech Connect

    Moyses Kuchnir et al.

    2002-08-23

    The A0 Photo-Injector is an electron accelerator located in the AZero high bay area of Fermilab. A pulsed laser system generates electron bunches by the photo-electric effect when hitting a photo-cathode in a 1.5-cell, 1.3 GHz RF gun. A 9-cell, 1.3 GHz superconducting resonant cavity then accelerates the electrons to 15 MeV. The 10 ps time resolved waveform of the laser pulses is transferred to the electron bunches. This report is focused on the first hardware component of this accelerator, the Photo-cathode Preparation System. The reason for its existence is in the nature of the photo-electric material film used: Cs{sub 2}Te (Cesium Telluride), a very reactive compound that once coated on the cathode requires that it be transported and used in ultra high vacuum (UHV), i.e. < 10{sup -9} Torr.

  19. Measurement of the neutron β-asymmetry parameter A0 with ultracold neutrons

    NASA Astrophysics Data System (ADS)

    Plaster, B.; Rios, R.; Back, H. O.; Bowles, T. J.; Broussard, L. J.; Carr, R.; Clayton, S.; Currie, S.; Filippone, B. W.; García, A.; Geltenbort, P.; Hickerson, K. P.; Hoagland, J.; Hogan, G. E.; Hona, B.; Holley, A. T.; Ito, T. M.; Liu, C.-Y.; Liu, J.; Makela, M.; Mammei, R. R.; Martin, J. W.; Melconian, D.; Mendenhall, M. P.; Morris, C. L.; Mortensen, R.; Pattie, R. W., Jr.; Pérez Galván, A.; Pitt, M. L.; Ramsey, J. C.; Russell, R.; Saunders, A.; Schmid, R.; Seestrom, S. J.; Sjue, S.; Sondheim, W. E.; Tatar, E.; Tipton, B.; Vogelaar, R. B.; VornDick, B.; Wrede, C.; Xu, Y. P.; Yan, H.; Young, A. R.; Yuan, J.

    2012-11-01

    We present a detailed report of a measurement of the neutron β-asymmetry parameter A0, the parity-violating angular correlation between the neutron spin and the decay electron momentum, performed with polarized ultracold neutrons (UCN). UCN were extracted from a pulsed spallation solid deuterium source and polarized via transport through a 7-T magnetic field. The polarized UCN were then transported through an adiabatic-fast-passage spin-flipper field region, prior to storage in a cylindrical decay volume situated within a 1-T 2×2π solenoidal spectrometer. The asymmetry was extracted from measurements of the decay electrons in multiwire proportional chamber and plastic scintillator detector packages located on both ends of the spectrometer. From an analysis of data acquired during runs in 2008 and 2009, we report A0=-0.11966±0.00089-0.00140+0.00123, from which we extract a value for the ratio of the weak axial-vector and vector coupling constants of the nucleon, λ=gA/gV=-1.27590±0.00239-0.00377+0.00331. Complete details of the analysis are presented.

  20. 26 CFR 1.907(a)-0 - Introduction (for taxable years beginning after December 31, 1982).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Introduction (for taxable years beginning after December 31, 1982). 1.907(a)-0 Section 1.907(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Income from Sources Without the United States § 1.907(a)-0 Introduction...

  1. Initial beam-profiling tests with the NML prototype station at the Fermilab A0 Photoinjector

    SciTech Connect

    Lumpkin, A.; Flora, R.; Johnson, A.S.; Ruan, J.; Santucci, J.; Scarpine, V.; Sun, Y.-E.; Thurman-Keup, R.; Church, M.; Wendt, M.; /Fermilab

    2011-03-01

    The beam-profile diagnostics station prototype for the superconducting rf electron linac being constructed at Fermilab at the New Muon Lab has been tested. The station uses intercepting radiation converter screens for the low-power beam mode: either a 100-{micro}m thick YAG:Ce single crystal scintillator or a 1-{micro}m thin Al optical transition radiation (OTR) foil. The screens are oriented with the surface perpendicular to the beam direction. A downstream mirror with its surface at 45 degrees to the beam direction is used to direct the radiation into the optical transport. The optical system has better than 20 (10) {micro}m rms spatial resolution when covering a vertical field of view of 18 (5) mm. The initial tests were performed at the A0 Photoinjector at a beam energy of {approx}15 MeV and with micropulse charges from 25 to 500 pC for beam sizes of 45 to 250 microns. Example results will be presented.

  2. Search for a low-mass higgs boson in Upsilon(3S)-->gammaA(0), A(0)-->tau(+)tau(-) at BABAR.

    PubMed

    Aubert, B; Karyotakis, Y; Lees, J P; Poireau, V; Prencipe, E; Prudent, X; Tisserand, V; Tico, J Garra; Grauges, E; Martinelli, M; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Battaglia, M; Brown, D N; Kerth, L T; Kolomensky, Yu G; Lynch, G; Osipenkov, I L; Tackmann, K; Tanabe, T; Hawkes, C M; Soni, N; Watson, A T; Koch, H; Schroeder, T; Asgeirsson, D J; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Randle-Conde, A; Blinov, V E; Bukin, A D; Buzykaev, A R; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Atmacan, H; Gary, J W; Liu, F; Long, O; Vitug, G M; Yasin, Z; Sharma, V; Campagnari, C; Hong, T M; Kovalskyi, D; Mazur, M A; Richman, J D; Beck, T W; Eisner, A M; Heusch, C A; Kroseberg, J; Lockman, W S; Martinez, A J; Schalk, T; Schumm, B A; Seiden, A; Wang, L; Winstrom, L O; Cheng, C H; Doll, D A; Echenard, B; Fang, F; Hitlin, D G; Narsky, I; Ongmongkolkul, P; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Bloom, P C; Ford, W T; Gaz, A; Hirschauer, J F; Nagel, M; Nauenberg, U; Smith, J G; Wagner, S R; Ayad, R; Toki, W H; Wilson, R J; Feltresi, E; Hauke, A; Jasper, H; Karbach, T M; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Kobel, M J; Nogowski, R; Schubert, K R; Schwierz, R; Bernard, D; Latour, E; Verderi, M; Clark, P J; Playfer, S; Watson, J E; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Fioravanti, E; Franchini, P; Luppi, E; Munerato, M; Negrini, M; Petrella, A; Piemontese, L; Santoro, V; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Contri, R; Guido, E; Lo Vetere, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Tosi, S; Chaisanguanthum, K S; Morii, M; Adametz, A; Marks, J; Schenk, S; Uwer, U; Bernlochner, F U; Klose, V; Lacker, H M; Lueck, T; Volk, A; Bard, D J; Dauncey, P D; Tibbetts, M; Behera, P K; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Derkach, D; da Costa, J Firmino; Grosdidier, G; Le Diberder, F; Lepeltier, V; Lutz, A M; Malaescu, B; Pruvot, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Touramanis, C; Bevan, A J; Clarke, C K; Di Lodovico, F; Sacco, R; Sigamani, M; Cowan, G; Paramesvaran, S; Wren, A C; Brown, D N; Davis, C L; Denig, A G; Fritsch, M; Gradl, W; Hafner, A; Alwyn, K E; Bailey, D; Barlow, R J; Jackson, G; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Salvati, E; Cowan, R; Dujmic, D; Fisher, P H; Henderson, S W; Sciolla, G; Spitznagel, M; Yamamoto, R K; Zhao, M; Patel, P M; Robertson, S H; Schram, M; Biassoni, P; Lazzaro, A; Lombardo, V; Palombo, F; Stracka, S; Cremaldi, L; Godang, R; Kroeger, R; Sonnek, P; Summers, D J; Zhao, H W; Simard, M; Taras, P; Nicholson, H; De Nardo, G; Lista, L; Monorchio, D; Onorato, G; Sciacca, C; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Wang, W F; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Castelli, G; Gagliardi, N; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Del Amo Sanchez, P; Ben-Haim, E; Bonneaud, G R; Briand, H; Chauveau, J; Hamon, O; Leruste, Ph; Marchiori, G; Ocariz, J; Perez, A; Prendki, J; Sitt, S; Gladney, L; Biasini, M; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Calderini, G; Carpinelli, M; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Lopes Pegna, D; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Anulli, F; Baracchini, E; Cavoto, G; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Gioi, L Li; Mazzoni, M A; Morganti, S; Piredda, G; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Franek, B; Olaiya, E O; Wilson, F F; Emery, S; Esteve, L; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Allen, M T; Aston, D; Bartoldus, R; Benitez, J F; Cenci, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Sevilla, M Franco; Gabareen, A M; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Lindquist, B; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; Neal, H; Nelson, S; O'Grady, C P; Ofte, I; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; West, C A; Wisniewski, W J; Wittgen, M; Wright, D H; Wulsin, H W; Yarritu, A K; Young, C C; Ziegler, V; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Bellis, M; Burchat, P R; Edwards, A J; Miyashita, T S; Ahmed, S; Alam, M S; Ernst, J A; Pan, B; Saeed, M A; Zain, S B; Soffer, A; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Wray, B C; Drummond, B W; Izen, J M; Lou, X C; Bianchi, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Choi, H H F; Hamano, K; King, G J; Kowalewski, R; Lewczuk, M J; Nugent, I M; Roney, J M; Sobie, R J; Gershon, T J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Puccio, E M T; Band, H R; Chen, X; Dasu, S; Flood, K T; Pan, Y; Prepost, R; Vuosalo, C O; Wu, S L

    2009-10-30

    We search for a light Higgs boson A0 in the radiative decay Upsilon(3S)-->gammaA(0), A(0)-->tau+tau-, tau+-->e+nu(e)nu(tau), or tau+-->mu+nu(mu)nu(tau). The data sample contains 122x10(6) Upsilon(3S) events recorded with the BABAR detector. We find no evidence for a narrow structure in the studied tau+tau- invariant mass region of 4.03gammaA(0))xB(A(0)-->tau+tau-)>(1.5-16)x10(-5) across the m(tau+tau-) range. We also set a 90% C.L. upper limit on the tau+tau- decay of the eta(b) at B(eta(b)-->tau+tau-)<8%. PMID:19905799

  3. A study of mass loss from the mid-ultraviolet spectrum of Alpha Cygni /A2 Ia/, Beta Orionis /B8 Ia/, and Eta Leonis /A0 Ib/

    NASA Technical Reports Server (NTRS)

    Lamers, H. J. G. L. M.; Stalio, R.; Kondo, Y.

    1978-01-01

    Results are presented for a study of mass loss from A and late-B supergiants based on high-resolution mid-UV spectra obtained with the echelle spectrograph of the Balloon-borne Ultraviolet Stellar Spectrometer. Spectra of Alpha Cyg, Beta Ori, Eta Leo, and Alpha Lyr are compared in selected wavelength regions; particular attention is given to previous observations of each star, the Mg II and Fe II resonance lines, lines due to other ions, and evidence for mass ejection. The results indicate that mass loss from late-B and A supergiants is variable, that a considerable fraction of envelope material is ejected in 'puffs', and that the puffs may be due to photospheric instabilities. A mass-loss rate of about 1 hundred-millionth of a solar mass per year is derived for Alpha Cyg and shown to be two orders of magnitude smaller than the value determined from the observed IR excess. This discrepancy is attributed to excess ionization in the envelope.

  4. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...-1, a single radioactive decay chain, in which radionuclides are present in their naturally occurring... radionuclide of that chain. In the case of radioactive decay chains in which any daughter radionuclide has a... NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Pt. 71,...

  5. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...-1, a single radioactive decay chain, in which radionuclides are present in their naturally occurring... radionuclide of that chain. In the case of radioactive decay chains in which any daughter radionuclide has a... NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Pt. 71,...

  6. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...-1, a single radioactive decay chain, in which radionuclides are present in their naturally occurring... radionuclide of that chain. In the case of radioactive decay chains in which any daughter radionuclide has a... NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Pt. 71,...

  7. SOY PROTEIN ISOLATE INDUCES CYP3A1 AND CYP3A2 IN PREPUBERTAL RATS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Feeding soy diets has been shown to induce cytochrome P450s in gene family CYP3A in Sprague-Dawley rat liver. We compared expression of CYP3A enzymes on PND33 rats fed casein or soy protein isolate (SPI+)-based AIN-93G diets continuously from gestational day 4 through PND 33 or the diets were switc...

  8. Measurement of the proton $A_1$ and $A_2$ spin asymmetries. Probing Color Forces

    SciTech Connect

    Armstrong, Whitney

    2015-05-01

    The Spin Asymmetries of the Nucleon Experiment (SANE) measured the proton spin structure function $g_2$ in a range of Bjorken x, 0.3 < x < 0.8, where extraction of the twist-3 matrix element $d_2^p$ (an integral of $g_2$ weighted by $x^2$) is most sensitive. The data was taken from $Q^2$ equal to 2.5 $GeV^2$ up to 6.5 $GeV^2$. In this polarized electron scattering off a polarized hydrogen target experiment, two double spin asymmetries, A∥ and A⊥ were measured using the BETA (Big Electron Telescope Array) Detector. BETA consisted of a scintillator hodoscope, gas Cerenkov counter, lucite hodoscope and a large lead glass electromagnetic calorimeter. With a unique open geometry, a threshold gas Cerenkov detector allowed BETA to cleanly identify electrons for this inclusive experiment. A measurement of $d_2^p$ is compared to lattice QCD calculations.

  9. Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2.

    PubMed

    Szabó, András; Pilsak, Claudia; Bence, Melinda; Witt, Heiko; Sahin-Tóth, Miklós

    2016-08-19

    The pancreas secretes digestive proenzymes typically in their monomeric form. A notable exception is the ternary complex formed by proproteinase E, chymotrypsinogen C, and procarboxypeptidase A (proCPA) in cattle and other ruminants. In the human and pig pancreas binary complexes of proCPA with proelastases were found. To characterize complex formation among human pancreatic protease zymogens in a systematic manner, we performed binding experiments using recombinant proelastases CELA2A, CELA3A, and CELA3B; chymotrypsinogens CTRB1, CTRB2, CTRC, and CTRL1; and procarboxypeptidases CPA1, CPA2, and CPB1. We found that proCELA3B bound not only to proCPA1 (KD 43 nm) but even more tightly to proCPA2 (KD 18 nm), whereas proCELA2A bound weakly to proCPA1 only (KD 152 nm). Surprisingly, proCELA3A, which shares 92% identity with proCELA3B, did not form stable complexes due to the evolutionary replacement of Ala(241) with Gly. The polymorphic nature of position 241 in both CELA3A (∼4% Ala(241) alleles) and CELA3B (∼2% Gly(241) alleles) points to individual variations in complex formation. The functional effect of complex formation was delayed procarboxypeptidase activation due to increased affinity of the inhibitory activation peptide, whereas proelastase activation was unchanged. We conclude that complex formation among human pancreatic protease zymogens is limited to a subset of proelastases and procarboxypeptidases. Complex formation stabilizes the inhibitory activation peptide of procarboxypeptidases and thereby increases zymogen stability and controls activation. PMID:27358403

  10. Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex.

    PubMed

    Berridge, Craig W; Spencer, Robert C

    2016-06-15

    The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed behavior. Moreover, dysregulated prefrontal cognitive dysfunction is associated with multiple psychiatric disorders. Norepinephrine (NE) signaling in the PFC is a critical modulator of prefrontal cognition and is targeted by a variety of drugs used to treat PFC-dependent cognitive dysfunction. Noradrenergic modulation of PFC-dependent cognition is complex, with concentration and receptor-specific actions that are likely dependent on neuronal activity state. Recent studies indicate that within the PFC, noradrenergic α1 and α2 receptors exert unique modulatory actions across distinct cognitive processes that allow for context-dependent modulation of cognition. Specifically, high affinity post-synaptic α2 receptors, engaged at moderate rates of NE release associated with moderate arousal levels, promote working memory. In contrast, lower affinity α1 receptors, engaged at higher rates of release associated with high arousal conditions (e.g. stress), impair working memory performance while promoting flexible attention. While these and other observations were initially interpreted to indicate high rates of NE release promotes the transition from focused to flexible/scanning attention, recent findings indicate that α1 receptors promote both focused and flexible attention. Collectively, these observations indicate that while α2 and α1 receptors in the PFC differentially modulate distinct cognitive processes, this cannot be simply ascribed to differential roles of these receptors in 'focused' vs. 'flexible' cognitive processes. Translationally, this information indicates that: (1) not all tests of prefrontal cognitive function may be appropriate for preclinical programs aimed at specific PFC-dependent disorders and (2) the treatment of specific PFC cognitive deficits may require the differential targeting of noradrenergic receptor subtypes. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26592951

  11. A lateral flow immunosensor for direct, sensitive, and highly selective detection of hemoglobin A1c in whole blood.

    PubMed

    Ang, Shu Hwang; Thevarajah, T Malathi; Woi, Pei Meng; Alias, Yatimah binti; Khor, Sook Mei

    2016-03-15

    An immunosensor that operates based on the principles of lateral flow was developed for direct detection of hemoglobin A1c (HbA1c) in whole blood. We utilized colloidal gold-functionalized antibodies to transduce the specific signal generated when sandwich immuno-complexes were formed on the strip in the presence of HbA1c. The number and intensity of the test lines on the strips indicate normal, under control, and elevated levels of HbA1c. In addition, a linear relationship between HbA1c levels and immunosensor signal intensity was confirmed, with a dynamic range of 4-14% (20-130 mmol mol(-1)) HbA1c. Using this linear relationship, we determined the HbA1c levels in blood as a function of the signal intensity on the strips. Measurements were validated using the Bio-Rad Variant II HPLC and DCA Vantage tests. Moreover, the immunosensor was verified to be highly selective for detection of HbA1c against HbA0, glycated species of HbA0, and HbA2. The limit of detection was found to be 42.5 μg mL(-1) (1.35 mmol mol(-1)) HbA1c, which is reasonably sensitive compared to the values reported for microarray immunoassays. The shelf life of the immunosensor was estimated to be 1.4 months when stored at ambient temperature, indicating that the immunoassay is stable. Thus, the lateral flow immunosensor developed here was shown to be capable of performing selective, accurate, rapid, and stable detection of HbA1c in human blood samples. PMID:26927875

  12. A 0.5 Tesla Transverse-Field Alternating Magnetic Field Demagnetizer

    NASA Astrophysics Data System (ADS)

    Schillinger, W. E.; Morris, E. R.; Finn, D. R.; Coe, R. S.

    2015-12-01

    We have built an alternating field demagnetizer that can routinely achieve a maximum field of 0.5 Tesla. It uses an amorphous magnetic core with an air-cooled coil. We have started with a 0.5 T design, which satisfies most of our immediate needs, but we can certainly achieve higher fields. In our design, the magnetic field is transverse to the bore and uniform to 1% over a standard (25 mm) paleomagnetic sample. It is powered by a 1 kW power amplifier and is compatible with our existing sample handler for automated demagnetization and measurement (Morris et al., 2009). It's much higher peak field has enabled us to completely demagnetize many of the samples that previously we could not with commercial equipment. This capability is especially needed for high-coercivity sedimentary and igneous rocks that contain magnetic minerals that alter during thermal demagnetization. It will also enable detailed automated demagnetization of high coercivity phases in extraterrestrial samples, such as native iron, iron-alloy and sulfide minerals that are common in lunar rocks and meteorites. Furthermore, it has opened the door for us to use the rock-magnetic technique of component analysis, using coercivity distributions derived from very detailed AF demagnetization of NRM and remanence produced in the laboratory to characterize the magnetic mineralogy of sedimentary rocks. In addition to the many benefits this instrument has brought to our own research, a much broader potential impact is to replace the transverse coils in automated AF demagnetization systems, which typically are limited to peak fields around 0.1 T.

  13. 26 CFR 1.907(a)-0 - Introduction (for taxable years beginning after December 31, 1982).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 9 2014-04-01 2014-04-01 false Introduction (for taxable years beginning after December 31, 1982). 1.907(a)-0 Section 1.907(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Income from Sources Without the United States §...

  14. 26 CFR 1.907(a)-0 - Introduction (for taxable years beginning after December 31, 1982).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 9 2012-04-01 2012-04-01 false Introduction (for taxable years beginning after December 31, 1982). 1.907(a)-0 Section 1.907(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Income from Sources Without the United States §...

  15. 26 CFR 1.907(a)-0 - Introduction (for taxable years beginning after December 31, 1982).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 9 2013-04-01 2013-04-01 false Introduction (for taxable years beginning after December 31, 1982). 1.907(a)-0 Section 1.907(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Income from Sources Without the United States §...

  16. 32 CFR 1636.3 - Basis for classification in Class 1-A-0.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Basis for classification in Class 1-A-0. 1636.3 Section 1636.3 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION OF CONSCIENTIOUS OBJECTORS § 1636.3 Basis for classification in Class 1-A-0. (a) A registrant...

  17. 32 CFR 1636.3 - Basis for classification in Class 1-A-0.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 6 2011-07-01 2011-07-01 false Basis for classification in Class 1-A-0. 1636.3 Section 1636.3 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION OF CONSCIENTIOUS OBJECTORS § 1636.3 Basis for classification in Class 1-A-0. (a) A registrant...

  18. Identification and analysis of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 in cynomolgus macaques.

    PubMed

    Uno, Yasuhiro; Hosaka, Shinya; Yamazaki, Hiroshi

    2014-12-01

    Cytochromes P450 (P450) are important for not only drug metabolism and toxicity, but also biosynthesis and metabolism of cholesterol and bile acids, and steroid synthesis. In cynomolgus macaques, widely used in biomedical research, we have characterized P450 cDNAs, which were isolated as expressed sequence tags of cynomolgus macaque liver. In this study, cynomolgus CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 cDNAs were characterized by sequence analysis, phylogenetic analysis and tissue expression pattern. By sequence analysis, these five cynomolgus P450s had high sequence identities (94-99%) to the human orthologs in amino acids. By phylogenetic analysis, each cynomolgus P450 was more closely related to the human ortholog as compared with the dog or rat ortholog. By quantitative polymerase chain reaction, among the 10 tissue types, CYP7A1 and CYP17A1 mRNAs were preferentially expressed in liver and adrenal gland, respectively. Cynomolgus CYP27A1 and CYP51A1 mRNAs were most abundantly expressed in liver and testis, respectively. Cynomolgus CYP20A1 mRNA was expressed in all the tissues, including brain and liver. Tissue expression patterns of each cynomolgus P450 were generally similar to that of the human ortholog. These results suggest the molecular similarities of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 between cynomolgus macaques and humans. PMID:25649950

  19. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests...

  20. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests...

  1. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests...

  2. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests...

  3. 32 CFR 1636.5 - Exclusion from Class 1-A-0 and Class 1-0.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... be excluded from Class 1-A-0 or Class 1-0: (a) Who asserts beliefs which are of a religious, moral or... participation in war does not rest at all upon moral, ethical, or religious principle, but instead rests...

  4. 15 CFR 0.735-10a-0.735-15 - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false 0.735-10a-0.735-15 Section 0.735-10a-0.735-15 Commerce and Foreign Trade Office of the Secretary of Commerce EMPLOYEE RESPONSIBILITIES AND CONDUCT Regulatory Limitations Upon Employee Conduct §§ 0.735-10a—0.735-15...

  5. 15 CFR 0.735-10a-0.735-15 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false 0.735-10a-0.735-15 Section 0.735-10a-0.735-15 Commerce and Foreign Trade Office of the Secretary of Commerce EMPLOYEE RESPONSIBILITIES AND CONDUCT Regulatory Limitations Upon Employee Conduct §§ 0.735-10a—0.735-15...

  6. 15 CFR 0.735-10a-0.735-15 - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false 0.735-10a-0.735-15 Section 0.735-10a-0.735-15 Commerce and Foreign Trade Office of the Secretary of Commerce EMPLOYEE RESPONSIBILITIES AND CONDUCT Regulatory Limitations Upon Employee Conduct §§ 0.735-10a—0.735-15...

  7. 15 CFR 0.735-10a-0.735-15 - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false 0.735-10a-0.735-15 Section 0.735-10a-0.735-15 Commerce and Foreign Trade Office of the Secretary of Commerce EMPLOYEE RESPONSIBILITIES AND CONDUCT Regulatory Limitations Upon Employee Conduct §§ 0.735-10a—0.735-15...

  8. 15 CFR 0.735-10a-0.735-15 - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false 0.735-10a-0.735-15 Section 0.735-10a-0.735-15 Commerce and Foreign Trade Office of the Secretary of Commerce EMPLOYEE RESPONSIBILITIES AND CONDUCT Regulatory Limitations Upon Employee Conduct §§ 0.735-10a—0.735-15...

  9. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Credits or refunds. 31.6402(a)-1 Section 31... Revenue Code of 1954) § 31.6402(a)-1 Credits or refunds. (a) In general. For regulations under section 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2,...

  10. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Credits or refunds. 31.6402(a)-1 Section 31... Revenue Code of 1954) § 31.6402(a)-1 Credits or refunds. (a) In general. For regulations under section 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2,...

  11. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Credits or refunds. 31.6402(a)-1 Section 31... Revenue Code of 1954) § 31.6402(a)-1 Credits or refunds. (a) In general. For regulations under section 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2,...

  12. Note on the photoproduction of the charged A1

    NASA Astrophysics Data System (ADS)

    Condo, G. T.; Handler, T.

    1987-05-01

    Arguments made nearly 15 years ago by Fox and Hey are updated in the light of recent experimental findings. These indicate that the charge-exchange photoproduction of the A1 should dominate that of the A2. Consistency with the experimental data demands an A1 mass of 1335+/-20 MeV and width of 180+/-55 MeV.

  13. Multifrequency Observations of BL Lacertae Object A0 0235+164

    NASA Astrophysics Data System (ADS)

    Howard, E. S.; Webb, J. R.; Benitez, E. M.; Balonek, T. J.; McGrath, E.; Shrader, C. R.; Inst. de Astronomia Team; CGRO/LHEA Team

    1999-05-01

    The BL Lacertae Object A0 0235+164 dramatically increased in brightness on October 20, 1997. This outburst was dectected with the 1 meter SARA (Southeastern Association for Research in Astronomy) telescope located at Kitt Peak National Observatory (KPNO). As a result of our observations, AO 0235+164 was also observed during the outburst by the Rossi X-ray Timing Experiment (RXTE), Foggy Bottom Observatory (Colgate), and University of Michigan 26 meter Radio telescope as a part of a Target of Opportunity (TOO) program. We present here the historical lightcurve A0 0235+164, multifrequency observations and multifrequency spectra collected during the 1997 through 1998 outburst.

  14. Experimental Study of Coherent Synchrotron Radiation in the Emittance Exchange Line at the A0-Photoinjector

    NASA Astrophysics Data System (ADS)

    Thangaraj, Jayakar C. T.; Thurman-Keup, R.; Johnson, A.; Lumpkin, A. H.; Edwards, H.; Ruan, J.; Santucci, J.; Sun, Y. E.; Church, M.; Piot, P.

    2010-11-01

    Next generation accelerators will require a high current, low emittance beam with a low energy spread. Such accelerators will employ advanced beam conditioning systems such as emittance exchangers to manipulate high brightness beams. One of the goals of the Fermilab A0 photoinjector is to investigate the transverse to longitudinal emittance exchange principle. Coherent synchrotron radiation could limit high current operation of the emittance exchanger. In this paper, we report on the preliminary experimental and simulation study of the coherent synchroton radiation (CSR) in the emittance exchange line at the A0 photoinjector.

  15. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

    PubMed Central

    Seiser, Eric L; van Leeuwen, Nienke; Tavendale, Roger; Bennett, Amanda J; Groves, Christopher J; Coleman, Ruth L; van der Heijden, Amber A; Beulens, Joline W; de Keyser, Catherine E; Zaharenko, Linda; Rotroff, Daniel M; Out, Mattijs; Jablonski, Kathleen A; Chen, Ling; Javorský, Martin; Židzik, Jozef; Levin, Albert M; Williams, L Keoki; Dujic, Tanja; Semiz, Sabina; Kubo, Michiaki; Chien, Huan-Chieh; Maeda, Shiro; Witte, John S; Wu, Longyang; Tkáč, Ivan; Kooy, Adriaan; van Schaik, Ron H N; Stehouwer, Coen D A; Logie, Lisa; Sutherland, Calum; Klovins, Janis; Pirags, Valdis; Hofman, Albert; Stricker, Bruno H; Motsinger-Reif, Alison A; Wagner, Michael J; Innocenti, Federico; 't Hart, Leen M; Holman, Rury R; McCarthy, Mark I; Hedderson, Monique M; Palmer, Colin N A; Florez, Jose C; Giacomini, Kathleen M; Pearson, Ewan R

    2016-01-01

    Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6×10−14) greater metformin-induced in haemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 is the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. PMID:27500523

  16. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

    PubMed

    Zhou, Kaixin; Yee, Sook Wah; Seiser, Eric L; van Leeuwen, Nienke; Tavendale, Roger; Bennett, Amanda J; Groves, Christopher J; Coleman, Ruth L; van der Heijden, Amber A; Beulens, Joline W; de Keyser, Catherine E; Zaharenko, Linda; Rotroff, Daniel M; Out, Mattijs; Jablonski, Kathleen A; Chen, Ling; Javorský, Martin; Židzik, Jozef; Levin, Albert M; Williams, L Keoki; Dujic, Tanja; Semiz, Sabina; Kubo, Michiaki; Chien, Huan-Chieh; Maeda, Shiro; Witte, John S; Wu, Longyang; Tkáč, Ivan; Kooy, Adriaan; van Schaik, Ron H N; Stehouwer, Coen D A; Logie, Lisa; Sutherland, Calum; Klovins, Janis; Pirags, Valdis; Hofman, Albert; Stricker, Bruno H; Motsinger-Reif, Alison A; Wagner, Michael J; Innocenti, Federico; Hart, Leen M 't; Holman, Rury R; McCarthy, Mark I; Hedderson, Monique M; Palmer, Colin N A; Florez, Jose C; Giacomini, Kathleen M; Pearson, Ewan R

    2016-09-01

    Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. PMID:27500523

  17. Current status of A1 adenosine receptor allosteric enhancers.

    PubMed

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Moorman, Allan R; Borea, Pier Andrea; Varani, Katia

    2015-01-01

    Adenosine is an ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1, A2A, A2B and A3 adenosine receptors (ARs). Allosteric enhancers to A1ARs may represent novel therapeutic agents because they increase the activity of these receptors by mediating a shift to their active form in the A1AR-G protein ternary complex. In this manner, they are able to amplify the action of endogenous adenosine, which is produced in high concentrations under conditions of metabolic stress. A1AR allosteric enhancers could be used as a justifiable alternative to the exogenous agonists that are characterized by receptor desensitization and downregulation. In this review, an analysis of some of the most interesting allosteric modulators of A1ARs has been reported. PMID:26144263

  18. Nucleon Structure with Domain Wall Fermions at a = 0.086 fm

    SciTech Connect

    Syritsyn, Sergey; Bratt, Jonathan; Lin, Meifeng; Meyer, Harvey; Negele, John; Pochinsky, Andrew; Procura, M.; Edwards, Robert; Orginos, Konstantinos; Richards, David; Engelhardt, Michael; Fleming, George; Haegler, Philipp; Musch, Bernhard; Renner, Dru; Schroers, Wolfram

    2008-12-01

    We present initial calculations of nucleon matrix elements of twist-two operators with 2+1 flavors of domain wall fermions at a lattice spacing a = 0.084 fm for pion masses down to 300 MeV. We also compare the results with the domain wall calculations on a coarser lattice.

  19. 26 CFR 1.641(a)-0 - Scope of subchapter J.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... mitigation of (i) the progressive rates of tax (including mitigation as a result of deferral of tax) or (ii...(a)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... any organization which is not to be classified for tax purposes as a trust under the...

  20. A-1 Test Stand work

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A structural steel beam to support the new thrust measurement system on the A-1 Test Stand at NASA's John C. Stennis Space Center is lifted to waiting employees for installation. The beam is part of the thrust takeout structure needed to support the new measurement system. Four such beams have been installed at the stand in preparation for installation of the system in upcoming weeks. Operators are preparing the stand for testing the next generation of rocket engines for the U.S. space program.

  1. Cerebellar Cortical Lamination and Foliation Require Cyclin A2

    PubMed Central

    Otero, José Javier; Kalaszczynska, Ilona; Michowski, Wojciech; Wong, Michael; Gygli, Patrick Edwin; Gokozan, Hamza Numan; Griveau, Amélie; Odajima, Junko; Czeisler, Catherine; Catacutan, Fay Patsy; Murnen, Alice; Schüler, Ulrich; Sicinski, Piotr; Rowitch, David

    2014-01-01

    The mammalian genome encodes two A-type cyclins, which are considered potentially redundant yet essential regulators of the cell cycle. Here, we tested requirements for cyclin A1 and cyclin A2 function in cerebellar development. Compound conditional loss of cyclin A1/A2 in neural progenitors resulted in severe cerebellar hypoplasia, decreased proliferation of cerebellar granule neuron progenitors (CGNP), and Purkinje (PC) neuron dyslamination. Deletion of cyclin A2 alone showed an identical phenotype, demonstrating that cyclin A1 does not compensate for cyclin A2 loss in neural progenitors. Cyclin A2 loss lead to increased apoptosis at early embryonic time points but not at post-natal time points. In contrast, neural progenitors of the VZ/SVZ did not undergo increased apoptosis, indicating that VZ/SVZ-derived and rhombic lip-derived progenitor cells show differential requirements to cyclin A2. Conditional knockout of cyclin A2 or the SHH proliferative target Nmyc in CGNP also resulted in PC neuron dyslamination. Although cyclin E1 has been reported to compensate for cyclin A2 function in fibroblasts and is upregulated in cyclin A2 null cerebella, cyclin E1 expression was unable to compensate for loss-of cyclin A2 function. PMID:24184637

  2. A2E and Lipofuscin.

    PubMed

    Crouch, Rosalie K; Koutalos, Yiannis; Kono, Masahiro; Schey, Kevin; Ablonczy, Zsolt

    2015-01-01

    Lipofuscin is highly fluorescent material, formed in several tissues but best studied in the eye. The accumulation of lipofuscin in the retinal pigment epithelium (RPE) is a hallmark of aging in the eye and has been implicated in various retinal degenerations, including age-related macular degeneration. The bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), formed from retinal, has been identified as a byproduct of the visual cycle, and numerous in vitro studies have found toxicity associated with this compound. The compound is known to accumulate in the RPE with age and was the first identified compound extracted from lipofuscin. Our studies have correlated the distribution of lipofuscin and A2E across the human and mouse RPE. Lipofuscin fluorescence was imaged in the RPE from human donors of various ages and from assorted mouse models. The spatial distribution of A2E was determined using matrix-assisted laser desorption-ionization imaging mass spectrometry on both flat-mounted and transversally sectioned RPE tissue. Our data support the clinical observations in humans of strong RPE fluorescence, increasing with age, in the central area of the RPE. However, there was no correlation between the distribution of A2E and lipofuscin, as the levels of A2E were highest in the far periphery and decreased toward the central region. Interestingly, in all the mouse models, A2E distribution and lipofuscin fluorescence correlate well. These data demonstrate that the accumulation of A2E is not responsible for the increase in lipofuscin fluorescence observed in the central RPE with aging in humans. PMID:26310170

  3. Optical alignment of a 0.5 meter ultra-violet spectrometer for Apollo 17

    NASA Technical Reports Server (NTRS)

    Schroader, I. H.; Holliday, C. T.; Bush, G. B.

    1973-01-01

    Description of the design and performance of a 0.5 m Ebert spectrometer mounted on Apollo 17 for research on the ultraviolet spectrum of the lunar atmosphere. The instrument was designed for operation in the range 1175 to 1675 A. A method was developed for aligning subassemblies in such a way that the assembled instrument would be aligned in the ultraviolet to an accuracy of 2 A with maximum efficiency.

  4. Transverse emittance and phase space program developed for use at the Fermilab A0 Photoinjector

    SciTech Connect

    Thurman-Keup, R.; Johnson, A.S.; Lumpkin, A.H.; Ruan, J.; /Fermilab

    2011-03-01

    The Fermilab A0 Photoinjector is a 16 MeV high intensity, high brightness electron linac developed for advanced accelerator R&D. One of the key parameters for the electron beam is the transverse beam emittance. Here we report on a newly developed MATLAB based GUI program used for transverse emittance measurements using the multi-slit technique. This program combines the image acquisition and post-processing tools for determining the transverse phase space parameters with uncertainties. An integral part of accelerator research is a measurement of the beam phase space. Measurements of the transverse phase space can be accomplished by a variety of methods including multiple screens separated by drift spaces, or by sampling phase space via pepper pots or slits. In any case, the measurement of the phase space parameters, in particular the emittance, can be drastically simplified and sped up by automating the measurement in an intuitive fashion utilizing a graphical interface. At the A0 Photoinjector (A0PI), the control system is DOOCS, which originated at DESY. In addition, there is a library for interfacing to MATLAB, a graphically capable numerical analysis package sold by The Mathworks. It is this graphical package which was chosen as the basis for a graphical phase space measurement system due to its combination of analysis and display capabilities.

  5. Quantitative, single-step dual measurement of hemoglobin A1c and total hemoglobin in human whole blood using a gold sandwich immunochromatographic assay for personalized medicine.

    PubMed

    Ang, Shu Hwang; Rambeli, Musalman; Thevarajah, T Malathi; Alias, Yatimah Binti; Khor, Sook Mei

    2016-04-15

    We describe a gold nanoparticle-based sandwich immunoassay for the dual detection and measurement of hemoglobin A1c (HbA1c) and total hemoglobin in the whole blood (without pretreatment) in a single step for personalized medicine. The optimized antibody-functionalized gold nanoparticles immunoreact simultaneously with HbA1c and total hemoglobin to form a sandwich at distinctive test lines to transduce visible signals. The applicability of this method as a personal management tool was demonstrated by establishing a calibration curve to relate % HbA1c, a useful value for type 2 diabetes management, to the signal ratio of captured HbA1c to all other forms of hemoglobin. The platform showed excellent selectivity (100%) toward HbA1c at distinctive test lines when challenged with HbA0, glycated HbA0 and HbA2. The reproducibility of the measurement was good (6.02%) owing to the dual measurement of HbA1c and total hemoglobin. A blood sample stability test revealed that the quantitative measurement of % HbA1c was consistent and no false-positive results were detected. Also, this method distinguished the blood sample with elevated HbF from the normal samples and the variants. The findings of this study highlight the potential of a lateral flow immunosensor as a simple, inexpensive, consistent, and convenient strategy for the dual measurement of HbA1c and total Hb to provide useful % HbA1c values for better on-site diabetes care. PMID:26606311

  6. Alterations of adenosine A1 receptors in morphine dependence.

    PubMed

    Kaplan, G B; Leite-Morris, K A; Sears, M T

    1994-09-19

    The possibility that central adenosine A1 and A2a receptors mediate opiate dependence was examined in morphine-treated mice using radioligand binding methods. Mice treated with morphine for 72 h demonstrated significant increases in naloxone precipitated abstinence behaviors of jumping, wet-dog shakes, teeth chattering, forepaw trends, forepaw tremors and diarrhea compared to vehicle-treated mice. Increased concentrations of cortical adenosine A1 receptor sites, but not striatal adenosine A2a sites, were found in saturation binding studies from morphine-dependent mice. Decreases in cortical A1 agonist binding affinity values along with increases in agonist binding sites were demonstrated in competition binding studies. These results suggest that adaptive changes of upregulation and sensitization of adenosine A1 receptors play a role in mediating the opiate abstinence syndrome. PMID:7820640

  7. An abundant dysfunctional apolipoprotein A1 in human atheroma.

    PubMed

    Huang, Ying; DiDonato, Joseph A; Levison, Bruce S; Schmitt, Dave; Li, Lin; Wu, Yuping; Buffa, Jennifer; Kim, Timothy; Gerstenecker, Gary S; Gu, Xiaodong; Kadiyala, Chandra S; Wang, Zeneng; Culley, Miranda K; Hazen, Jennie E; Didonato, Anthony J; Fu, Xiaoming; Berisha, Stela Z; Peng, Daoquan; Nguyen, Truc T; Liang, Shaohong; Chuang, Chia-Chi; Cho, Leslie; Plow, Edward F; Fox, Paul L; Gogonea, Valentin; Tang, W H Wilson; Parks, John S; Fisher, Edward A; Smith, Jonathan D; Hazen, Stanley L

    2014-02-01

    Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl(-) system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall. PMID:24464187

  8. Recent developments in A2B adenosine receptor ligands.

    PubMed

    Kalla, Rao V; Zablocki, Jeff; Tabrizi, Mojgan Aghazadeh; Baraldi, Pier Giovanni

    2009-01-01

    A selective, high-affinity A(2B) adenosine receptor (AR) antagonist will be useful as a pharmacological tool to help determine the role of the A(2B)AR in inflammatory diseases and angiogenic diseases. Based on early A(2B)AR-selective ligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754: K(i)(hA(2B)) = 2 nM; K(i)(hA(1)) = 403 nM; K(i)(hA(2A)) = 503 NM, and K(i)(hA(3)) = 570 nM), several groups have discovered second-generation A(2B)AR ligands that are suitable for development. Scientists at CV Therapeutics have discovered the selective, high-affinity A(2B)AR antagonist 22, a 8-(4-pyrazolyl)-xanthine derivative, (CVT-6883, K(i)(hA(2B)) = 22 nM; K(i)(hA(1)) = 1,940 nM; K(i)(hA(2A)) = 3,280; and K(i)(hA(3)) = 1,070 nM). Compound 22 has demonstrated favorable pharmacokinetic (PK) properties (T(1/2) = 4 h and F > 35% rat), and it is a functional antagonist at the A(2B)AR(K (B) = 6 nM). In a mouse model of asthma, compound 22 demonstrated a dose-dependent efficacy supporting the role of the A(2B)AR in asthma. In two Phase I clinical trails, 22 (CVT-6883) was found to be safe, well tolerated, and suitable for once-daily dosing. Baraldi et al. have independently discovered a selective, high-affinity A(2B)AR antagonist, 30 (MRE2029F20), 8-(5-pyrazolyl)-xanthine (K(i)(hA(2B)) = 5.5 nM; K(i)(hA(1)) = 200 nM; K(i)(hA(2A), A(3)) > 1,000, that has been selected for development in conjunction with King Pharmaceuticals. Compound 30 has been demonstrated to be a functional antagonist of the A(2B)AR, and it has been radiolabeled for use in pharmacological studies. A third compound, 58 (LAS-38096), is a 2-aminopyrimidine derivative (discovered by the Almirall group) that has high A(2B)AR affinity and selectivity (K(i)(hA(2B)) = 17 nM; K(i)(hA(1)) > 1,000 nM; K(i)(hA(2A)) > 2,500; and K(i)(hA(3)) > 1,000 nM), and 58 has been moved into preclinical safety testing. A fourth selective, high-affinity A(2B)AR antagonist, 54 (OSIP339391 K(i))(hA(2B)) = 0.5 nM; K(i))(hA(1

  9. Noncontact excitation of guided waves (A0 mode) using an electromagnetic acoustic transducer (EMAT)

    NASA Astrophysics Data System (ADS)

    Fromme, Paul

    2016-02-01

    Fatigue damage can develop in aircraft structures at locations of stress concentration, such as fasteners, and has to be detected before reaching a critical size to ensure safe aircraft operation. Guided ultrasonic waves offer an efficient method for the detection and characterization of such defects in large aerospace structures. Electromagnetic acoustic transducers (EMAT) for the noncontact excitation of guided ultrasonic waves were developed. The transducer development for the specific excitation of the A0 Lamb wave mode with an out-of-plane Lorentz force is explained. The achieved radial and angular dependency of the excited guided wave pulses were measured using a noncontact laser interferometer. Based on the induced eddy currents in the plate a theoretical model was developed. The application of the developed transducers for defect detection in aluminum components using fully noncontact guided wave measurements was demonstrated. Excitation of the A0 Lamb wave mode was achieved using the developed EMAT transducer and the guided wave propagation and scattering was measured using a noncontact laser interferometer.

  10. Radiation shielding for superconducting RF cavity test facility at A0

    SciTech Connect

    Dhanaraj, N.; Ginsburg, C.; Rakhno, I.; Wu, G.; /Fermilab

    2008-11-01

    The results of Monte Carlo radiation shielding study performed with the MARS15 code for the vertical test facility at the A0 north cave enclosure at Fermilab are presented and discussed. The vertical test facility at the A0 north cave is planned to be used for testing 1.3 GHz single-cell superconducting RF cavities with accelerating length of 0.115 m. The operations will be focused on high accelerating gradients--up to 50 MV/m. In such a case the facility can be a strong radiation source [1]. When performing a radiation shielding design for the facility one has to take into account gammas generated due to interactions of accelerated electrons with cavity walls and surroundings (for example, range of 3.7-MeV electrons in niobium is approximately 3.1 mm while the thickness of the niobium walls of such RF cavities is about 2.8 mm). The electrons are usually the result of contamination in the cavity. The radiation shielding study was performed with the MARS15 Monte Carlo code [2]. A realistic model of the source term has been used that describes spatial, energy and angular distributions of the field-emitted electrons inside the RF cavities. The results of the calculations are normalized using the existing experimental data on measured dose rate in the vicinity of such RF cavities.

  11. Development of Power Electronics for a 0.2kW-Class Ion Thruster

    NASA Technical Reports Server (NTRS)

    Pinero, Luis R.; Patterson, Michael J.; Bowers, Glen E.

    1997-01-01

    Applications that might benefit from low power ion propulsion systems include Earth-orbit magnetospheric mapping satellite constellations, low Earth-orbit satellites, geosynchronous Earth-orbit satellite north-south stationkeeping, and asteroid orbiters. These spacecraft are likely to have masses on the order of 50 to 500 kg with up to 0.5 kW of electrical power available. A power processing unit for a 0.2 kW-class ion thruster is currently under development for these applications. The first step in this effort is the development and testing of a 0.24 kW beam power supply. The design incorporates a 20 kHz full bridge topology with multiple secondaries connected in series to obtain outputs of up to 1200 V(sub DC). A current-mode control pulse width modulation circuit built using discrete components was selected for this application. An input voltage of 28 +/- 4 V(sub DC) was assumed, since the small spacecraft for which this system is targeted are anticipated to have unregulated low voltage busses. Efficiencies in excess of 91 percent were obtained at maximum output power. The total mass of the breadboard was less than 1.0 kg and the component mass was 0.53 kg. It is anticipated that a complete flight power processor could weigh about 2.0 kg.

  12. An abundant dysfunctional apolipoprotein A1 in human atheroma

    PubMed Central

    Huang, Ying; DiDonato, Joseph A.; Levison, Bruce S.; Schmitt, Dave; Li, Lin; Wu, Yuping; Buffa, Jennifer; Kim, Timothy; Gerstenecker, Gary; Gu, Xiaodong; Kadiyala, Chandra; Wang, Zeneng; Culley, Miranda K.; Hazen, Jennie E.; DiDonato, Anthony J.; Fu, Xiaoming; Berisha, Stela; Peng, Daoquan; Nguyen, Truc; Liang, Shaohong; Chuang, Chia-Chi; Cho, Leslie; Plow, Edward F.; Fox, Paul L.; Gogonea, Valentin; Tang, W.H. Wilson; Parks, John S.; Fisher, Edward A.; Smith, Jonathan D.; Hazen, Stanley L.

    2014-01-01

    Recent studies indicate high density lipoproteins (HDL) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma, are dysfunctional and extensively oxidized by myeloperoxidase (MPO), while in vitro oxidation of apoA1/HDL by MPO impairs its cholesterol acceptor function. We developed a high affinity monoclonal antibody (mAb) that specifically recognizes apoA1/HDL modified by the MPO/H2O2/Cl-system using phage display affinity maturation. An oxindolyl alanine (2-OH-Trp) moiety at tryptophan 72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirm a critical role for apoA1 Trp72 in MPO-mediated inhibition of ABCA1-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation, but accounts for 20% of the apoA1 in atherosclerotic plaque. OxTrp72-apoA1 recovered from human atheroma or plasma was lipid-poor, virtually devoid of cholesterol acceptor activity, and demonstrated both potent pro-inflammatory activities on endothelial cells and impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n=627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a pro-atherogenic process in the artery wall. PMID:24464187

  13. 26 CFR 1.50A-1 - Determination of amount.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Computing Credit for Expenses of Work Incentive Programs § 1.50A-1 Determination of amount. (a) In general. Except as otherwise provided in this section and in § 1.50A-2, the amount of the work incentive program... certain capital gains of subchapter S corporations), and any additional tax imposed for the taxable...

  14. Theoretical study on a 0.6 THz third harmonic gyrotron

    NASA Astrophysics Data System (ADS)

    Yuan, Xuesong; Lan, Ying; Ma, Chunyan; Han, Yu; Yan, Yang

    2011-10-01

    A theoretical study on a 0.6 THz third harmonic TE37 mode gyrotron oscillator is reported in this paper in order to develop a compact, reliable, and high power terahertz radiation source. An output power of 4 kW can be generated in the TE37 mode (0.6 THz) at a resonant magnetic field of 7.86 T by the gyrotron oscillator operating at 55 kV/2 A with an electron beam radius of 0.32 mm. A magnetron injection gun (MIG) with high compression ratio has been designed. The simulation results of MIG show that the velocity ratio α is 1.37, and the perpendicular velocity spread and parallel velocity spread are 6.1% and 8.9%, respectively.

  15. Theoretical study on a 0.6 THz third harmonic gyrotron

    SciTech Connect

    Yuan Xuesong; Ma Chunyan; Han Yu; Yan Yang; Lan Ying

    2011-10-15

    A theoretical study on a 0.6 THz third harmonic TE{sub 37} mode gyrotron oscillator is reported in this paper in order to develop a compact, reliable, and high power terahertz radiation source. An output power of 4 kW can be generated in the TE{sub 37} mode (0.6 THz) at a resonant magnetic field of 7.86 T by the gyrotron oscillator operating at 55 kV/2 A with an electron beam radius of 0.32 mm. A magnetron injection gun (MIG) with high compression ratio has been designed. The simulation results of MIG show that the velocity ratio {alpha} is 1.37, and the perpendicular velocity spread and parallel velocity spread are 6.1% and 8.9%, respectively.

  16. pt5m - a 0.5 m robotic telescope on La Palma

    NASA Astrophysics Data System (ADS)

    Hardy, L. K.; Butterley, T.; Dhillon, V. S.; Littlefair, S. P.; Wilson, R. W.

    2015-12-01

    pt5m is a 0.5 m robotic telescope located on the roof of the 4.2 m William Herschel Telescope (WHT) building, at the Roque de los Muchachos Observatory, La Palma. Using a five-position filter wheel and CCD detector, and bespoke control software, pt5m provides a high-quality robotic observing facility. The telescope first began robotic observing in 2012, and is now contributing to transient follow-up and time-resolved astronomical studies. In this paper, we present the scientific motivation behind pt5m, as well as the specifications and unique features of the facility. We also present an example of the science we have performed with pt5m, where we measure the radius of the transiting exoplanet WASP-33b. We find a planetary radius of 1.603 ± 0.014RJ.

  17. Elemental Abundance Analyses with DAO Spectrograms XXXVII. The Normal A0 IV Star γ Geminorum

    NASA Astrophysics Data System (ADS)

    Adelman, Saul J.; Gulliver, Austin F.; Kaewkornmaung, Pongsakorn

    2015-04-01

    We performed a fine analysis of the normal sharp-lined A0 IV star γ Geminorum with spectra having signal-to-noise ratios at the continuum of 500-1200 that were consistent with previous studies of this series. Our spectra have wavelength ranges of λλ3829-4730, 4873-4931, 4983-5042, and 5070-5210. The spectra measured with the program REDUCE have a two-pixel resolution of 0.072 Å. We used ATLAS9 models and the program WIDTH9 to derive the abundances of the metals. Most derived abundances are close to solar with the abundances of the heaviest elements Zr, Ba, La, Ce, and Nd showing greater than solar values. This suggests by comparison with the abundances of other normal and Am stars that γ Gem might exhibit an incipient Am star phenomenon.

  18. Design optimization of a 0.1-ton/day active magnetic regenerative hydrogen liquefier

    NASA Astrophysics Data System (ADS)

    Zhang, L.; Sherif, S. A.; DeGregoria, A. J.; Zimm, C. B.; Veziroglu, T. N.

    2000-04-01

    A design optimization procedure of a 0.1-ton/day active magnetic regenerative (AMR) hydrogen liquefier model is described. The liquefier is proposed for the industrial liquid hydrogen market with overall efficiency being the primary measure of performance. This performance is described here in terms of particle size, bed length, and inter-stage temperature. Efficiency comparable to larger gas cycle plants is predicted. The magnetic liquefier may be modified to operate as a two-stage magnetic refrigerator between 77 and 20 K with high efficiency. The paper describes an optimization method as applied to the design of a two-stage AMR hydrogen liquefier and presents the associated results. A five-parameter optimization process is performed since there are five changeable parameters; the low- and high-stage particle sizes, the low- and high-stage bed lengths, and the inter-stage temperature. Model results are presented and compared with experimental results of an actual liquefier.

  19. Single-shot electro-optic sampling of coherent transition radiation at the A0 Photoinjector

    SciTech Connect

    Maxwell, T.J.; Ruan, J.; Piot, P.; Thurman-Keup, R.; /Fermilab

    2011-08-01

    Future collider applications and present high-gradient laser plasma wakefield accelerators operating with picosecond bunch durations place a higher demand on the time resolution of bunch distribution diagnostics. This demand has led to significant advancements in the field of electro-optic sampling over the past ten years. These methods allow the probing of diagnostic light such as coherent transition radiation or the bunch wakefields with sub-picosecond time resolution. Potential applications in shot-to-shot, non-interceptive diagnostics continue to be pursued for live beam monitoring of collider and pump-probe experiments. Related to our developing work with electro-optic imaging, we present results on single-shot electro-optic sampling of the coherent transition radiation from bunches generated at the A0 photoinjector.

  20. Numerical study on a 0.4 THz second harmonic gyrotron with high power

    SciTech Connect

    Chaojun, Lei; Sheng, Yu; Hongfu, Li; Yinghui, Liu; Xinjian, Niu; Qixiang, Zhao

    2013-07-15

    Terahertz and sub-terahertz science and technology are promising topics today. However, it is difficult to obtain high power source of terahertz wave. In this paper, the mode competition and beam-wave interaction in a gradually tapered cavity are studied to achieve high efficiency of a 0.4THz second harmonic gyrotron in practice. In order to attain high power and stable radiation, the TE{sub 32,5} mode is selected as the operating mode of the desired gyrotron to realize single mode oscillation. The issues of studying on the high-order mode gyrotrons are solved effectively by transforming the generalized telegraphist's equations. The efficiency and output power of the gyrotron under different conditions have been calculated by the code, which is based on the transformed equations. Consequently, the results show that single mode second harmonic radiation with power of over 150 kW at frequency of 0.4 THz could be achieved.

  1. Bunch Length Monitoring at the A0 Photoinjector Using a Quasi-Optical Schottky Detector

    SciTech Connect

    Kazakevich, G.; Davidsaver, M.; Edwards, H.; Fliller, R.; Koeth, T.; Lumpkin, A.; Nagaitsev, S.; Ruan, J.; Thurman-Keup, R.; Jeong, Y.U.; Kubarev, V.; /Novosibirsk, IYF

    2009-05-01

    Noninvasive bunch duration monitoring has a crucial importance for modern accelerators intended for short wavelength FEL's, colliders and in some beam dynamics experiments. Monitoring of the bunch compression in the Emittance Exchange Experiment at the A0 Photoinjector was done using a parametric presentation of the bunch duration via Coherent Synchrotron Radiation (CSR) emitted in a dipole magnet and measured with a wideband quasi-optical Schottky Barrier Detector (SBD). The monitoring resulted in a mapping of the quadrupole parameters allowing a determination of the region of highest compression of the bunch in the sub-picosecond range. The obtained data were compared with those measured using the streak camera. A description of the technique and the results of simulations and measurements are presented and discussed in this report.

  2. Design study of a 0.4 THz 100 kW pulsed gyrotron

    SciTech Connect

    Choi, E.M.

    2011-07-01

    We present a status of development of a 0.4 THz, 100 kW pulsed gyrotron at UNIST 0.4 THz, 100 kW gyrotron is currently under design for a remote radioactive material detection. A magnetic injection gun (MIG) is used for the electron gun with a beam voltage of 70 kV and beam current of 10 A with a pulse duration of 10 usec. A second harmonic cavity for the gyrotron interaction is considered for the high power THz gyrotron. Numerical optimization of the electron gun design and the cavity is performed in the study. In this paper, we briefly report the design study of the gyrotron. (author)

  3. Investigation of possible csr induced energy spread effects with the A0 photoinjector bunch compressor

    SciTech Connect

    Fliller, R.P., III; Edwards, H.; Kazakevich, G.; Thurman-Keup, R.M.; Ruan, J.; /Fermilab

    2008-06-01

    The bunch compressor of the A0 Photoinjector at Fermilab was removed this past spring to install a transverse to longitudinal emittance exchange experiment. Prior to its removal questions arose about the possibility of observing the effects of Coherent Synchrotron Radiation on the compressed beam. The energy spread of the beam with and without compression was measured to observe any changes. Various beam charges were used to look for square law effects associated with CSR. No direct observation of CSR in the compressor was attempted because the design of the vacuum chamber did not allow it. In this paper we report the results of these experiments and comparison with simulations using ASTRA and CSRTrack. The results are also compared with analytical approximations.

  4. A1C Test and Diabetes

    MedlinePlus

    ... laboratory tests. How does the A1C relate to estimated average glucose? Estimated average glucose (eAG) is calculated from the A1C. ... levels have the A1C test twice a year. Estimated average glucose (eAG) is calculated from the A1C ...

  5. Infrastructure Development of Single Cell Testing Capability at A0 Facility

    SciTech Connect

    Dhanaraj, Nandhini; Padilla, R.; Reid, J.; Khabiboulline, T.; Ge, M.; Mukherjee, A.; Rakhnov, I.; Ginsburg, C.; Wu, G.; Harms, E.; Carter, H.; /Fermilab

    2009-09-01

    The objective of this technical note is to document the details of the infrastructure development process that was realized at the A0 photo injector facility to establish RF cold testing capability for 1.3 GHz superconducting niobium single cell cavities. The activity began the last quarter of CY 2006 and ended the first quarter of CY 2009. The whole process involved addressing various aspects such as design of vertical insert and lifting fixture, modification of existing RF test station and design of new couplers, development of a Temperature Mapping (T-Map) system, radiation considerations for the test location (north cave), update of existing High Pressure Rinse (HPR) system, preparation of necessary safety documents and eventually obtaining an Operational Readiness Clearance (ORC). Figure 1 illustrates the various components of the development process. In the past, the north cave test station at A0 has supported the cold testing 3.9 GHz nine cell and single cell cavities, thus some of the components were available for use and some needed modification. The test dewar had the capacity to accommodate 1.3 GHz single cells although a new vertical insert that could handle both cavity types (1.3 and 3.9 GHz) had to be designed. The existing cryogenic system with an average capacity of {approx} 0.5 g/sec was deemed sufficient. The RF system was updated with broadband components and an additional amplifier with higher power capacity to handle higher gradients usually achieved in 1.3 GHz cavities. The initial testing phase was arbitrated to proceed with fixed power coupling. A new temperature mapping system was developed to provide the diagnostic tool for hot spot studies, quench characterization and field emission studies. The defining feature of this system was the use of diode sensors instead of the traditional carbon resistors as sensing elements. The unidirectional current carrying capacity (forward bias) of the diodes provided for the ease of multiplexing of the

  6. Effect of mutations in the human immunoglobulin A1 (IgA1) hinge on its susceptibility to cleavage by diverse bacterial IgA1 proteases.

    PubMed

    Senior, Bernard W; Woof, Jenny M

    2005-03-01

    Components of the human immunoglobulin A1 (IgA1) hinge governing sensitivity to cleavage by bacterial IgA1 proteases were investigated. Recombinant antibodies with distinct hinge mutations were constructed from a hybrid comprised of human IgA2 bearing half of the human IgA1 hinge region. This hybrid antibody and all the mutant antibodies derived from it were resistant to cleavage by the IgA1 proteases from Streptococcus oralis and Streptococcus mitis biovar 1 strains but were cleaved to various degrees by those of Streptococcus pneumoniae, some Streptococcus sanguis strains, and the type 1 and 2 IgA1 proteases of Haemophilus influenzae, Neisseria meningitidis, and Neisseria gonorrhoeae. Remarkably, those proteases that cleave a Pro-Ser peptide bond in the wild-type IgA1 hinge were able to cleave mutant antibodies lacking a Pro-Ser peptide bond in the hinge, and those that cleave a Pro-Thr peptide bond in the wild-type IgA1 hinge were able to cleave mutant antibodies devoid of a Pro-Thr peptide bond in the hinge. Thus, the enzymes can cleave alternatives to their preferred postproline peptide bond when such a bond is unavailable. Peptide sequence analysis of a representative antibody digestion product confirmed this conclusion. The presence of a cleavable peptide bond near the CH2 end of the hinge appeared to result in greater cleavage than if the scissile bond was at the CH1 end of the hinge. Proline-to-serine substitution at residue 230 in a hinge containing potentially cleavable Pro-Ser and Pro-Thr peptide bonds increased the resistance of the antibody to cleavage by many IgA1 proteases. PMID:15731049

  7. Spectroscopic and Photometric Variability in the A0 Supergiant HR 1040

    NASA Astrophysics Data System (ADS)

    Corliss, David J.; Morrison, Nancy D.; Adelman, Saul J.

    2015-12-01

    A time-series analysis of spectroscopic and photometric observables of the A0 Ia supergiant HR 1040 has been performed, including equivalent widths, radial velocities, and Strömgren photometric indices. The data, obtained from 1993 through 2007, include 152 spectroscopic observations from the Ritter Observatory 1 m telescope and 269 Strömgren photometric observations from the Four College Automated Photoelectric Telescope. Typical of late B- and early A-type supergiants, HR 1040 has a highly variable Hα profile. The star was found to have an intermittent active phase marked by correlation between the Hα absorption equivalent width and blue-edge radial velocity and by photospheric connections observed in correlations to equivalent width, second moment and radial velocity in Si ii λλ6347, 6371. High-velocity absorption (HVA) events were observed only during this active phase. HVA events in the wind were preceded by photospheric activity, including Si ii radial velocity oscillations 19-42 days prior to onset of an HVA event and correlated increases in Si ii Wλ and second moment from 13 to 23 days before the start of the HVA event. While increases in various line equivalent widths in the wind prior to HVA events have been reported in the past in other stars, our finding of precursors in enhanced radial velocity variations in the wind and at the photosphere is a new result.

  8. A 0.9-V pulse frequency modulation photosensor based on capacitive feedback reset

    NASA Astrophysics Data System (ADS)

    Yasuoka, Koutaro; Kagawa, Keiichiro; Ohta, Jun; Nunoshita, Masahiro

    2005-03-01

    We are developing a retinal prosthesis vision chip based on a pulse-frequency-modulation (PFM) photosensor. Because the device is implanted in the eye ball and is powered by RF coil coupling with limited energy, low voltage and small current operation is required to achieve low power dissipation. We propose a capacitive-feedback-reset method for the PFM vision chip. The proposed method uses capacitive feed back through the junction capacitance of the photodiode and gate-source overlap capacitance of the reset transistor. In the proposed PFM circuit, the feed-through effect in resetting contributes to avoid current competition, so that the high dynamic range can be achieved even at the low voltage operation. We have fabricated a pixel TEG circuit in a 0.35-μm CMOS technology. The PFM photosensor circuit is composed of a four-stage inverter-chain. Dynamic range of 136dB has been achieved with 0.8-V power supply.

  9. Hydrogen permeation and diffusion in a 0. 2C-13Cr martensitic stainless steel

    SciTech Connect

    Xu, J.; Sun, X.K. . State Key Lab. of RSA); Yuan, X.Z.; Wei, B.M. . Dept. of Applied Chemistry)

    1993-10-01

    The phenomenon of hydrogen embrittlement for engineering alloys, especially for alloy steels, has long attracted the attention of material researchers. Presently, it is thought that the occurrence of the phenomenon correlates with the processes of hydrogen entry and transport in metals. Therefore, a great effort has been made to understand the hydrogen permeation and diffusion in metals and alloys. Even so, the knowledge of the hydrogen permeation and diffusion in steels with a martensitic structure is still limited. In most of the investigations performed on martensite, the electrochemical permeation technique was employed for measurement; hence, only limited data near ambient temperature have been determined. A few results obtained at higher temperature are very scattered also. For instance, the hydrogen diffusivity of AISI 4130 steel in the quenched and tempered (martensite) condition is 2 orders of magnitude higher than of cryoformed 301 stainless steel (containing 90% of [alpha][prime] martensite). In the present work, the hydrogen permeability and diffusivity of a 0.2C-13Cr martensitic stainless steel (2Cr13), roughly corresponding to AISI 420, was determined by means of the gaseous permeation technique. Measurements were made above ambient temperature.

  10. Stability of buprenorphine, haloperidol and glycopyrrolate mixture in a 0.9% sodium chloride solution.

    PubMed

    Jäppinen, A; Kokki, H; Naaranlahti, T J; Rasi, A S

    1999-12-01

    Combinations of opioids and adjuvant drug solutions are often used in clinical practice while little information is available on their microbiological or chemical stability. Currently there are no commercially available, prepacked, ready-to-use epidural or subcutaneous mixtures. Thus, epidural and subcutaneous analgesic mixtures must be prepared in the pharmacy on an as-needed basis. Such mixtures are typically used for the treatment of severe pain in cancer patients. The aim of this study was to investigate the microbiological and chemical stability of a buprenorphine, haloperidol and glycopyrrolate mixture in a 0.9% sodium chloride solution. A high performance liquid chromatographic (HPLC) method and pH-meter were used to conduct the analyses. Antimicrobial activity of each component was studied by an agar dilution method. According to the results from the chemical and microbiological stability studies, this mixture can be stored in polypropylene (PP) syringes and polyvinyl chloride (PVC) medication cassettes for at least 30 days at either 21 degrees C or 4 degrees C, and for 16 days in PP syringes at 36 degrees C, and for 9 days in PVC medication cassettes at 36 degrees C. PMID:10658237

  11. Design considerations and parameter study for a 0.5TeV PWFA afterburner

    NASA Astrophysics Data System (ADS)

    Huang, Chengkun; Lu, W.; Tzoufras, M.; Zhou, M.; Decyk, V. K.; Joshi, C.; Mori, W. B.

    2007-11-01

    A recent plasma wakefield acceleration (PWFA) experiment using short (˜100fs), high peak current (>10KA) electron beam as driver has demonstrated sustained acceleration gradients of ˜50GeV/m over 85 cm distance [1]. The rapid progress of PWFA experiments has attracted interest regarding the possibility of making an afterburner for a linear collider. In the afterburner concept, an electron beam is placed into the wakefield to extract energy deposited in the wake. We investigate the afterburner concept based on the present understanding of the key physics. Possible design scenarios such as single stage acceleration or integrated design with plasma lens final focusing are studied. The final energy, charges, emittance, energy spread and energy stability of the accelerated electron beam are taken as intrinsic design considerations. Parameters are suggested for a 0.5 TeV afterburner. We also present full scale 3D particle-in-cell simulations of the possible design using a highly efficient and accurate quasi-static code QuickPIC. [1] Blumenfeld et. al., Nature 445, 741 (2007).

  12. Analysis of Interlayer Shorts in a 0.5 {micro}m CMOS IC Technology

    SciTech Connect

    Cole, E.I.; Henderson, C.L.; Soden, J.M.

    1999-03-12

    Sandia is manufacturing CMOS ICs with 0.5 {micro}m LOCOS and shallow trench isolation (STI) technologies and is developing a 0.35 {micro}m SOI technology. A program based on burn-in and life tests is being used to qualify the 0.5 {micro}m technologies for delivery of high reliability ICs to customers for military and space applications. Representative ICs from baseline wafer lots are assembled using a high reliability process with multilayer hermetic, ceramic packages. These ICs are electrically tested before, during, and after burn-in and subsequent 1000 hour dynamic and static life tests. Two types of ICS are being used for this qualification, a 256K bit SRAM and a Microcontroller Core (MCC). Over 600 ICs have successfully completed these qualification tests, resulting in a failure rate estimate of less than 4 FITS for satellite applications. Recently, a group of SRAMS from a development wafer lot incorporating nonqualified processes of the 0.5 {micro}m LOCOS technology had an unusually high number of failures during the initial electrical test after packaging. The investigation of these failures is described.

  13. An a0 resonance in strongly coupled πη, KK¯ scattering from lattice QCD

    DOE PAGESBeta

    Dudek, Jozef J.; Edwards, Robert G.; Wilson, David J.

    2016-05-11

    Here, we present the first calculation of coupled-channel meson-meson scattering in the isospinmore » $=1$, $G$-parity negative sector, with channels $$\\pi \\eta$$, $$K\\overline{K}$$ and $$\\pi \\eta'$$, in a first-principles approach to QCD. From the discrete spectrum of eigenstates in three volumes extracted from lattice QCD correlation functions we determine the energy dependence of the $S$-matrix, and find that the $S$-wave features a prominent cusp-like structure in $$\\pi \\eta \\to \\pi \\eta$$ close to $$K\\overline{K}$$ threshold coupled with a rapid turn on of amplitudes leading to the $$K\\overline{K}$$ final-state. This behavior is traced to an $a_0(980)$-like resonance, strongly coupled to both $$\\pi \\eta$$ and $$K\\overline{K}$$, which is identified with a pole in the complex energy plane, appearing on only a single unphysical Riemann sheet. Consideration of $D$-wave scattering suggests a narrow tensor resonance at higher energy.« less

  14. A 0.33-THz second-harmonic frequency-tunable gyrotron

    NASA Astrophysics Data System (ADS)

    Zheng-Di, Li; Chao-Hai, Du; Xiang-Bo, Qi; Li, Luo; Pu-Kun, Liu

    2016-02-01

    Dynamics of the axial mode transition process in a 0.33-THz second-harmonic gyrotron is investigated to reveal the physical mechanism of realizing broadband frequency tuning in an open cavity circuit. A new interaction mechanism about propagating waves, featured by wave competition and wave cooperation, is presented and provides a new insight into the beam-wave interaction. The two different features revealed in the two different operation regions of low-order axial modes (LOAMs) and high-order axial modes (HOAMs) respectively determine the characteristic of the overall performance of the device essentially. The device performance is obtained by the simulation based on the time-domain nonlinear theory and shows that using a 12-kV/150-mA electron beam and TE-3,4 mode, the second harmonic gyrotron can generate terahertz radiations with frequency-tuning ranges of about 0.85 GHz and 0.60 GHz via magnetic field and beam voltage tuning, respectively. Additionally, some non-stationary phenomena in the mode startup process are also analyzed. The investigation in this paper presents guidance for future developing high-performance frequency-tunable gyrotrons toward terahertz applications. Project supported by the National Natural Science Foundation of China (Grant Nos. 61471007, 61531002, 61522101, and 11275206) and the Seeding Grant for Medicine and Information Science of Peking University, China (Grant No. 2014-MI-01).

  15. Asymmetric electron transfer in cyanobacterial Photosystem I: charge separation and secondary electron transfer dynamics of mutations near the primary electron acceptor A0.

    PubMed

    Dashdorj, Naranbaatar; Xu, Wu; Cohen, Rachel O; Golbeck, John H; Savikhin, Sergei

    2005-02-01

    Point mutations were introduced near the primary electron acceptor sites assigned to A0 in both the PsaA and PsaB branches of Photosystem I in the cyanobacterium Synechocystis sp. PCC 6803. The residues Met688PsaA and Met668PsaB, which provide the axial ligands to the Mg2+ of the eC-A3 and eC-B3 chlorophylls, were changed to leucine and asparagine (chlorophyll notation follows Jordan et al., 2001). The removal of the ligand is expected to alter the midpoint potential of the A0/A0- redox pair and result in a change in the intrinsic charge separation rate and secondary electron transfer kinetics from A0- to A1. The dynamics of primary charge separation and secondary electron transfer were studied at 690 nm and 390 nm in these mutants by ultrafast optical pump-probe spectroscopy. The data reveal that mutations in the PsaB branch do not alter electron transfer dynamics, whereas mutations in the PsaA branch have a distinct effect on electron transfer, slowing down both the primary charge separation and the secondary electron transfer step (the latter by a factor of 3-10). These results suggest that electron transfer in cyanobacterial Photosystem I is asymmetric and occurs primarily along the PsaA branch of cofactors. PMID:15542554

  16. HIGH-RESOLUTION OBSERVATIONS AND THE PHYSICS OF HIGH-VELOCITY CLOUD A0

    SciTech Connect

    Verschuur, Gerrit L.

    2013-04-01

    The neutral hydrogen structure of high-velocity cloud A0 (at about -180 km s{sup -1}) has been mapped with a 9.'1 resolution. Gaussian decomposition of the profiles is used to separately map families of components defined by similarities in center velocities and line widths. About 70% of the H I gas is in the form of a narrow, twisted filament whose typical line widths are of the order of 24 km s{sup -1}. Many bright features with narrow line widths of the order of 6 km s{sup -1}, clouds, are located in and near the filament. A third category with properties between those of the filament and clouds appears in the data. The clouds are not always co-located with the broader line width filament emission as seen projected on the sky. Under the assumption that magnetic fields underlie the presence of the filament, a theorem is developed for its stability in terms of a toroidal magnetic field generated by the flow of gas along field lines. It is suggested that the axial magnetic field strength may be derived from the excess line width of the H I emission over and above that due to kinetic temperature by invoking the role of Alfven waves that create what is in essence a form of magnetic turbulence. At a distance of 200 pc the axial and the derived toroidal magnetic field strengths in the filament are then about 6 {mu}G while for the clouds they are about 4 {mu}G. The dependence of the derived field strength on distance is discussed.

  17. Corrosion and Tribocorrosion Performance of Thermally Oxidized Commercially Pure Titanium in a 0.9% NaCl Solution

    NASA Astrophysics Data System (ADS)

    Bailey, R.; Sun, Y.

    2015-04-01

    In the present work, the corrosion and tribocorrosion characteristics of thermally oxidized commercially pure titanium in a 0.9% NaCl solution have been investigated. Thermal oxidation (TO) of CP-Ti was carried out at a temperature of 625 °C for 20 h. This treatment results in a multi-layered structure consisting of a 1 µm rutile (TiO2) film and a 9 µm α-titanium oxygen diffusion zone (ODZ) (α-Ti(O)). Electrochemical tests were carried out on surfaces created at various depths from the TO-Ti original surface. It was found that the rutile film generated through TO offers excellent corrosion resistance over that of untreated Ti. Testing also provided evidence that oxygen content in the upper part of the ODZ (depths <5 µm from the surface) helps accelerate passive film formation and thus reduce the corrosion of CP-Ti. Tribo-electrochemical testing of TO-Ti was carried out against an alumina counter face under a load of 2 N and various anodic and cathodic potentials. It is initially shown that the rutile oxide layer offers both low friction and much better resistance to material removal during tribocorrosion than untreated CP-Ti. During sliding wear at open circuit potential, four frictional zones can be identified in a typical friction curve, each having its own characteristics corresponding to the oxide layer, the gradual or partial removal of the oxide layer, the diffusion zone, and the substrate. An unusual anodic protection behavior of the oxide film has also been observed. When the TO-Ti is polarized anodically during sliding, the durability of the oxide layer is prolonged, resulting in low friction and much reduced material loss. When cathodically charged to -1500 mVSCE during sliding, both the TO-Ti and untreated CP-Ti experience a reduction in material loss. This is believed to be related to hydrogen evolution and titanium hydride formation.

  18. An Observation of a Transverse to Longitudinal Emittance Exchange at the Fermilab A0 Photoinjector

    SciTech Connect

    Koeth, Timothy W

    2009-05-01

    An experimental program to perform a proof of principle of transverse to longitudinal emittance exchange (ϵxin ↔ ϵzout and ϵxin ↔ ϵzout) has been developed at the Fermilab A0 Photoinjector. A new beamline, including two magnetic dogleg channels and a TM110 deflecting mode radio frequency cavity, were constructed for the emittance exchange experiment. The first priority was a measurement of the Emittance Exchange beamline transport matrix. The method of difference orbits was used to measure the transport matrix. Through varying individual beam input vector elements, such as xin, x'in, yin, y'in, zin, or δin, and measuring the changes in all of the beam output vector's elements, xout, x'out, yout, y'out, zout, δout, the full 6 x 6 transport matrix was measured. The measured emittance exchange transport matrix was in overall good agreement with our calculated transport matrix. A direct observation of an emittance exchange was performed by measuring the electron beam's characteristics before and after the emittance exchange beamline. Operating with a 14.3 MeV, 250pC electron bunch, ϵzin of 21.1 ± 1.5 mm • mrad was observed to be exchanged with ϵxout of 20.8 ± 2.00 mm • mrad. Diagnostic limitations in the ϵzout measurement did not account for an energy-time correlation, thus potentially returning values larger than the actual longitudinal emittance. The ϵxin of 4.67 ± 0.22 mm • mrad was observed to be exchanged with ϵzout of 7.06 ± 0.43 mm • mrad. The apparent ϵzoutgrowth is consistent with calculated values in which the correlation term is neglected.

  19. Aldehyde dehydrogenase 1A1 in stem cells and cancer

    PubMed Central

    Tomita, Hiroyuki; Tanaka, Kaori; Tanaka, Takuji; Hara, Akira

    2016-01-01

    The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies. PMID:26783961

  20. A 0. 5 to 3. 0 MeV monoenergetic positron beam

    SciTech Connect

    Huomo, H.; AsokaKumar, P.; Henderson, S.D.; Phlips, B.F.; Mayer, R.; McDonough, J.; Hacker, H.; McCorkle, S.; Schnitzenbaumer, P.; Greenberg, J.S.

    1988-01-01

    An adjustable, 0.5--3 MeV monoenergetic positron beam has been constructed at Brookhaven. Currently a /sup 22/Na source with a W(100) foil transmission moderator produces a 1.1 mm FWHN beam with an intensity of 3/times/10/sup 5/ e/sup +//sec at a target located downstream from the accelerator. The divergence of the beam is less than 0.1/degree/ at 2.2 MeV energy. A SOA gun with 2 lens transport system brings the beam to a focus at the entrance of an electrostatic 3 MeV Dynamitron accelerator. The post acceleration beam transport system comprises 3 focusing solenolds, 4 sets of steering magnets and a 90/degree/ double focusing bending magnet. The beam energy spread at the target is <1 keV FWHN deduced from the beam size. Below we describe the positron extraction optics and acceleration, the construction of the beamline and the beam diagnostic devices. The salient beam parameters are listed at the end of this paper. 2 refs., 3 figs., 1 tab.

  1. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  2. 22 CFR 3a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Definitions. 3a.1 Section 3a.1 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.1 Definitions. For purposes of this part— (a) Applicant means any person...

  3. 32 CFR 352a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Purpose. 352a.1 Section 352a.1 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under provisions...

  4. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  5. 32 CFR 242a.1 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Applicability. 242a.1 Section 242a.1 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.1 Applicability. These...

  6. 12 CFR 708a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 6 2011-01-01 2011-01-01 false Definitions. 708a.1 Section 708a.1 Banks and Banking NATIONAL CREDIT UNION ADMINISTRATION REGULATIONS AFFECTING CREDIT UNIONS BANK CONVERSIONS AND MERGERS Conversion of Insured Credit Unions to Mutual Savings Banks § 708a.1 Definitions. As used in this part: Clear and conspicuous means text...

  7. 77 FR 43196 - Approval and Promulgation of Implementation Plans; North Carolina; 110(a)(1) and (2...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-24

    ... for section 110(a)(2)(D)(i) for the 2006 24-hour PM 2.5 NAAQS for North Carolina. See 76 FR 43167... AGENCY 40 CFR Part 52 Approval and Promulgation of Implementation Plans; North Carolina; 110(a)(1) and (2... provide detail on how North Carolina's SIP addresses 110(a)(2)(C). 110(a)(2)(A): Emission limits and......

  8. Cyclosporine a 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis

    PubMed Central

    2012-01-01

    Background To evaluate the treatment with topical 0.05% cyclosporine A (CsA) in patients with subepithelial corneal infiltrates (SEI). Methods We reviewed 16 patients (22 eyes) before and after the treatment with 0.05% CsA eye drops. All patients had been treated previously with topical corticosteroids without any improvement and also they had to stop the medication secondary to intraocular pressure elevation. The objective data recorded included best-corrected visual acuity (BCVA), evaluation of corneal subepithelial infiltrate scores (CSIS), intraocular pressure (IOP) prior to treatment and the last follow-up visit. Results Six males (37.5%) and 10 females (62.5%), mean age of 35.2 ± 16.6 years, were included. The patients’ average topical CsA use duration was 5.1 ± 3.5 months (1 – 13 months). The average follow up time of the patients was 9.2 ± 4.7 months (4 – 22 months). One patient, although he didn’t have a 0 scale of SCIS, did not show up for follow up examinations after six months. The mean BCVA (logarithm of the minimum angle of resolution) before and after the treatment were 0.15 ± 0.15 and 0.07 ± 0.07 respectively, CSIS 1.68 ± 0.89 and 0.23 ± 0.53 respectively, IOP 18.50 ± 3.82 and 16.86 ± 2.76 mmHg respectively. There were statistically significant improvements in BCVA (p = 0.002), reduction of CSIS (p = 0.002) and reduction of IOP (p < 0.001) prior to treatment and the last follow-up visit. 18 eyes (81.9%) showed clinical improvement and 4 (18.1%) had decreased SEI which did not fully disappear during the treatment period. The eyes which reached CSIS score 0 (18 eyes) were treated with CsA for 1 – 13 months; while the eyes which had clinical improvement but had not CSIS score 0 (4 eyes) were decided to discontinue of CsA treatment in last follow-up visit. There were recurrences in 2 eyes 3 months after the treatment. Patients reported reduction in the severity of symptoms after the

  9. Electronic and vibronic states of the acceptor-bound-exciton complex (A0,X) in CdS. II. Determination of the fine structure of the (A0,XB) electronic states by high-resolution excitation spectroscopy

    NASA Astrophysics Data System (ADS)

    Gutowski, J.

    1985-03-01

    In a previous paper [R. Baumert, I. Broser, J. Gutowski, and A. Hoffman, Phys. Rev. B 27, 6263 (1983)] it has been shown that high-density, high-resolution excitation spectroscopy gives new information on the electronic and vibronic excited states of the acceptor-bound-exciton complex (A0,XA) with two holes from the A valence band in CdS. We now report on corresponding results for the (A0,XB) configuration which includes one hole from the second B valence band. This complex is unstable for a very fast B-->A hole conversion, and therefore gives rise to a set of excitation resonances of the I1 luminescence arising from the (A0,XA) recombination. A detailed theoretical analysis of the energetic structure of the (A0,XB) complex including the dependence on the excitation intensity and on an applied magnetic field allows the correct assignment of the excitation resonances to the (A0,XB) fine-structure levels originating from the interparticle-exchange interactions. It is shown that the magnetic field is a suitable means of distinguishing the different (A0,XB) ground-state levels. The magnetic field also creates allowed transitions which are dipole forbidden in the zero-field case. A self-contained model of the (A0,XB) complex thus can be developed, including all symmetry states and yielding adequate values for the exchange energies within the complex.

  10. Atomic Scale coexistence of Periodic and quasiperiodic order in a2-fold A1-Ni-Co decagonal quasicrystal surface

    SciTech Connect

    Park, Jeong Young; Ogletree, D. Frank; Salmeron, Miquel; Ribeiro,R.A.; Canfield, P.C.; Jenks, C.J.; Thiel, P.A.

    2005-11-14

    Decagonal quasicrystals are made of pairs of atomic planes with pentagonal symmetry periodically stacked along a 10-fold axis. We have investigated the atomic structure of the 2-fold surface of a decagonal Al-Ni-Co quasicrystal using scanning tunneling microscopy (STM). The surface consists of terraces separated by steps of heights 1.9, 4.7, 7.8, and 12.6{angstrom} containing rows of atoms parallel to the 10-fold direction with an internal periodicity of 4{angstrom}. The rows are arranged aperiodically, with separations that follow a Fibonacci sequence and inflation symmetry. The results indicate that the surfaces are preferentially Al-terminated and in general agreement with bulk models.

  11. Gold-induced nanowires on the Ge(100) surface yield a 2D and not a 1D electronic structure

    NASA Astrophysics Data System (ADS)

    de Jong, N.; Heimbuch, R.; Eliëns, S.; Smit, S.; Frantzeskakis, E.; Caux, J.-S.; Zandvliet, H. J. W.; Golden, M. S.

    2016-06-01

    Atomic nanowires on semiconductor surfaces induced by the adsorption of metallic atoms have attracted a lot of attention as possible hosts of the elusive, one-dimensional Tomonaga-Luttinger liquid. The Au/Ge(100) system in particular is the subject of controversy as to whether the Au-induced nanowires do indeed host exotic, 1D (one-dimensional) metallic states. In light of this debate, we report here a thorough study of the electronic properties of high quality nanowires formed at the Au/Ge(100) surface. The high-resolution ARPES data show the low-lying Au-induced electronic states to possess a dispersion relation that depends on two orthogonal directions in k space. Comparison of the E (kx,ky) surface measured using high-resolution ARPES to tight-binding calculations yields hopping parameters in the two different directions that differ by approximately factor of two. Additionally, by pinpointing the Au-induced surface states in the first, second, and third surface Brillouin zones and analyzing their periodicity in k||, the nanowire propagation direction seen clearly in STM can be imported into the ARPES data. We find that the larger of the two hopping parameters corresponds, in fact, to the direction perpendicular to the nanowires (tperp). This proves that the Au-induced electron pockets possess a two-dimensional, closed Fermi surface, and this firmly places the Au/Ge(100) nanowire system outside potential hosts of a Tomonaga-Luttinger liquid. We combine these ARPES data with scanning tunneling spectroscopic measurements of the spatially resolved electronic structure and find that the spatially straight—wirelike—conduction channels observed up to energies of order one electron volt below the Fermi level do not originate from the Au-induced states seen in the ARPES data. The former are rather more likely to be associated with bulk Ge states that are localized to the subsurface region. Despite our proof of the 2D (two-dimentional) nature of the Au-induced nanowire and subsurface Ge-related states, an anomalous suppression of the density of states at the Fermi level is observed in both the STS and ARPES data, and this phenomenon is discussed in the light of the effects of disorder.

  12. Genetic complexity of the human surfactant-associated proteins SP-A1 and SP-A2

    PubMed Central

    Silveyra, Patricia; Floros, Joanna

    2012-01-01

    Pulmonary surfactant protein A (SP-A) plays a key role in innate lung host defense, in surfactant-related functions, and in parturition. In the course of evolution, the genetic complexity of SP-A has increased, particularly in the regulatory regions (i.e. promoter, untranslated regions). Although most species have a single SP-A gene, two genes encode SP-A in humans and primates (SFTPA1and SFTPA2). This may account for the multiple functions attributed to human SP-A, as well as the regulatory complexity of its expression by a relatively diverse set of protein and non-protein cellular factors. The interplay between enhancer cis-acting DNA sequences and trans-acting proteins that recognize these DNA elements is essential for gene regulation, primarily at the transcription initiation level. Furthermore, regulation at the mRNA level is essential to ensure proper physiological levels of SP-A under different conditions. To date, numerous studies have shown significant complexity of the regulation of SP-A expression at different levels, including transcription, splicing, mRNA decay, and translation. A number of trans-acting factors have also been described to play a role in the control of SP-A expression. The aim of this report is to describe the genetic complexity of the SFTPA1 and SFTPA2 genes, as well as to review regulatory mechanisms that control SP-A expression in humans and other animal species. PMID:23069847

  13. Led Astray by Hemoglobin A1c

    PubMed Central

    Chen, Jean; Diesburg-Stanwood, Amy; Bodor, Geza; Rasouli, Neda

    2016-01-01

    Hemoglobin A1c (A1c) is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient’s A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient’s A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his “diabetes management” and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants. PMID:26848480

  14. Reversibility of Intersystem Crossing in the {a}1A1(000) and {a}1A1(010) States of Methylene, CH_2

    NASA Astrophysics Data System (ADS)

    Le, Anh T.; Sears, Trevor; Hall, Gregory

    2015-06-01

    The lowest energy singlet ( {a}1A1) and triplet ( {X}3B1) electronic states of methylene, CH_2, are only separated by 3150 wn, but differ greatly in chemical reactivity. Overall methylene reaction rates and chemical behavior are therefore strongly dependent on collisionally-mediated singlet-triplet interconversion. Collisions with inert partners tend to depopulate the excited singlet state and populate vibrationally excited triplet levels in CH_2. This process is generally considered as irreversible for large molecules, however, this is not the case for small molecules such as CH_2. An investigation of the decay kinetics of CH_2 in the presence of argon and various amounts of oxygen has been carried out using transient frequency modulation (FM) absorption spectroscopy, to monitor ortho and para rotational levels in both the {a}1A1(000) and {a}1A1(010) states. In the {a}1A1(000) state, all observed rotational levels follow double exponential decay kinetics, a direct consequence of reversible intersystem crossing. The relative amplitude of the slower decay component is an indicator of how quickly the reverse crossing from excited triplet levels becomes significant during the reaction and relaxation of singlet methylene. The para rotational levels show more obvious signs of reversibility than ortho rotational levels. Adding oxygen enhances the visibility of reversibility for both ortho and para levels. However, in the {a}1A1(010) state where the FM signal is 5-10 times smaller than the {a}1A1(000) state, there is no evidence of double exponential decay kinetics. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 and DE-SC0012704 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences.

  15. The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells.

    PubMed

    Tardito, Saverio; Isella, Claudio; Medico, Enzo; Marchiò, Luciano; Bevilacqua, Elena; Hatzoglou, Maria; Bussolati, Ovidio; Franchi-Gazzola, Renata

    2009-09-01

    The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitin-proteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2alpha phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2alpha, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2alpha phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2alpha phosphorylation and the UPR. PMID:19561079

  16. Pharmacogenetics of SULT1A1

    PubMed Central

    Daniels, Jaclyn; Kadlubar, Susan

    2015-01-01

    Cytosolic SULT1A1 participates in the bioconversion of a plethora of endogenous and xenobiotic substances. Genetic variation in this important enzyme such as SNPs can vary by ethnicity and have functional consequences on its activity. Most SULT1A1 genetic variability studies have been centered on the SULT1A1*1/2 SNP. Highlighted here are not only this SNP, but other genetic variants associated with SULT1A1 that could modify drug efficacy and xenobiotic metabolism. Some studies have investigated how differential metabolism of xenobiotic substances influences susceptibility to or protection from cancer in multiple sites. This review will focus primarily on the impact of SULT1A1 genetic variation on the response to anticancer therapeutic agents and subsequently how it relates to environmental and dietary exposure to both cancer-causing and cancer-preventative compounds. PMID:25493573

  17. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  18. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  19. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  20. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  1. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  2. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  3. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  4. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  5. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  6. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  7. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  8. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  9. 32 CFR 352a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Applicability. 352a.2 Section 352a.2 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.2 Applicability. This part applies to the Office of the Secretary of Defense...

  10. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 51a.2 Section 51a.2 Public Health... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  11. 7 CFR 1a.2 - Authorization.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Authorization. 1a.2 Section 1a.2 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.2 Authorization. Any official of the Office of Inspector General who is designated by the Inspector General according to §§ 1a.3 and 1a.5...

  12. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 2a.2 Section 2a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services...

  13. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 2a.2 Section 2a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services...

  14. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 2a.2 Section 2a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services...

  15. 14 CFR 374a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Applicability. 374a.2 Section 374a.2 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.2 Applicability....

  16. 32 CFR 383a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Applicability. 383a.2 Section 383a.2 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.2 Applicability. This part applies to the Office of...

  17. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  18. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  19. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  20. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  1. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  2. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 59a.2 Section 59a.2 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.2 Definitions. Undefined...

  3. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 59a.2 Section 59a.2 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.2 Definitions. Undefined...

  4. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 59a.2 Section 59a.2 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.2 Definitions. Undefined...

  5. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 59a.2 Section 59a.2 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.2 Definitions. Undefined...

  6. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 59a.2 Section 59a.2 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.2 Definitions. Undefined...

  7. 14 CFR 374a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Applicability. 374a.2 Section 374a.2 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.2 Applicability....

  8. 7 CFR 15a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Definitions. 15a.2 Section 15a.2 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.2 Definitions. As used in this part, the term: (a) Title IX means title IX of the Education Amendments...

  9. The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women

    PubMed Central

    Nordmark, Anna; Lundgren, Stefan; Ask, Birgitta; Granath, Fredrik; Rane, Anders

    2002-01-01

    Aims To investigate the influence of the CYP1A2*1F mutation on CYP1A2 activity in smoking and nonsmoking pregnant women. Methods Pregnant women (n = 904) who served as control subjects in a case-control study of early fetal loss were investigated. They were phenotyped for CYP1A2 using dietary caffeine and the urinary ratio AFMU + 1X + 1 U/1,7 U. An assay for CYP1A2*1F using 5′-nuclease assay (Taqman) was developed to genotype the population. Results The frequencies of *1 A and *1F alleles among Swedish women were 0.29 and 0.71, respectively. There was no statistically significant difference in CYP1A2 activity between the genotypes, although a trend towards enhanced activity was observed in *1F/*1F (log MRc 0.77) and *1F/*1 A (log MRc 0.82) genotypes compared with the *1 A/*1 A genotype (log MRc 0.71) (anovaP = 0.07). The mean difference between the *1 A homozygotes and the heterozygotes was 0.11 [95% confidence interval of the difference: (−0.21, −0.01)] and that between the *1 A and *1F homozygotes was 0.05 [95% confidence interval of the difference: (−0.13, 0.03)]. No significant effect (P = 0.22) of the *1F on CYP1A2 activity was observed in smokers, tested using an interaction term (smoking * genotype) in the anova model (*1F/*1F log MRc 0.79, *1F/*1 A log MRc 0.86, and *1 A/*1 A log MRc 0.73). In smokers, there was no difference in ratio between homozygotes for the *1 A and *1F alleles [mean difference −0.06; 95% confidence interval of the difference: −0.22, 0.11] or between *1 A/*1 A and *1 A/*1F genotypes [mean difference −0.13; 95% confidence interval of the difference: −0.29, 0.04]. Conclusions The effect of the CYP1A2*1F mutation on CYP1A2 activity in smoking pregnant women could not be confirmed. PMID:12445029

  10. A1C Test and Diabetes

    MedlinePlus

    ... of Diabetes Educators American Diabetes Association JDRF MedlinePlus Diabetes Disease Organizations ​There are many organizations who provide ... KB). Alternate Language URL The A1C Test and Diabetes Page Content On this page: What is the ...

  11. A-1 modification work under way

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Phil Schemanski of Pratt & Whitney Rocketdyne removes equipment inside the thrust drum on the A-1 Test Stand as part of a comprehensive modification project to prepare for testing the new J-2X engine.

  12. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... the person's average blood sugar levels over that time. Why It's Done Doctors use the hemoglobin A1c test to determine if your child's diabetes management plan needs to be adjusted. Typically the test ...

  13. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  14. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...) of the Act and 8 CFR 213a.2(c)(1)(i), and who, as permitted by section 213A(f)(5)(A) of the Act, is... requirements of section 213A(f)(1)(A), (B), (C), and (E) of the Act and 8 CFR 213a.2(c)(1)(i), who is related... intention to maintain that residence for the foreseeable future. Federal poverty line means the level...

  15. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... who meets the requirements of section 213A(f)(1)(A), (B), (C), and (E) of the Act and 8 CFR 213a.2(c... 213A(f)(1)(A), (B), (C), and (E) of the Act and 8 CFR 213a.2(c)(1)(i), who is related to the principal... intention to maintain that residence for the foreseeable future. Federal poverty line means the level...

  16. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Stennis Space Center employees maneuver a new thrust measurement system in preparation for its installation on the A-1 Test Stand on March 3. The system was fabricated by Thrust Measurement Systems in Illinois and represents a state-of-the-art upgrade from the equipment used on the stand for more than 40 years. The A-1 Test Stand is being upgraded to provide testing for the next generation of rocket engines for America's space program.

  17. The role of Ile87 of CYP158A2 in oxidative coupling reaction

    SciTech Connect

    Zhao, Bin; Bellamine, Aouatef; Lei, Li; Waterman, Michael R.

    2012-05-15

    Both CYP158A1 and CYP158A2 are able to catalyze an oxidative C-C coupling reaction producing biflaviolin or triflaviolin in Streptomyces coelicolor A3(2). The substrate-bound crystal structures of CYP158A2 and CYP158A1 reveal that the side chain of Ile87 in CYP158A2 points to the active site contacting the distal flaviolin molecule, however, the bulkier side chain of Lys90 in CYP158A1 (corresponding to Ile87 in CYP158A2) is toward the distal surface of the protein. These results suggest that these residues could be important in determining product regiospecificity. In order to explore the role of the two residues in catalysis, the reciprocal mutants, Ile87Lys and Lys90Ile, of CYP158A2 and CYP158A1, respectively, were generated and characterized. The mutant Ile87Lys enzyme forms two isomers of biflaviolin instead of three isomers of biflaviolin in wild-type CYP158A2. CYP158A1 containing the substitution of lysine with isoleucine has the same catalytic activity compared with the wild-type CYP158A1. The crystal structure of Ile87Lys showed that the BC loop in the mutant is in a very different orientation compared with the BC loop in both CYP158A1/A2 structures. These results shed light on the mechanism of the oxidative coupling reaction catalyzed by cytochrome P450.

  18. The Role of Ile87 of CYP158A2 in Oxidative Coupling Reaction

    PubMed Central

    Zhao, Bin; Bellamine, Aouatef; Lei, Li; Waterman, Michael R.

    2012-01-01

    Both CYP158A1 and CYP158A2 are able to catalyze an oxidative C-C coupling reaction producing biflaviolin or triflaviolin in Streptomyces coelicolor A3(2). The substrate-bound crystal structures of CYP158A2 and CYP158A1 reveal that the side chain of Ile87 in CYP158A2 points to the active site contacting the distal flaviolin molecule, however, the bulkier side chain of Lys90 in CYP158A1 (corresponding to Ile87 in CYP158A2) is toward the distal surface of the protein. These results suggest that these residues could be important in determining product regiospecificity. In order to explore the role of the two residues in catalysis, the reciprocal mutants, Ile87Lys and Lys90Ile, of CYP158A2 and CYP158A1, respectively, were generated and characterized. The mutant Ile87Lys enzyme forms two isomers of biflaviolin instead of three isomers of biflaviolin in wild-type CYP158A2. CYP158A1 containing the substitution of lysine with isoleucine has the same catalytic activity compared with the wild-type CYP158A1. The crystal structure of Ile87Lys showed that the BC loop in the mutant is in a very different orientation compared with the BC loop in both CYP158A1/A2 structures. These results shed light on the mechanism of the oxidative coupling reaction catalyzed by cytochrome P450. PMID:22203090

  19. Determination of the Electron-Antineutrino Angular Correlation Coefficient a0 in Unpolarized Neutron β-Decay

    PubMed Central

    Byrne, J.

    2005-01-01

    The coefficient a0 has been derived from a measurement of the integral spectrum of recoil protons stored in a quasi-Penning trap with inhomogeneous magnetic field and adiabatic focusing onto an electro-static mirror of potential variable in 10 V steps between 0 V and 850 V. Correction for incomplete transfer of energy from transverse to longitudinal degrees of freedom, and the violation of the adiabatic conditions on reflection at the mirror, is carried out by alternately measuring the spectrum at trapping times of 1 ms and 2 ms. The results a0 = −0.1054 ± 0.0055 and |λ | = 1.271 ± 0.018 are comparable in precision with existing measurements of a0. PMID:27308156

  20. Determination of the Electron-Antineutrino Angular Correlation Coefficient a0 in Unpolarized Neutron β-Decay.

    PubMed

    Byrne, J

    2005-01-01

    The coefficient a 0 has been derived from a measurement of the integral spectrum of recoil protons stored in a quasi-Penning trap with inhomogeneous magnetic field and adiabatic focusing onto an electro-static mirror of potential variable in 10 V steps between 0 V and 850 V. Correction for incomplete transfer of energy from transverse to longitudinal degrees of freedom, and the violation of the adiabatic conditions on reflection at the mirror, is carried out by alternately measuring the spectrum at trapping times of 1 ms and 2 ms. The results a 0 = -0.1054 ± 0.0055 and |λ | = 1.271 ± 0.018 are comparable in precision with existing measurements of a 0. PMID:27308156

  1. Photoaffinity labeling of A1-adenosine receptors

    SciTech Connect

    Klotz, K.N.; Cristalli, G.; Grifantini, M.; Vittori, S.; Lohse, M.J.

    1985-11-25

    The ligand-binding subunit of the A1-adenosine receptor has been identified by photoaffinity labeling. A photolabile derivative of R-N6-phenylisopropyladenosine, R-2-azido-N6-p-hydroxyphenylisopropyladenosine (R-AHPIA), has been synthesized as a covalent specific ligand for A1-adenosine receptors. In adenylate cyclase studies with membranes of rat fat cells and human platelets, R-AHPIA has adenosine receptor agonist activity with a more than 60-fold selectivity for the A1-subtype. It competes for (TH)N6-phenylisopropyladenosine binding to A1-receptors of rat brain membranes with a Ki value of 1.6 nM. After UV irradiation, R-AHPIA binds irreversibly to the receptor, as indicated by a loss of (TH)N6-phenylisopropyladenosine binding after extensive washing; the Ki value for this photoinactivation is 1.3 nM. The p-hydroxyphenyl substituent of R-AHPIA can be directly radioiodinated to give a photoaffinity label of high specific radioactivity ( SVI-AHPIA). This compound has a KD value of about 1.5 nM as assessed from saturation and kinetic experiments. Adenosine analogues compete for SVI-AHPIA binding to rat brain membranes with an order of potency characteristic for A1-adenosine receptors. Dissociation curves following UV irradiation at equilibrium demonstrate 30-40% irreversible specific binding. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicates that the probe is photoincorporated into a single peptide of Mr = 35,000. Labeling of this peptide can be blocked specifically and stereoselectively by adenosine receptor agonists and antagonists in a manner which is typical for the A1-subtype. The results indicate that SVI-AHPIA identifies the ligand-binding subunit of the A1-adenosine receptor, which is a peptide with Mr = 35,000.

  2. The linker between the D3 and A1 domains of vWF suppresses A1-GPIbα catch bonds by site-specific binding to the A1 domain

    PubMed Central

    Tischer, Alexander; Cruz, Miguel A; Auton, Matthew

    2013-01-01

    Platelet attachment to von Willebrand factor (vWF) requires the interaction between the platelet GP1bα and exposed vWF-A1 domains. Structural insights into the mechanism of the A1-GP1bα interaction have been limited to an N-terminally truncated A1 domain that lacks residues Q1238 − E1260 that make up the linker between the D3 and A1 domains of vWF. We have demonstrated that removal of these residues destabilizes quaternary interactions in the A1A2A3 tridomain and contributes to platelet activation under high shear (Auton et al., J Biol Chem 2012;287:14579–14585). In this study, we demonstrate that removal of these residues from the single A1 domain enhances platelet pause times on immobilized A1 under rheological shear. A rigorous comparison between the truncated A1-1261 and full length A1-1238 domains demonstrates a kinetic stabilization of the A1 domain induced by these N-terminal residues as evident in the enthalpy of the unfolding transition. This stabilization occurs through site and sequence-specific binding of the N-terminal peptide to A1. Binding of free N-terminal peptide to A1-1261 has an affinity and this binding although free to dissociate is sufficient to suppress the platelet pause times to levels comparable to A1-1238 under shear stress. Our results support a dual-structure/function role for this linker region involving a conformational equilibria that maintains quaternary A domain associations in the inactive state of vWF at low shear and an intra-A1-domain conformation that regulates the strength of platelet GP1bα-vWF A1 domain associations in the active state of vWF at high shear. PMID:23775931

  3. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor.

    PubMed

    Johansson, B; Halldner, L; Dunwiddie, T V; Masino, S A; Poelchen, W; Giménez-Llort, L; Escorihuela, R M; Fernández-Teruel, A; Wiesenfeld-Hallin, Z; Xu, X J; Hårdemark, A; Betsholtz, C; Herlenius, E; Fredholm, B B

    2001-07-31

    Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A(1) receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important. PMID:11470917

  4. A 0.18 μm biosensor front-end based on 1/f noise, distortion cancelation and chopper stabilization techniques.

    PubMed

    Balasubramanian, Viswanathan; Ruedi, Pierre-Francois; Temiz, Yuksel; Ferretti, Anna; Guiducci, Carlotta; Enz

    2013-10-01

    This paper presents a novel sensor front-end circuit that addresses the issues of 1/f noise and distortion in a unique way by using canceling techniques. The proposed front-end is a fully differential transimpedance amplifier (TIA) targeted for current mode electrochemical biosensing applications. In this paper, we discuss the architecture of this canceling based front-end and the optimization methods followed for achieving low noise, low distortion performance at minimum current consumption are presented. To validate the employed canceling based front-end, it has been realized in a 0.18 μm CMOS process and the characterization results are presented. The front-end has also been tested as part of a complete wireless sensing system and the cyclic voltammetry (CV) test results from electrochemical sensors are provided. Overall current consumption in the front-end is 50 μA while operating on a 1.8 V supply. PMID:24232627

  5. 44 CFR Appendix A(1) to Part 61 - Appendix A(1) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(1) to Part 61 A(1) Appendix A(1) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  6. Application of RADSAFE to Model Single Event Upset Response of a 0.25 micron CMOS SRAM

    NASA Technical Reports Server (NTRS)

    Warren, Kevin M.; Weller, Robert A.; Sierawski, Brian; Reed, Robert A.; Mendenhall, Marcus H.; Schrimpf, Ronald D.; Massengill, Lloyd; Porter, Mark; Wilkerson, Jeff; LaBel, Kenneth A.; Adams, James

    2006-01-01

    The RADSAFE simulation framework is described and applied to model Single Event Upsets (SEU) in a 0.25 micron CMOS 4Mbit Static Random Access Memory (SRAM). For this circuit, the RADSAFE approach produces trends similar to those expected from classical models, but more closely represents the physical mechanisms responsible for SEU in the SRAM circuit.

  7. Search for dimuon decays of a light scalar boson in radiative transitions Upsilon-->gammaA0.

    PubMed

    Aubert, B; Karyotakis, Y; Lees, J P; Poireau, V; Prencipe, E; Prudent, X; Tisserand, V; Garra Tico, J; Grauges, E; Martinelli, M; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Battaglia, M; Brown, D N; Kerth, L T; Kolomensky, Yu G; Lynch, G; Osipenkov, I L; Petigura, E; Tackmann, K; Tanabe, T; Hawkes, C M; Soni, N; Watson, A T; Koch, H; Schroeder, T; Asgeirsson, D J; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Randle-Conde, A; Blinov, V E; Bukin, A D; Buzykaev, A R; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Atmacan, H; Gary, J W; Liu, F; Long, O; Vitug, G M; Yasin, Z; Sharma, V; Campagnari, C; Hong, T M; Kovalskyi, D; Mazur, M A; Richman, J D; Beck, T W; Eisner, A M; Heusch, C A; Kroseberg, J; Lockman, W S; Martinez, A J; Schalk, T; Schumm, B A; Seiden, A; Wang, L; Winstrom, L O; Cheng, C H; Doll, D A; Echenard, B; Fang, F; Hitlin, D G; Narsky, I; Ongmongkolku, P; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Bloom, P C; Ford, W T; Gaz, A; Hirschauer, J F; Nagel, M; Nauenberg, U; Smith, J G; Wagner, S R; Ayad, R; Toki, W H; Wilson, R J; Feltresi, E; Hauke, A; Jasper, H; Karbach, T M; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Kobel, M J; Nogowski, R; Schubert, K R; Schwierz, R; Volk, A; Bernard, D; Latour, E; Verderi, M; Clark, P J; Playfer, S; Watson, J E; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Fioravanti, E; Franchini, P; Luppi, E; Munerato, M; Negrini, M; Petrella, A; Piemontese, L; Santoro, V; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Contri, R; Guido, E; Lo Vetere, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Tosi, S; Chaisanguanthum, K S; Morii, M; Adametz, A; Marks, J; Schenk, S; Uwer, U; Bernlochner, F U; Klose, V; Lacker, H M; Bard, D J; Dauncey, P D; Tibbetts, M; Behera, P K; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Derkach, D; Firmino da Costa, J; Grosdidier, G; Le Diberder, F; Lepeltier, V; Lutz, A M; Malaescu, B; Pruvot, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Touramanis, C; Bevan, A J; Clarke, C K; Di Lodovico, F; Sacco, R; Sigamani, M; Cowan, G; Paramesvaran, S; Wren, A C; Brown, D N; Davis, C L; Denig, A G; Fritsch, M; Gradl, W; Hafner, A; Alwyn, K E; Bailey, D; Barlow, R J; Jackson, G; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Salvati, E; Cowan, R; Dujmic, D; Fisher, P H; Henderson, S W; Sciolla, G; Spitznagel, M; Yamamoto, R K; Zhao, M; Patel, P M; Robertson, S H; Schram, M; Biassoni, P; Lazzaro, A; Lombardo, V; Palombo, F; Stracka, S; Bauer, J M; Cremaldi, L; Godang, R; Kroeger, R; Sonnek, P; Summers, D J; Zhao, H W; Simard, M; Taras, P; Nicholson, H; De Nardo, G; Lista, L; Monorchio, D; Onorato, G; Sciacca, C; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; LoSecco, J M; Wang, W F; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Castelli, G; Gagliardi, N; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; del Amo Sanchez, P; Ben-Haim, E; Bonneaud, G R; Briand, H; Chauveau, J; Hamon, O; Leruste, Ph; Marchiori, G; Ocariz, J; Perez, A; Prendki, J; Sitt, S; Gladney, L; Biasini, M; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Calderini, G; Carpinelli, M; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Lopes Pegna, D; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Anulli, F; Baracchini, E; Cavoto, G; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Franek, B; Olaiya, E O; Wilson, F F; Emery, S; Esteve, L; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Allen, M T; Aston, D; Bartoldus, R; Benitez, J F; Cenci, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Franco Sevilla, M; Gabareen, A M; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Lindquist, B; Luitz, S; Luth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Muller, D R; Neal, H; Nelson, S; O'Grady, C P; Ofte, I; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; West, C A; Wisniewski, W J; Wittgen, M; Wright, D H; Wulsin, H W; Yarritu, A K; Young, C C; Ziegler, V; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Burchat, P R; Edwards, A J; Miyashita, T S; Ahmed, S; Alam, M S; Ernst, J A; Pan, B; Saeed, M A; Zain, S B; Soffer, A; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Wray, B C; Drummond, B W; Izen, J M; Lou, X C; Bianchi, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Choi, H H F; Hamano, K; King, G J; Kowalewski, R; Lewczuk, M J; Nugent, I M; Roney, J M; Sobie, R J; Gershon, T J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Puccio, E M T; Band, H R; Chen, X; Dasu, S; Flood, K T; Pan, Y; Prepost, R; Vuosalo, C O; Wu, S L

    2009-08-21

    We search for evidence of a light scalar boson in the radiative decays of the Upsilon(2S) and Upsilon(3S) resonances: Upsilon(2S,3S)-->gammaA0, A0-->mu+mu-. Such a particle appears in extensions of the standard model, where a light CP-odd Higgs boson naturally couples strongly to b quarks. We find no evidence for such processes in the mass range 0.212 < or = mA0 < or = 9.3 GeV in the samples of 99 x 10(6) Upsilon(2S) and 122 x 10(6) Upsilon(3S) decays collected by the BABAR detector at the SLAC PEP-II B factory and set stringent upper limits on the effective coupling of the b quark to the A0. We also limit the dimuon branching fraction of the etab meson: B(etab-->mu+mu-)<0.9% at 90% confidence level. PMID:19792717

  8. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  9. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  10. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  11. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  12. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  13. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... more of the following areas of major life activity: (i) Self-care, (ii) receptive and expressive..., services to pregnant women or children under 18 years of age, or treatment in the interest of public health..., if any, or (2) a crime treated as a misdemeanor under 8 CFR 245a.1(p). For purposes of...

  14. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., if any, or (2) a crime treated as a misdemeanor under 8 CFR 245a.1(p). For purposes of this... CFR part 245a, the crime shall be treated as a misdemeanor. (q) Subject of an Order to Show Cause... interview to obtain an immigrant visa at a Consulate or Embassy in Canada or Mexico but who subsequently...

  15. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... which will be codified at 32 CFR part 168b. ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  16. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... which will be codified at 32 CFR part 168b. ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  17. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... which will be codified at 32 CFR part 168b. ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  18. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... which will be codified at 32 CFR part 168b. ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  19. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... which will be codified at 32 CFR part 168b. ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191....

  20. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... crime treated as a misdemeanor under 8 CFR 245a.1(p). For purposes of this definition, any crime... the term such alien actually served. Under this exception, for purposes of 8 CFR part 245a, the crime... the applicant had violated his or her nonimmigrant student status prior to January 1, 1982. A...

  1. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... crime treated as a misdemeanor under 8 CFR 245a.1(p). For purposes of this definition, any crime... the term such alien actually served. Under this exception, for purposes of 8 CFR part 245a, the crime... the applicant had violated his or her nonimmigrant student status prior to January 1, 1982. A...

  2. The Major Prognostic Features of Nuclear Receptor NR5A2 in Infiltrating Ductal Breast Carcinomas

    PubMed Central

    Chang, Li-Yun; Liu, Li-Yu D.; Roth, Don A.; Kuo, Wen-Hung; Hwa, Hsiao-Lin; Chang, King-Jen; Hsieh, Fon-Jou

    2015-01-01

    Background. Gene expression profiles of 181 breast cancer samples were analyzed to identify prognostic features of nuclear receptors NR5A1 and NR5A2 based upon their associated transcriptional networks. Methods. A supervised network analysis approach was used to build the NR5A-mediated transcriptional regulatory network. Other bioinformatic tools and statistical methods were utilized to confirm and extend results from the network analysis methodology. Results. NR5A2 expression is a negative factor in breast cancer prognosis in both ER(−) and ER(−)/ER(+) mixed cohorts. The clinical and cohort significance of NR5A2-mediated transcriptional activities indicates that it may have a significant role in attenuating grade development and cancer related signal transduction pathways. NR5A2 signature that conditions poor prognosis was identified based upon results from 15 distinct probes. Alternatively, the expression of NR5A1 predicts favorable prognosis when concurrent NR5A2 expression is low. A favorable signature of eight transcription factors mediated by NR5A1 was also identified. Conclusions. Correlation of poor prognosis and NR5A2 activity is identified by NR5A2-mediated 15-gene signature. NR5A2 may be a potential drug target for treating a subset of breast cancer tumors across breast cancer subtypes, especially ER(−) breast tumors. The favorable prognostic feature of NR5A1 is predicted by NR5A1-mediated 8-gene signature. PMID:26366408

  3. 12 CFR 261a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Definitions. 261a.2 Section 261a.2 Banks and... citizen of the United States or an alien lawfully admitted for permanent residence. (d) Maintain includes... print, or photograph. (f) Routine use means, with respect to disclosure of a record, the use of...

  4. 42 CFR 85a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 85a.2 Section 85a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH... Health of the Centers for Disease Control and Prevention, Department of Health and Human Services....

  5. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... military requirement. (3) Properties subject to special legislation directing a particular action. (4... subject to section 202(a)(2) of the Federal Property and Administrative Service Act of 1949, as amended... HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  6. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... military requirement. (3) Properties subject to special legislation directing a particular action. (4... subject to section 202(a)(2) of the Federal Property and Administrative Service Act of 1949, as amended... HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  7. CphA2 is a novel type of cyanophycin synthetase in N2-fixing cyanobacteria.

    PubMed

    Klemke, Friederike; Nürnberg, Dennis J; Ziegler, Karl; Beyer, Gabriele; Kahmann, Uwe; Lockau, Wolfgang; Volkmer, Thomas

    2016-03-01

    Most cyanobacteria use a single type of cyanophycin synthetase, CphA1, to synthesize the nitrogen-rich polymer cyanophycin. The genomes of many N2-fixing cyanobacteria contain an additional gene that encodes a second type of cyanophycin synthetase, CphA2. The potential function of this enzyme has been debated due to its reduced size and the lack of one of the two ATP-binding sites that are present in CphA1. Here, we analysed CphA2 from Anabaena variabilis ATCC 29413 and Cyanothece sp. PCC 7425. We found that CphA2 polymerized the dipeptide β-aspartyl-arginine to form cyanophycin. Thus, CphA2 represents a novel type of cyanophycin synthetase. A cphA2 disruption mutant of A. variabilis was generated. Growth of this mutant was impaired under high-light conditions and nitrogen deprivation, suggesting that CphA2 plays an important role in nitrogen metabolism under N2-fixing conditions. Electron micrographs revealed that the mutant had fewer cyanophycin granules, but no alteration in the distribution of granules in its cells was observed. Localization of CphA2 by immunogold electron microscopy demonstrated that the enzyme is attached to cyanophycin granules. Expression of CphA1 and CphA2 was examined in Anabaena WT and cphA mutant cells. Whilst the CphA1 level increased upon nitrogen deprivation, the CphA2 level remained nearly constant. PMID:26781249

  8. Folate and Thiamine Transporters mediated by Facilitative Carriers (SLC19A1-3 and SLC46A1) and Folate Receptors

    PubMed Central

    Zhao, Rongbao; Goldman, I. David

    2013-01-01

    The reduced folate carrier (RFC,SLC19A1), thiamine transporter-1 (ThTr1,SLC19A2) and thiamine transporter-2 (ThTr2,SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT,SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease). PMID:23506878

  9. Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors.

    PubMed

    Zhao, Rongbao; Goldman, I David

    2013-01-01

    The reduced folate carrier (RFC, SLC19A1), thiamine transporter-1 (ThTr1, SLC19A2) and thiamine transporter-2 (ThTr2, SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT, SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease). PMID:23506878

  10. Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways

    PubMed Central

    Soranzo, Nicole; Sanna, Serena; Wheeler, Eleanor; Gieger, Christian; Radke, Dörte; Dupuis, Josée; Bouatia-Naji, Nabila; Langenberg, Claudia; Prokopenko, Inga; Stolerman, Elliot; Sandhu, Manjinder S.; Heeney, Matthew M.; Devaney, Joseph M.; Reilly, Muredach P.; Ricketts, Sally L.

    2010-01-01

    OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron

  11. Evaluation of the Temperature Stability of a Low-Frequency a0 Mode Transducer Developed for Shm Applications

    NASA Astrophysics Data System (ADS)

    Clarke, T.; Simonetti, F.; Rokhlin, S.; Cawley, P.

    2008-02-01

    A piezoelectric-based transducer generating high purity A0 mode guided waves at low frequencies (around 20 kHz) was developed. Parametric studies were undertaken by varying the backing mass length, the transducer diameter and the thickness of a soft front layer. Results obtained by FEM were validated by experimental measurements and showed that signals with A0/S0 energy ratios substantially above 40 dB can be obtained. The amplitude, phase and frequency stability of signals produced by these transducers and the general robustness of an experimental pitch-catch system were evaluated in an environment subjected to 10 °C temperature shifts. Temperature compensation and baseline subtraction methods were applied to the signals and residual signal amplitude of -38 dB in relation to the amplitude of the first arrival was obtained. Reflections from a weak reflector attached to the plate were identifiable even with a 10 °C temperate change.

  12. Echoes of the electroweak phase transition: discovering a second Higgs doublet through A0→ZH0.

    PubMed

    Dorsch, G C; Huber, S J; Mimasu, K; No, J M

    2014-11-21

    The existence of a second Higgs doublet in nature could lead to a cosmological first-order electroweak phase transition and explain the origin of the matter-antimatter asymmetry in the Universe. We obtain the spectrum and properties of the new scalars H0, A0, and H(±) that signal such a phase transition and show that the observation of the decay A0→ZH0 at LHC would be a "smoking gun" signature of these scenarios. We analyze the LHC search prospects for this decay in the ℓℓbb and ℓℓW(+)W(-) final states, arguing that current data may be sensitive to this signature in the former channel as well as there being great potential for a discovery in either channel at the very early stages of the 14 TeV run. PMID:25479487

  13. Tensile properties of AZ11A-0 magnesium-alloy sheet under rapid-heating and constant temperature

    NASA Technical Reports Server (NTRS)

    Kurg, Ivo M

    1956-01-01

    Specimens of AZ31A-0 magnesium alloy sheet were heated to rupture at nominal rates of 0.2 F to 100 F per second under constant tensile load conditions. The data are presented and compared with the results of conventional tensile stress-strain tests at elevated temperatures after 1.2-hour exposure. A temperature-rate parameter was used to construct master curves from which stresses and temperatures for yield and rupture can be predicted under rapid-heating conditions. A comparison of the elevated-temperature tensile properties of AZ31A-0 and HK31XA-H24 magnesium-alloy sheet under both constant-temperature and rapid-heating conditions is included.

  14. Search for the a0(980)-f0(980) mixing in weak decays of Ds/Bs mesons

    NASA Astrophysics Data System (ADS)

    Wang, Wei

    2016-08-01

    Scalar mesons a00 (980) and f0 (980) can mix with each other through isospin violating effects, and the mixing intensity has been predicted at the percent level in various theoretical models. However the mixing has not been firmed established on the experimental side to date. In this work we explore the possibility to extract the a0-f0 mixing intensity using weak decays of heavy mesons: Ds → [π0 η ,π+π- ]e+ ν, Bs → [π0 η ,π+π- ]ℓ+ℓ- and the Bs → J / ψ [π0 η ,π+π- ] decays. Based on the large amount of data accumulated by various experimental facilities including BEPC-II, LHC, Super KEKB and the future colliders, we find that the a0-f0 mixing intensity might be determined to a high precision, which will lead to a better understanding of the nature of scalar mesons.

  15. Spectral Line Polarisation Atlases for 53 Cam (A4p) and alpha 2 CVn (A0p)

    NASA Astrophysics Data System (ADS)

    Wade, G. A.

    2002-08-01

    Wade, Donati & Landstreet (2000) presented a atlas of the R=35,000 Stokes IQUV spectrum of the cool magnetic Ap star beta CrB in the spectral range 450-660 nm. In this report we present analogous atlases for the well-studied magnetic Ap stars 53 Cam (HD 65339, A4p) and alpha 2 CVn (HD 112413, A0p).

  16. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Employees at NASA's John C. Stennis Space Center complete installation of the new thrust measurement system on the A-1 Test Stand. The new TMS is a state-of-the-art upgrade from the previous system, which was installed when the testing structure was built in the 1960s. It is an advanced calibration system capable of measuring vertical and horizontal thrust loads with accuracy within 0.15 percent at 225,000 pounds. It also will allow engineers to measure thrust as they gimbal (or tilt) engines during tests. The new TMS is part of upgrades for the A-1 Test Stand in preparation for testing the next generation of American space program rocket engines.

  17. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A new thrust measurement system is lifted onto the A-1 Test Stand deck at NASA's John C. Stennis Space Center in preparation for its installation. The new system is a state-of-the-art upgrade for the testing structure, which is being prepared for testing of next-generation rocket engines. The system was fabricated by Thrust Measurement Systems in Illinois at a cost of about $3.5 million.

  18. Orally Active Adenosine A1 Receptor Agonists with Antinociceptive Effects in Mice

    PubMed Central

    Korboukh, Ilia; Hull-Ryde, Emily A.; Rittiner, Joseph E.; Randhawa, Amarjit S.; Coleman, Jennifer; Fitzpatrick, Brendan J.; Setola, Vincent; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.; Jin, Jian

    2012-01-01

    Adenosine A1 receptor (A1AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A1AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A1AR agonists, some of which are structurally related to adenosine 5′-monophosphate (5′-AMP), a naturally occurring nucleotide that itself activates A1AR. These novel compounds potently activate A1AR in several orthogonal in vitro assays and are subtype selective for A1AR over A2AAR, A2BAR, and A3AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A1AR knockout mice, revealing a strict dependence on A1AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (Ki of 36 nM for the human A1AR) make this compound potentially suitable as a therapeutic. PMID:22738238

  19. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  20. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  1. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  2. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  3. 26 CFR 1.691(a)-2 - Inclusion in gross income by recipients.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Inclusion in gross income by recipients. 1.691(a)-2 Section 1.691(a)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Inclusion in gross income by recipients. (a) Under section 691(a)(1), income in respect of a decedent...

  4. 76 FR 21682 - Approval and Promulgation of Air Quality Implementation Plans; Louisiana; Section 110(a)(2...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-18

    ... NAAQS for ozone (62 FR 38856) and PM (62 FR 38652). For ozone we set an 8-hour standard of 0.08 parts... Federal Register notices (62 FR 38856 and 62 FR 38652). Under sections 110(a)(1) and (2) of the Act... 110(a)(2)(D)(i). EPA previously approved the State's 110(a)(2)(D)(i) submission (72 FR...

  5. 26 CFR 1.1031(a)-2 - Additional rules for exchanges of personal property.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... property. 1.1031(a)-2 Section 1.1031(a)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...)-2 Additional rules for exchanges of personal property. (a) Introduction. Section 1.1031(a)-1(b... property for property of a different kind or class. This section contains additional rules for...

  6. A1.5 Fusion Performance

    SciTech Connect

    Amendt, P

    2011-03-31

    Analysis and radiation hydrodynamics simulations for expected high-gain fusion target performance on a demonstration 1-GWe Laser Inertial Fusion Energy (LIFE) power plant in the mid-2030s timeframe are presented. The required laser energy driver is 2.2 MJ at a 0.351-{micro}m wavelength, and a fusion target gain greater than 60 at a repetition rate of 16 Hz is the design goal for economic and commercial attractiveness. A scaling-law analysis is developed to benchmark the design parameter space for hohlraum-driven central hot-spot ignition. A suite of integrated hohlraum simulations is presented to test the modeling assumptions and provide a basis for a near-term experimental resolution of the key physics uncertainties on the National Ignition Facility (NIF). The NIF is poised to demonstrate ignition by 2012 based on the central hot spot (CHS) mode of ignition and propagating thermonuclear burn [1]. This immediate prospect underscores the imperative and timeliness of advancing inertial fusion as a carbon-free, virtually limitless source of energy by the mid-21st century to substantially offset fossil fuel technologies. To this end, an intensive effort is underway to leverage success at the NIF and to provide the foundations for a prototype 'LIFE.1' engineering test facility by {approx}2025, followed by a commercially viable 'LIFE.2' demonstration power plant operating at 1 GWe by {approx}2035. The current design goal for LIFE.2 is to accommodate {approx}2.2 MJ of laser energy (entering the high-Z radiation enclosure or 'hohlraum') at a 0.351-{micro}m wavelength operating at a repetition rate of 16 Hz and to provide a fusion target yield of 132 MJ. To achieve this design goal first requires a '0-d' analytic gain model that allows convenient exploration of parameter space and target optimization. This step is then followed by 2- and 3-dimensional radiation-hydrodynamics simulations that incorporate laser beam transport, x-ray radiation transport, atomic physics, and

  7. Characterization of a human surfactant protein A1 (SP-A1) gene-specific antibody; SP-A1 content variation among individuals of varying age and pulmonary health.

    PubMed

    Tagaram, Hephzibah Rani S; Wang, Guirong; Umstead, Todd M; Mikerov, Anatoly N; Thomas, Neal J; Graff, Gavin R; Hess, Joseph C; Thomassen, Mary Jane; Kavuru, Mani S; Phelps, David S; Floros, Joanna

    2007-05-01

    The human surfactant protein A (SP-A) locus consists of two functional genes (SP-A1, SP-A2) with gene-specific products exhibiting qualitative and quantitative differences. The aim here was twofold: 1) generate SP-A1 gene-specific antibody, and 2) use this to assess gene-specific SP-A content in the bronchoalveolar lavage fluid (BALF). An SP-A1-specific polyclonal antibody (hSP-A1_Ab(68-88)_Col) was raised in chicken, and its specificity was determined by immunoblot and ELISA using mammalian Chinese hamster ovary (CHO) cell-expressed SP-A1 and SP-A2 variants and by immunofluorescence with stably transfected CHO cell lines expressing SP-A1 or SP-A2 variants. SP-A1 content was evaluated according to age and lung status. A gradual decrease (P < 0.05) in SP-A1/SP-A ratio was observed in healthy subjects (HS) with increased age, although no significant change was observed in total SP-A content among age groups. Total SP-A and SP-A1 content differed significantly between alveolar proteinosis (AP) patients and HS, with no significant difference observed in SP-A1/SP-A ratio between AP and HS. The cystic fibrosis (CF) ratio was significantly higher compared with AP, HS, and noncystic fibrosis (NCF), even though SP-A1 and total SP-A were decreased in CF compared with most of the other groups. The ratio was higher in culture-positive vs. culture-negative samples from CF and NCF (P = 0.031). A trend of an increased ratio was observed in culture-positive CF (0.590 +/- 0.10) compared with culture-positive NCF (0.368 +/- 0.085). In summary, we developed and characterized an SP-A1 gene-specific antibody and used it to identify gene-specific SP-A content in BALFs as a function of age and lung health. PMID:17189324

  8. Reliability assessment of a 1 MV LTD.

    SciTech Connect

    Portillo, Salvador; Chavez, Raymond; Molina, Isidro; Kim, Alexandre A.; Johnson, David L.; Maenchen, John Eric; Leckbee, Joshua J.; Ziska, Derek Raymond

    2005-07-01

    A 1 MV linear transformer driver (LTD) is being tested with a large area e-beam diode load at Sandia National Laboratories (SNL). The experiments will be utilized to determine the repeatability of the output pulse and the reliability of the components. The 1 MV accelerator is being used to determine the feasibility of designing a 6 MV LTD for radiography experiments. The peak voltage, risetime, and pulse width as well as the cavity timing jitter are analyzed to determine the repeatability of the output pulse.

  9. Wind-Tunnel Investigation of an NACA 23021 Airfoil with a 0.32-Airfoil-Chord Double Slotted Flap

    NASA Technical Reports Server (NTRS)

    Fischel, Jack; Riebe, John M

    1944-01-01

    An investigation was made in the LMAL 7- by 10-foot wind tunnel of a NACA 23021 airfoil with a double slotted flap having a chord 32 percent of the airfoil chord (0.32c) to determine the aerodynamic section characteristics with the flaps deflected at various positions. The effects of moving the fore flap and rear flap as a unit and of deflecting or removing the lower lip of the slot were also determined. Three positions were selected for the fore flap and at each position the maximum lift of the airfoil was obtained with the rear flap at the maximum deflection used at that fore-flap position. The section lift of the airfoil increased as the fore flap was extended and maximum lift was obtained with the fore flap deflected 30 deg in the most extended position. This arrangement provided a maximum section lift coefficient of 3.31, which was higher than the value obtained with either a 0.2566c or a 0.40c single-slotted-flap arrangement and 0.25 less than the value obtained with a 0.4c double-slotted-flap arrangement on the same airfoil. The values of the profile-drag coefficient obtained with the 0.32c double slotted flap were larger than those for the 0.2566c or 0.40c single slotted flaps for section lift coefficients between 1.0 and approximately 2.7. At all values of the section lift coefficient above 1.0, the 0.40c double slotted flap had a lower profile drag than the 0.32c double slotted flap. At various values of the maximum section lift coefficient produced by various flap defections, the 0.32c double slotted flap gave negative section pitching-moment coefficients that were higher than those of other slotted flaps on the same airfoil. The 0.32c double slotted flap gave approximately the same maximum section lift coefficient as, but higher profile-drag coefficients over the entire lift range than, a similar arrangement of a 0.30c double slotted flap on an NACA 23012 airfoil.

  10. Performance and loads data from a hover test of a 0.658-scale V-22 rotor and wing

    NASA Technical Reports Server (NTRS)

    Felker, Fort F.; Signor, David B.; Young, Larry A.; Betzina, Mark D.

    1987-01-01

    A hover test of a 0.658-scale model of a V-22 rotor and wing was conducted at the Outdoor Aerodynamic Research Facility at Ames Research Center. The primary objectives of the test were to obtain accurate measurements of the hover performance of the rotor system, and to measure the aerodynamic interactions between the rotor and wing. Data were acquired for rotor tip Mach numbers ranging from 0.1 to 0.73. This report presents data on rotor performance, rotor-wake downwash velocities, rotor system loads, wing forces and moments, and wing surface pressures.

  11. Wing Download Results from a Test of a 0.658-Scale V-22 Rotor and Wing

    NASA Technical Reports Server (NTRS)

    Felker, Fort F.

    1992-01-01

    A test of a 0.658-scale V-22 rotor and wing was conducted in the 40 x 80 Foot Wind Tunnel at Ames Research Center. One of the principal objectives of the test was to measure the wing download in hover for a variety of test configurations. The wing download and surface pressures were measured for a wide range of thrust coefficients, with five different flap angles, two nacelle angles, and both directions or rotor rotation. This paper presents these results, and describes a new method for interpreting wing surface pressure data in hover. This method shows that the wing flap can produce substantial lift loads in hover.

  12. A 12b 200kS/s 0.52mA 0.47mm2 Algorithmic A/D Converter for MEMS Applications

    NASA Astrophysics Data System (ADS)

    Kim, Young-Ju; Choi, Hee-Cheol; Lee, Seung-Hoon; Cho, Dongil “Dan”

    This work describes a 12b 200kS/s 0.52mA 0.47mm2 ADC for sensor applications such as motor control, 3-phase power control, and CMOS image sensors simultaneously requiring ultra-low power and small size. The proposed ADC is based on the conventional algorithmic architecture with a recycling signal path to optimize sampling rate, resolution, chip area, and power consumption. The input SHA with eight input channels employs a folded-cascode amplifier to achieve a required DC gain and a high phase margin. A 3-D fully symmetric layout with critical signal lines shielded reduces the capacitor and device mismatch of the multiplying D/A converter while switched-bias power-reduction circuits minimize the power consumption of analog amplifiers. Current and voltage references are integrated on chip with optional off-chip voltage references for low glitch noise. The down-sampling clock signal selects the sampling rate of 200kS/s and 10kS/s with a further reduced power depending on applications. The prototype ADC in a 0.18μm n-well 1P6M CMOS process demonstrates a maximum measured DNL and INL within 0.40 LSB and 1.97 LSB and shows a maximum SNDR and SFDR of 55dB and 70dB at all sampling frequencies up to 200kS/s, respectively. The ADC occupies an active die area of 0.47mm2 and consumes 0.94mW at 200kS/s and 0.63mW at 10kS/s with a 1.8V supply.

  13. METSAT: Advanced Microwave Sounding Unit-A2 (AMSU-A2) structural mathematical model

    NASA Technical Reports Server (NTRS)

    Ely, Wayne

    1995-01-01

    This plan describes the Structural Mathematical Model of the METSAT AMSU-A2 instrument. The model is used to verify the structural adequacy of the AMSU-A2 instrument for the specified loading environments.

  14. ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease.

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-07-01

    Apolipoprotein A1 (ApoA1) is a main protein moiety in high-density lipoprotein (HDL) particles. Generally, ApoA1 and HDL are considered as atheroprotective. In prooxidant and inflammatory microenvironment in the vicinity to the atherosclerotic lesion, ApoA1/HDL are subjected to modification. The chemical modifications such as oxidation, nitration, etc result in altering native architecture of ApoA1 toward dysfunctionality and abnormality. Neutrophil myeloperoxidase has a prominent role in this mechanism. Neo-epitopes could be formed and then exposed that makes them immunogenic. Indeed, these epitopes may be recognized by immune cells and induce production of proatherogenic ApoA1-specific IgG antibodies. These antibodies are biologically relevant because they are able to react with Toll-like receptor (TLR)-2 and TLR4 in target cells and induce a variety of pro-inflammatory responses. Epidemiological and functional studies underline a prognostic value of ApoA1 self-antibodies for several cardiovascular diseases, including myocardial infarction, acute coronary syndrome, and severe carotid stenosis. PMID:27183204

  15. Spatial resolution limits of YAG:CE powder beam-profile monitors at the Fermilab A0 photoinjector

    SciTech Connect

    Lumpkin, A.H.; Johnson, A.S.; Ruan, J.; Santucci, J.; Sun, Y.-E.; Thurman-Keup, R.; /Fermilab

    2009-10-01

    The A0 photoinjector (A0PI) facility at Fermilab has an ongoing proof-of-principle experiment to demonstrate the exchange of the transverse horizontal and longitudinal emittances. This experiment relies on measurements of the transverse emittances and longitudinal emittance upstream and downstream of the exchanger beamline. At several locations along the accelerator beamline, YAG:Ce powder scintillator screens are used to determine beam size, divergence when the screen is downstream of a set of 50-micron-wide tungsten slits, and energy spread when used in an electron beam spectrometer. We have recently performed direct comparisons of beam image and slit image sizes using both the optical transition radiation (OTR) screens and the YAG:Ce screens. For micropulse charges of 250 pC and with beam energies of 15 MeV, we systematically observed larger beam image sizes with the YAG:Ce screens than with the OTR screens. We deduced a YAG:Ce screen spatial resolution limit of sigma = 140 to 180 microns. This term is large enough relative to the actual beam sizes and slit image sizes to be needed as a correction term subtracted in quadrature.

  16. A 0.15-scale study of configuration effects on the aerodynamic interaction between main rotor and fuselage

    NASA Technical Reports Server (NTRS)

    Trept, Ted

    1984-01-01

    Hover and forward flight tests were conducted to investigate the mutual aerodynamic interaction between the main motor and fuselage of a conventional helicopter configuration. A 0.15-scale Model 222 two-bladed teetering rotor was combined with a 0.15-scale model of the NASA Ames 40x80-foot wind tunnel 1500 horsepower test stand fairing. Configuration effects were studied by modifying the fairing to simulate a typical helicopter forebody. Separation distance between rotor and body were also investigated. Rotor and fuselage force and moment as well as pressure data are presented in graphical and tabular format. Data was taken over a range of thrust coefficients from 0.002 to 0.007. In forward flight speed ratio was varied from 0.1 to 0.3 with shaft angle varying from +4 to -12 deg. The data show that the rotors effect on the fuselage may be considerably more important to total aircraft performance than the effect of the fuselage on the rotor.

  17. 44 CFR Appendix A(2) to Part 61 - Appendix A(2) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(2) to Part 61 A(2) Appendix A(2) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  18. Myodegeneration in EDA-A2 Transgenic Mice Is Prevented by XEDAR Deficiency

    PubMed Central

    Newton, Kim; French, Dorothy M.; Yan, Minhong; Frantz, Gretchen D.; Dixit, Vishva M.

    2004-01-01

    EDA-A1 and EDA-A2 are members of the tumor necrosis factor family of ligands. The products of alternative splicing of the ectodysplasin (EDA) gene, EDA-A1 and EDA-A2 differ by an insertion of two amino acids and bind to distinct receptors. The longer isoform, EDA-A1, binds to EDAR and plays an important role in sweat gland, hair, and tooth development; mutations in EDA, EDAR, or the downstream adaptor EDARADD cause hypohidrotic ectodermal dysplasia. EDA-A2 engages the receptor XEDAR, but its role in the whole organism is less clear. We have generated XEDAR-deficient mice by gene targeting and transgenic mice expressing secreted forms of EDA-A1 or EDA-A2 downstream of the skeletal muscle-specific myosin light-chain 2 or skin-specific keratin 5 promoter. Mice lacking XEDAR were indistinguishable from their wild-type littermates, but EDA-A2 transgenic mice exhibited multifocal myodegeneration. This phenotype was not observed in the absence of XEDAR. Skeletal muscle in EDA-A1 transgenic mice was unaffected, but their sebaceous glands were hypertrophied and hyperplastic, consistent with a role for EDA-A1 in the development of these structures. These data indicate that XEDAR-transduced signals are dispensable for development of ectoderm-derived organs but might play a role in skeletal muscle homeostasis. PMID:14749376

  19. The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation

    SciTech Connect

    Mayo, Jaime L.; Holden, Devin N.; Barrow, Jeffery R.; Bridgewater, Laura C.

    2009-08-01

    The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with an Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.

  20. PLC Software Program for Leak Detector Station A1 SALW-LD-ST-A1

    SciTech Connect

    KOCH, M.R.

    2001-01-25

    This document describes the software program for the programmable logic controller for the leak detector station ''SALW-LD-ST-A1''. The appendices contains a copy of the printout of the software program.

  1. Landing impact studies of a 0.3-scale model air cushion landing system for a Navy fighter airplane

    NASA Technical Reports Server (NTRS)

    Leland, T. J. W.; Thompson, W. C.

    1975-01-01

    An experimental study was conducted in order to determine the landing-impact behavior of a 0.3-scale, dynamically (but not physically) similar model of a high-density Navy fighter equipped with an air cushion landing system. The model was tested over a range of landing contact attitudes at high forward speeds and sink rates on a specialized test fixture at the Langley aircraft landing loads and traction facility. The investigation indicated that vertical acceleration at landing impact was highly dependent on the pitch angle at ground contact, the higher acceleration of approximately 5g occurring near zero body-pitch attitude. A limited number of low-speed taxi tests were made in order to determine model stability characteristics. The model was found to have good pitch-damping characteristics but stability in roll was marginal.

  2. Ugrades of beam diagnostics in support of emittance-exchange experiments at the Fermilab A0 photoinjector

    SciTech Connect

    Lumpkin, A.H.; Johnson, A.S.; Ruan, J.; Santucci, J.; Sun, Y.-E.; Thurman-Keup, R.; Edwards, H.; /Fermilab

    2011-01-01

    The possibility of using electron beam phase space manipulations to support a free-electron laser accelerator design optimization has motivated our research. An ongoing program demonstrating the exchange of transverse horizontal and longitudinal emittances at the Fermilab A0 photoinjector has benefited recently from the upgrade of several of the key diagnostics stations. Accurate measurements of these properties upstream and downstream of the exchanger beamline are needed. Improvements in the screen resolution term and reduced impact of the optical system's depth-of-focus by using YAG:Ce single crystals normal to the beam direction will be described. The requirement to measure small energy spreads (<10 keV) in the spectrometer and the exchange process which resulted in bunch lengths less than 500 fs led to other diagnostics performance adjustments and upgrades as well. A longitudinal to transverse exchange example is also reported.

  3. Experimental studies on coherent synchrotron radiaiton in the emittance exchange line at the Fermilab A0 Photoinjector

    SciTech Connect

    Thangaraj, J.C.T.; Keup, R.; Johnson, A.; ruan, J.; Piot, P.; Church, M.; Edwards, H.; Lumpkin, A.; Sun, Y.-E.; Santucci, J.; /Fermilab

    2011-03-01

    Future accelerators will employ advanced beam conditioning systems such as emittance exchangers to manipulate high brightness beams. Coherent synchrotron radiation (CSR) in the dipoles could limit the performance of the emittance exchanger. In this paper, we report the experimental studies on measuring CSR and its effects on the beam at the A0 photoinjector in the emittance exchange line. After reporting the CSR power measurements, we report on the diagnostic scheme based on a weak skew quad in the emittance exchange line to study the CSR effects on the beam and other beam dynamics. In this work, we have reported on CSR measurements and the effect of skew quad on the dogleg line with the 5-cell turned on and off. We plan to study CSR effects on the bunch with the 5-cell on at larger chirp. This is will not only increase the CSR self-effect but also reduce the beamsize at the screen for convenient beamsize measurements.

  4. Determination of U (1 )A restoration from pion and a0 -meson screening masses: Toward the chiral regime

    NASA Astrophysics Data System (ADS)

    Ishii, Masahiro; Yonemura, Koji; Takahashi, Junichi; Kouno, Hiroaki; Yahiro, Masanobu

    2016-01-01

    We incorporate the effective restoration of U (1 )A symmetry in the 2 +1 -flavor entanglement Polyakov-loop extended Nambu-Jona-Lasinio (EPNJL) model by introducing a temperature-dependent strength K (T ) to the Kobayashi-Maskawa-'t Hooft determinant interaction. T dependence of K (T ) is well determined from pion and a0-meson screening masses obtained by lattice QCD (LQCD) simulations with improved p4 staggered fermions. The strength is strongly suppressed in the vicinity of the pseudocritical temperature of chiral transition. The EPNJL model with the K (T ) well reproduces meson susceptibilities calculated by LQCD with domain-wall fermions. The model shows that the chiral transition is second order at the "light-quark chiral-limit" point where the light quark mass is zero and the strange quark mass is fixed at the physical value. This indicates that there exists a tricritical point. Hence, the location is estimated.

  5. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and... subdivision or agency, business trust, partnership, association, or other legal entity. (c) Research means... includes, but is not limited to, behavioral science studies, surveys, evaluations, and...

  6. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and... subdivision or agency, business trust, partnership, association, or other legal entity. (c) Research means... includes, but is not limited to, behavioral science studies, surveys, evaluations, and...

  7. 29 CFR 1912a.2 - Membership.

    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.2 Membership. The Committee is a... labor, two members will represent the occupational health professions, two members will represent...

  8. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is a... labor, two members will represent the occupational health professions, two members will represent...

  9. 29 CFR 4041A.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... plan year, available resources as described in section 4245(b)(3) of ERISA. Benefits subject to... Relating to Labor (Continued) PENSION BENEFIT GUARANTY CORPORATION PLAN TERMINATIONS TERMINATION OF MULTIEMPLOYER PLANS General Provisions § 4041A.2 Definitions. The following terms are defined in § 4001.1...

  10. 29 CFR 4041A.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... plan year, available resources as described in section 4245(b)(3) of ERISA. Benefits subject to... Relating to Labor (Continued) PENSION BENEFIT GUARANTY CORPORATION PLAN TERMINATIONS TERMINATION OF MULTIEMPLOYER PLANS General Provisions § 4041A.2 Definitions. The following terms are defined in § 4001.1...

  11. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  12. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  13. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  14. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  15. The A2 Experiment Program at MAMI

    NASA Astrophysics Data System (ADS)

    Briscoe, William; A2 Collaboration

    2014-09-01

    The Mainz Microtron MAMI is an accelerator for electron beams run by the Institut für Kernphysik of the Johannes Gutenberg-Universität Mainz used for hadron physics experiments. Of it's three active experimental halls, the A2 facility, which features the presence of the SLAC Crystal Ball detector, has produced a plethora of experimental results, which has contributed to the understanding of the structure of the nucleon. An overview and update of the current A2 program will be presented. The Mainz Microtron MAMI is an accelerator for electron beams run by the Institut für Kernphysik of the Johannes Gutenberg-Universität Mainz used for hadron physics experiments. Of it's three active experimental halls, the A2 facility, which features the presence of the SLAC Crystal Ball detector, has produced a plethora of experimental results, which has contributed to the understanding of the structure of the nucleon. An overview and update of the current A2 program will be presented. Funded in part by SFB 1044. US collaborators funded by USDOE and USNSF.

  16. Rat Organic Anion Transporting Protein 1A1 (OATP1A1)

    PubMed Central

    Xiao, Yansen; Nieves, Edward; Angeletti, Ruth H.; Orr, George A.; Wolkoff, Allan W.

    2008-01-01

    Rat organic anion transporting protein 1a1 (oatp1a1), a hepatocyte basolateral plasma membrane protein, mediates transport of various amphipathic compounds. Our previous studies indicated that serine phosphorylation of a single tryptic peptide inhibits its transport activity without changing its cell surface content. The site of phosphorylation is unknown and was the subject of the present study. Following immunoaffinity chromatographic purification from rat liver, oatp1a1 was subjected to trypsin digestion and MALDI-TOF. Except for predicted N-glycosylated peptides, 97% of oatp1a1 tryptic peptides were observed. A single tryptic phosphopeptide was found in the C-terminus (aa 626-647), existing in unphosphorylated, singly, or doubly phosphorylated forms, and sensitive to alkaline phosphatase treatment. β-elimination reaction resulted in mass loss of 98 or 196 Da from this peptide, and subsequent Michael addition with cysteamine increased masses by the predicated 77 and 154 Da, indicating that oatp1a1 can be singly or doubly phosphorylated at serine or threonine residues in the C-terminal sequence SSATDHT (aa 634-640). Subsequent tandem MS/MS analysis revealed that phosphorylation at S634 accounted for all singly phosphorylated peptide, while phosphorylation at S634 and S635 accounted for all doubly phosphorylated peptide. These findings identify the site of oatp1a1 phosphorylation and demonstrate that it is an ordered process, in which phosphorylation at S634 precedes that at S635. The mechanism by which phosphorylation results in loss of transport activity in hepatocytes remains to be established. Whether phosphorylation near the C-terminus inhibits C-terminal oligomerization of oatp1a1, required for normal transport function, can be speculated upon, but is as yet unknown. PMID:16519530

  17. A 1-D dusty plasma photonic crystal

    SciTech Connect

    Mitu, M. L.; Ticoş, C. M.; Toader, D.; Banu, N.; Scurtu, A.

    2013-09-21

    It is demonstrated numerically that a 1-D plasma crystal made of micron size cylindrical dust particles can, in principle, work as a photonic crystal for terahertz waves. The dust rods are parallel to each other and arranged in a linear string forming a periodic structure of dielectric-plasma regions. The dispersion equation is found by solving the waves equation with the boundary conditions at the dust-plasma interface and taking into account the dielectric permittivity of the dust material and plasma. The wavelength of the electromagnetic waves is in the range of a few hundred microns, close to the interparticle separation distance. The band gaps of the 1-D plasma crystal are numerically found for different types of dust materials, separation distances between the dust rods and rod diameters. The distance between levitated dust rods forming a string in rf plasma is shown experimentally to vary over a relatively wide range, from 650 μm to about 1350 μm, depending on the rf power fed into the discharge.

  18. The Vacuolar ATPase a2-subunit regulates Notch signaling in triple-negative breast cancer cells

    PubMed Central

    Pamarthy, Sahithi; Jaiswal, Mukesh K.; Kulshreshtha, Arpita; Katara, Gajendra K.; Gilman-Sachs, Alice; Beaman, Kenneth D.

    2015-01-01

    Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer with poor prognosis for which no targeted therapies are currently available. Notch signaling has been implicated in breast cancer but the factors that control Notch in TNBC are unknown. Because the Vacuolar ATPase has been shown to be important in breast cancer invasiveness, we investigated the role of a2-subunit isoform of Vacuolar ATPase (a2V) in regulating Notch signaling in TNBC. Confocal microscopy revealed that among all the ‘a’ subunit isoforms, a2V was uniquely expressed on the plasma membrane of breast cancer cells. Both a2V and NOTCH1 were elevated in TNBC tumors tissues and cell lines. a2V knockdown by siRNA as well as V-ATPase inhibition by Bafilomycin A1 (Baf A1) in TNBC cell lines enhanced Notch signaling by increasing the expression of Notch1 intracellular Domain (N1ICD). V-ATPase inhibition blocked NICD degradation by disrupting autophagy and lysosomal acidification as demonstrated by accumulation of LC3B and diminished expression of LAMP1 respectively. Importantly, treatment with Baf A1 or anti-a2V, a novel-neutralizing antibody against a2V hindered cell migration of TNBC cells. Our findings indicate that a2V regulates Notch signaling through its role in endolysosomal acidification and emerges as a potential target for TNBC. PMID:26418877

  19. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy

    PubMed Central

    Alavi, Marcel V.; Mao, Mao; Pawlikowski, Bradley T.; Kvezereli, Manana; Duncan, Jacque L.; Libby, Richard T.; John, Simon W. M.; Gould, Douglas B.

    2016-01-01

    Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1+/Δex41mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes. PMID:26813606

  20. Development of Selective Inhibitors for Human Aldehyde Dehydrogenase 3A1 (ALDH3A1) for the Enhancement of Cyclophosphamide Cytotoxicity

    PubMed Central

    Parajuli, Bibek; Georgiadis, Taxiarchis M.; Fishel, Melissa L.; Hurley, Thomas D.

    2014-01-01

    Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemo-resistance by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues such as mafosfamide (MF), ifosfamide (IFM), 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 may permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1 selective inhibitor, CB29, previously identified in a high throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate-binding site of ALDH3A1. Cellular proliferation of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as the ALDH3A1 non-expressing lung fibroblast cells, CCD-13Lu, is unaffected by treatment with CB29 and its analogues alone. However, the sensitivity toward the anti-proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumour cells. In contrast, the sensitivity of CCD-13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1 or ALDH2 isoenzymes at concentrations up to 250 μM. Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which may be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1-positive cancer cells to oxazaphosphorines. PMID:24677340

  1. Architecture for a 1-GHz Digital RADAR

    NASA Technical Reports Server (NTRS)

    Mallik, Udayan

    2011-01-01

    An architecture for a Direct RF-digitization Type Digital Mode RADAR was developed at GSFC in 2008. Two variations of a basic architecture were developed for use on RADAR imaging missions using aircraft and spacecraft. Both systems can operate with a pulse repetition rate up to 10 MHz with 8 received RF samples per pulse repetition interval, or at up to 19 kHz with 4K received RF samples per pulse repetition interval. The first design describes a computer architecture for a Continuous Mode RADAR transceiver with a real-time signal processing and display architecture. The architecture can operate at a high pulse repetition rate without interruption for an infinite amount of time. The second design describes a smaller and less costly burst mode RADAR that can transceive high pulse repetition rate RF signals without interruption for up to 37 seconds. The burst-mode RADAR was designed to operate on an off-line signal processing paradigm. The temporal distribution of RF samples acquired and reported to the RADAR processor remains uniform and free of distortion in both proposed architectures. The majority of the RADAR's electronics is implemented in digital CMOS (complementary metal oxide semiconductor), and analog circuits are restricted to signal amplification operations and analog to digital conversion. An implementation of the proposed systems will create a 1-GHz, Direct RF-digitization Type, L-Band Digital RADAR--the highest band achievable for Nyquist Rate, Direct RF-digitization Systems that do not implement an electronic IF downsample stage (after the receiver signal amplification stage), using commercially available off-the-shelf integrated circuits.

  2. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

    The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials. In addition to HDL infusion therapy an alternative way to exploit beneficial cardiovascular effects of HDL/ApoA-1 is to use gene transfer. Preclinical studies have shown evidence of benefit using this approach; however clinical validation is yet lacking. This review summarizes our current knowledge of the aforementioned strategies. PMID:26388776

  3. Induction of cytochrome P-450 1A2 by oxidized tryptophan in Hepa lclc7 cells.

    PubMed

    Sindhu, R K; Mitsuhashi, M; Kikkawa, Y

    2000-03-01

    Recent studies from this laboratory have demonstrated that L-tryptophan, after oxidation either by UV-irradiation or ozone, induces aryl hydrocarbon receptor (AhR) activation and binding of the liganded AhR complex to its specific DNA recognition site, thereby initiating transcription of the cytochrome P-450 1a1 (Cyp1a1) gene with concomitant increase of CYP1A1 protein and 7-ethoxyresorufin O-deethylase activity in wild-type mouse hepatoma cells, Hepa lclc7 (Hepa-1), in culture. Temporary inhibition of protein synthesis by cycloheximide resulted in superinduction of oxidized tryptophan-inducible CYP1A1 mRNA, protein, and 7-ethoxyresorufin O-deethylase activity in Hepa-1 cells. In the present communication, the results obtained by immunoblot analyses with monoclonal CYP1A1/1A2 antibody (NIH 1-7-1) demonstrate that both UV- or ozone-oxidized tryptophan also induce CYP1A2 protein in Hepa-1 cells. CYP1A2 mRNA, detected by reverse transcription-polymerase chain reaction, was markedly induced in the UV- or ozone-oxidized tryptophan-treated cells. Temporary inhibition of protein synthesis by cycloheximide further induced oxidized tryptophan-inducible CYP1A2 mRNA as well as the protein in Hepa-1 cells. This is the first report demonstrating the induction of CYP1A2 mRNA and protein in Hepa-1 cells. PMID:10688617

  4. A 0.5-V Six-Transistor Static Random Access Memory with Ferroelectric-Gate Field Effect Transistors

    NASA Astrophysics Data System (ADS)

    Tanakamaru, Shuhei; Hatanaka, Teruyoshi; Yajima, Ryoji; Miyaji, Kousuke; Takahashi, Mitsue; Sakai, Shigeki; Takeuchi, Ken

    2010-12-01

    A 0.5 V six-transistor static random access memory (6T-SRAM) with ferroelectric-gate field-effect-transistors (Fe-FETs) is proposed and experimentally demonstrated for the first time. During the read and the hold, the threshold voltage (VTH) of Fe-FETs automatically changes to increase the static noise margin (SNM) by 60%. During the stand-by, the VTH of the proposed SRAM cell increases to decrease the leakage current by 42%. In case of the read, the VTH of the read transistor decreases and increases the cell read current to achieve the fast read. During the write, the VTH of the SRAM cell dynamically changes and assist the cell data to flip, realizing a write assist function. The enlarged SNM realizes the VDD reduction by 0.11 V, which decreases the active power by 32%. The proposed SRAM layout is the same as the conventional 6T-SRAM and there is no area penalty.

  5. Large in-plane spin-dephasing anisotropy in a [0 0 1]-grown two-dimensional electron system

    NASA Astrophysics Data System (ADS)

    Korn, T.; Stich, D.; Schulz, R.; Schuh, D.; Wegscheider, W.; Schüller, C.

    2008-03-01

    A large anisotropy in the spin dephasing times for the different in-plane directions of [0 0 1] quantum wells has been predicted in calculations by Averkiev and Golub [Phys. Rev. B 60 (1999) 15582] for systems with both Rashba and Dresselhaus spin-orbit fields. Here, we present time-resolved Faraday rotation measurements performed in the Voigt geometry on a high-mobility 2D electron system grown on a [0 0 1] substrate. An out-of-plane spin polarization is created in the sample by a circularly polarized pump pulse. The magnetic field applied in the sample plane forces the spins to precess perpendicular to it. For a magnetic field applied along [1 1 0], the spins precess into the [1 1bar 0] direction, which is in the sample plane, for a magnetic field along [1 1bar 0], the spins precess into the [1 1 0] direction. The experimentally determined spin dephasing times for these two different cases differ by about 60%, demonstrating that the predicted anisotropy is present in our sample.

  6. A 0.8-4.2 GHz monolithic all-digital PLL based frequency synthesizer for wireless communications

    NASA Astrophysics Data System (ADS)

    Yuanxin, Zhao; Yuanpei, Gao; Wei, Li; Ning, Li; Junyan, Ren

    2015-01-01

    A 0.8-4.2 GHz monolithic all-digital PLL based frequency synthesizer for wireless communications is successfully realized by the 130 nm CMOS process. A series of novel methods are proposed in this paper. Two band DCOs with high frequency resolution are utilized to cover the frequency band of interest, which is as wide as 2.5 to 5 GHz. An overflow counter is proposed to prevent the “pulse-swallowing” phenomenon so as to significantly reduce the locking time. A NTW-clamp digital module is also proposed to prevent the overflow of the loop control word. A modified programmable divider is presented to prevent the failure operation at the boundary. The measurement results show that the output frequency range of this frequency synthesizer is 0.8-4.2 GHz. The locking time achieves a reduction of 84% at 2.68 GHz. The best in-band and out-band phase noise performances have reached -100 dBc/Hz, and -125 dBc/Hz respectively. The lowest reference spur is -58 dBc.

  7. Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas.

    PubMed

    Bouguéon, Guillaume; Lagarce, Frédéric; Martin, Ludovic; Pailhoriès, Hélène; Bastiat, Guillaume; Vrignaud, Sandy

    2016-07-25

    Medicines for the treatment of rare diseases frequently do not attract the interest of the pharmaceutical industry, and hospital pharmacists are thus often requested by physicians to prepare personalized medicines. Tuberous Sclerosis Complex (TSC) is a rare disease that causes disfiguring lesions named facial angiofibromas. Various topical formulations of rapamycin (=sirolimus) have been proved effective in treating these changes in small case series. The present study provides for the first time characterization of a 0.1% rapamycin cream formulation presenting good rapamycin solubilisation. The first step of the formulation is solubilisation of rapamycin in Transcutol(®), and the second step is the incorporation of the mixture in an oil-in-water cream. A HPLC stability-indicating method was developed. Rapamycin concentration in the cream was tested by HPLC and confirmed that it remained above 95% of the initial concentration for at least 85days, without characteristic degradation peaks. The preparation met European Pharmacopoeia microbial specifications throughout storage in aluminum tubes, including when patient use was simulated. Odour, appearance and colour of the preparation were assessed and no change was evidenced during storage. The rheological properties of the cream also remained stable throughout storage. To conclude, we report preparation of a novel cream formulation presenting satisfactory rapamycin solubilisation for the treatment of TSC cutaneous manifestations, with stability data. The cream is currently being used by our patients. Efficacy and tolerance will be reported later. PMID:27260135

  8. A 0.7 V, 40 nW Compact, Current-Mode Neural Spike Detector in 65 nm CMOS.

    PubMed

    Yao, Enyi; Chen, Yi; Basu, Arindam

    2016-04-01

    In this paper, we describe a novel low power, compact, current-mode spike detector circuit for real-time neural recording systems where neural spikes or action potentials (AP) are of interest. Such a circuit can enable massive compression of data facilitating wireless transmission. This design can generate a high signal-to-noise ratio (SNR) output by approximating the popularly used nonlinear energy operator (NEO) through standard analog blocks. We show that a low pass filter after the NEO can be used for two functions-(i) estimate and cancel low frequency interference and (ii) estimate threshold for spike detection. The circuit is implemented in a 65 nm CMOS process and occupies 200 μm × 150 μ m of chip area. Operating from a 0.7 V power supply, it consumes about 30 nW of static power and 7 nW of dynamic power for 100 Hz input spike rate making it the lowest power consuming spike detector reported so far. PMID:26168445

  9. A 0.1–1.5 GHz, low jitter, area efficient PLL in 55-nm CMOS process

    NASA Astrophysics Data System (ADS)

    Bo, Zhong; Zhangming, Zhu

    2016-05-01

    A 0.1–1.5 GHz, 3.07 pS root mean squares (RMS) jitter, area efficient phase locked loop (PLL) with multiphase clock outputs is presented in this paper. The size of capacitor in the low pass filter (LPF) is significantly decreased by implementing a dual path charge pump (CP) technique in this PLL. Subject to specified power consumption, a novel optimization method is introduced to optimize the transistor size in the voltage control oscillator (VCO), CP and phase/frequency detector (PFD) in order to minimize clock jitter. This method could improve 3–6 dBc/Hz phase noise. The proposed PLL has been fabricated in 55 nm CMOS process with an integrated 16 pF metal–oxide–metal (MOM) capacitor, occupies 0.05 mm2 silicon area, the measured total power consumption is 2.8 mW @ 1.5 GHz and the phase noise is ‑102 dBc/Hz @ 1 MHz offset frequency. Project supported by the National Natural Science Foundation of China (Nos. 61234002, 61322405, 61306044, 61376033) and the National High-Tech Program of China (No. 2013AA014103).

  10. VizieR Online Data Catalog: Radial velocities of 107 B8-A0 stars (Albitzky, 1947)

    NASA Astrophysics Data System (ADS)

    Albitzky, V. A.

    2014-05-01

    In Table XII are given the final values of the observed radial velocities for 107 stars. For 16 of these stars the radial velocities have been admitted to be variable which makes 14% of the total number of the stars observed. This percentage is smaller than that usually accepted, viz. about 25-30%; but with so small dispersion as ours one must be more careful in announcing the variability of a radial velocity. The data of the Table XII are self-explanatory; the magnitudes are visual and the spectral types are those of H.D. in the column 8 are given the numbers of spectrograms measured. In the remarks betGC signifies Burnham's General catalogue of Double Stars, etc.; Moore - J.H. Moore, General Catalogue of the Radial Velocities of Star, etc.; D.D.O. - Publications of the David Dunlap Observatory, University of Toronto, Vol. I, Nr. 3. (2). For 91 stars with adopted constant velocities the mean value of p.e's is +/-3.57km/s and the number of spectrograms per star is 5.3. For the catalogue D.D.O. corresponding data are +/-2.85km/s and 5.8 (for stars B8-A0). The lower precision of the present catalogue may be explained by the small dispersion of our spectrograph: 75Å/mm instead of 33-66Å/mm for D.D.O. (1 data file).

  11. Pressure distributions on a 0.02-scale Space Shuttle orbiter nose at Mach 21.5 in helium

    NASA Technical Reports Server (NTRS)

    Ashby, George C., Jr.; Bernot, Peter T.; Woods, William C.

    1994-01-01

    Pressure distributions on a 0.02-scale model of the Space Shuttle orbiter forward fuselage were obtained in the 22-inch aerodynamic leg of the Langley Hypersonic Helium Tunnel Facility at a nominal free-stream Mach number of 21.5 and a ratio of specific heats of 1.67 for inclusion in the database of the Shuttle entry air data system (SEADS). The data were measured at model angles of attack of 0 deg to 50 deg in 5 deg increments for zero sideslip angle and at model sideslip angles of -5 deg to 5 deg for angles of attack equal to 5, 20, 35, and 40 deg. These data displayed trends similar to those observed in other wind tunnels at Mach 6 and 10 in air. Specifically noted is a shift in the location of the stagnation point at angles of attack above 15 deg; this effect did not, however, occur in flight. By comparison, the data obtained at Mach 6 in the Langley Hypersonic CF4 Tunnel, corresponding to a lower ratio of specific heats in the postshock region than those in helium and air, showed some reduction of the stagnation point shift at the higher angles of attack. The differences between flight and wind tunnel pressure distributions are believed due primarily to high-temperature gas chemistry effects in flight, which include lower effective specific heat ratios but which were not completely duplicated in the wind tunnels.

  12. A current mode feed-forward gain control system for a 0.8 V CMOS hearing aid

    NASA Astrophysics Data System (ADS)

    Fanyang, Li; Haigang, Yang; Fei, Liu; Tao, Yin

    2011-06-01

    A current mode feed-forward gain control (CMFGC) technique is presented, which is applied in the front-end system of a hearing aid chip. Compared with conventional automatic gain control (AGC), CMFGC significantly improves the total harmonic distortion (THD) by digital gain control. To attain the digital gain control codes according to the extremely weak output signal from the microphone, a rectifier and a state controller implemented in current mode are proposed. A prototype chip has been designed based on a 0.13 μm standard CMOS process. The measurement results show that the supply voltage can be as low as 0.6 V. And with the 0.8 V supply voltage, the THD is improved and below 0.06% (-64 dB) at the output level of 500 mVp-p, yet the power consumption is limited to 40 μW. In addition, the input referred noise is only 4 μVrms and the maximum gain is maintained at 33 dB.

  13. Transducing Energy Loss in Water Electrolysis with a 0D Ion-Sensitive Field-Effect Transistor

    NASA Astrophysics Data System (ADS)

    Clement, Nicolas; Nishiguchi, Katsuhiko; Dufrêche, Jean-François; Guérin, David; Patriarche, Gilles; Troadec, David; Fujiwara, Akira; Vuillaume, Dominique

    2013-03-01

    In order to produce hydrogen as a fuel source of the future, water electrolysis is one of the most ``promising'' green approaches. Although electrolysis efficiency can be as high as 80%, it still means that at least 20% of the energy is lost. The use of transducers to collect the energy loss in water electrolysis is attractive. Among the various transducers, several ideas have been proposed such as an air bubble powered rotary driving apparatus or a microcantilever vibrating after impact of each bubble. However, the main source of energy lost appears at electrode interfaces with the presence of a double layer of ions acting as a resistor and capacitor. In this study, we show that using a 0D - ultra low noise - ISFET, allows getting the energy coming from the double layer fluctuation at each H2 bubble emission. Interestingly, the output signal that can be tuned with salt concentration and electrolysis current exactly corresponds to that of action potential which could be useful for bio-applications. In addition, electrical detection of bubbles emission at single bubble level also opens the door to optimization of hydrolysis efficiency and further save energy for hydrogen production.

  14. Disulfide Bond Oxidoreductase DsbA2 of Legionella pneumophila Exhibits Protein Disulfide Isomerase Activity

    PubMed Central

    Kpadeh, Zegbeh Z.; Jameson-Lee, Max; Yeh, Anthony J.; Chertihin, Olga; Shumilin, Igor A.; Dey, Rafik; Day, Shandra R.

    2013-01-01

    The extracytoplasmic assembly of the Dot/Icm type IVb secretion system (T4SS) of Legionella pneumophila is dependent on correct disulfide bond (DSB) formation catalyzed by a novel and essential disulfide bond oxidoreductase DsbA2 and not by DsbA1, a second nonessential DSB oxidoreductase. DsbA2, which is widely distributed in the microbial world, is phylogenetically distinct from the canonical DsbA oxidase and the DsbC protein disulfide isomerase (PDI)/reductase of Escherichia coli. Here we show that the extended N-terminal amino acid sequence of DsbA2 (relative to DsbA proteins) contains a highly conserved 27-amino-acid dimerization domain enabling the protein to form a homodimer. Complementation tests with E. coli mutants established that L. pneumophila dsbA1, but not the dsbA2 strain, restored motility to a dsbA mutant. In a protein-folding PDI detector assay, the dsbA2 strain, but not the dsbA1 strain, complemented a dsbC mutant of E. coli. Deletion of the dimerization domain sequences from DsbA2 produced the monomer (DsbA2N), which no longer exhibited PDI activity but complemented the E. coli dsbA mutant. PDI activity was demonstrated in vitro for DsbA2 but not DsbA1 in a nitrocefin-based mutant TEM β-lactamase folding assay. In an insulin reduction assay, DsbA2N activity was intermediate between those of DsbA2 and DsbA1. In L. pneumophila, DsbA2 was maintained as a mixture of thiol and disulfide forms, while in E. coli, DsbA2 was present as the reduced thiol. Our studies suggest that DsbA2 is a naturally occurring bifunctional disulfide bond oxidoreductase that may be uniquely suited to the majority of intracellular bacterial pathogens expressing T4SSs as well as in many slow-growing soil and aquatic bacteria. PMID:23435972

  15. A 0.4-2.3 GHz broadband power amplifier extended continuous class-F design technology

    NASA Astrophysics Data System (ADS)

    Chen, Peng; He, Songbai

    2015-08-01

    A 0.4-2.3 GHz broadband power amplifier (PA) extended continuous class-F design technology is proposed in this paper. Traditional continuous class-F PA performs in high-efficiency only in one octave bandwidth. With the increasing development of wireless communication, the PA is in demand to cover the mainstream communication standards' working frequencies from 0.4 GHz to 2.2 GHz. In order to achieve this objective, the bandwidths of class-F and continuous class-F PA are analysed and discussed by Fourier series. Also, two criteria, which could reduce the continuous class-F PA's implementation complexity, are presented and explained to investigate the overlapping area of the transistor's current and voltage waveforms. The proposed PA design technology is based on the continuous class-F design method and divides the bandwidth into two parts: the first part covers the bandwidth from 1.3 GHz to 2.3 GHz, where the impedances are designed by the continuous class-F method; the other part covers the bandwidth from 0.4 GHz to 1.3 GHz, where the impedance to guarantee PA to be in high-efficiency over this bandwidth is selected and controlled. The improved particle swarm optimisation is employed for realising the multi-impedances of output and input network. A PA based on a commercial 10 W GaN high electron mobility transistor is designed and fabricated to verify the proposed design method. The simulation and measurement results show that the proposed PA could deliver 40-76% power added efficiency and more than 11 dB power gain with more than 40 dBm output power over the bandwidth from 0.4-2.3 GHz.

  16. Aerodynamic Characteristics of a 0.04956-Scale Model of the Convair F-102A Airplane at Transonic Speeds

    NASA Technical Reports Server (NTRS)

    Tempelmeyer, Kenneth E.; Osborne, Robert S.

    1955-01-01

    Tests have been conducted in the Langley 8-foot transonic tunnel on a 0.04956-scale model of the Convair F-102A airplane which employed an indented and extended fuselage, cambered wing leading edges, and deflected wing tips. Force and moment characteristics were obtained for Mach numbers from 0.60 to 1.135 at angles of attack up to 20 . In addition, tests were made over a limited angle-of-attack range to determine the effects of the cambered leading edges, deflected tips, and a nose section with a smooth area distribution. Fuselage modifications employed on the F-102A were responsible for a 25.percent reduction in the minimum drag-coefficient rise between the Mach numbers of 0.85 and 1.075 when compared with that for the earlier versions of the F-102. Although the wing modifications increased the F-102A subsonic minimum drag-coefficient level approximately 0.0020, they produced large decreases in drag at lifting conditions over that for the original (plane-wing) F-102. The F-102A had 15 to 25 percent higher maximum lift-drag ratios than did the original F-102. The F-102A had about 15 percent lower maximum lift-drag ratios at Mach numbers below 0.95 and slightly higher maximum lift-drag ratios at supersonic speeds when compared with those ratios for sn earlier modified-wing version of the F-102. Chordwise wing fences which provided suitable longitudinal stability for the original F-102 were not adequate for the cambered-wing F-102A The pitching-moment curves indicated a region of near neutral stability with possible pitch-up tendencies for the F-102A at high subsonic Mach numbers for lift coefficients between about 0.4 and 0.5.

  17. The Cardioprotective Protein Apolipoprotein A1 Promotes Potent Anti-tumorigenic Effects*♦

    PubMed Central

    Zamanian-Daryoush, Maryam; Lindner, Daniel; Tallant, Thomas C.; Wang, Zeneng; Buffa, Jennifer; Klipfell, Elizabeth; Parker, Yvonne; Hatala, Denise; Parsons-Wingerter, Patricia; Rayman, Pat; Yusufishaq, Mohamed Sharif S.; Fisher, Edward A.; Smith, Jonathan D.; Finke, Jim; DiDonato, Joseph A.; Hazen, Stanley L.

    2013-01-01

    Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b+ F4/80+ macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic. PMID:23720750

  18. Aldehyde Dehydrogenase 1A1: Friend or Foe to Female Metabolism?

    PubMed Central

    Petrosino, Jennifer M.; DiSilvestro, David; Ziouzenkova, Ouliana

    2014-01-01

    In this review, we summarize recent advances in understanding vitamin A-dependent regulation of sex-specific differences in metabolic diseases, inflammation, and certain cancers. We focus on the characterization of the aldehyde dehydrogenase-1 family of enzymes (ALDH1A1, ALDH1A2, ALDH1A3) that catalyze conversion of retinaldehyde to retinoic acid. Additionally, we propose a “horizontal transfer of signaling” from estrogen to retinoids through the action of ALDH1A1. Although estrogen does not directly influence expression of Aldh1a1, it has the ability to suppress Aldh1a2 and Aldh1a3, thereby establishing a female-specific mechanism for retinoic acid generation in target tissues. ALDH1A1 regulates adipogenesis, abdominal fat formation, glucose tolerance, and suppression of thermogenesis in adipocytes; in B cells, ALDH1A1 plays a protective role by inducing oncogene suppressors Rara and Pparg. Considering the conflicting responses of Aldh1a1 in a multitude of physiological processes, only tissue-specific regulation of Aldh1a1 can result in therapeutic effects. We have shown through successful implantation of tissue-specific Aldh1a1−/− preadipocytes that thermogenesis can be induced in wild-type adipose tissues to resolve diet-induced visceral obesity in females. We will briefly discuss the emerging role of ALDH1A1 in multiple myeloma, the regulation of reproduction, and immune responses, and conclude by discussing the role of ALDH1A1 in future therapeutic applications. PMID:24594504

  19. 77 FR 23181 - Approval and Promulgation of Implementation Plans; Florida; 110(a)(1) and (2) Infrastructure...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-18

    ... 0.12 parts per million (ppm) to 0.08 ppm. See 62 FR 38856. Pursuant to section 110(a)(1) of the CAA... section 110(a)(2) necessary to implement the 1997 8-hour ozone NAAQS. See 73 FR 16205. For those states... revision, which was submitted to comply with CAIR. See 72 FR 58016 (October 12, 2007). In so doing,...

  20. Characterization of dihydro-A2PE: an Intermediate in the A2E Biosynthetic Pathway†

    PubMed Central

    Kim, So R.; He, Jiangtao; Yanase, Emiko; Jang, Young P.; Berova, Nina; Nakanishi, Koji; Sparrow, Janet R.

    2008-01-01

    Bisretinoid lipofuscin pigments that accumulate in retinal pigment epithelial cells are implicated in the etiology of several forms of macular degeneration including juvenile onset Stargardt disease, Best vitelliform macular degeneration and age-related macular degeneration. One of these compounds, A2E, is generated by phosphate hydrolysis of a phosphatidylpyridinium bisretinoid (A2PE) that forms within photoreceptor outer segments. Here we demonstrate that the formation of the aromatic pyridinium ring of A2PE follows from the oxidation of a dihydropyridinium intermediate. Time-dependent density functional theory calculation, based on the structure of dihydro-A2E, produced a simulated UV-visible absorbance spectrum characterized by maxima of 494 and 344 nm. Subsequently, a compound exhibiting similar UV-visible absorbance maxima (λmax 490 and 330 nm) was identified in the A2E biomimetic reaction mixture. By liquid chromatography-mass spectrometry (LC-MS) this bischromophore had the expected mass of the dihydro-pyridinium bisretinoid. The compound also exhibited the behavior of a biosynthetic intermediate, since it formed in advance of the final product A2E and was consumed as A2E accumulated. Moreover, under deoxygenated conditions, conversion to the aromatic pyridinium bisretinoid was inhibited. Taken together, these findings indicate that A2E biosynthesis involves the oxidation of a dihydropyridinium intermediate dihydro-A2PE. An understanding of the biosynthetic pathways of retinal pigment epithelial lipofuscin pigments is critical to the development of therapies for macular degeneration that are based on limiting the formation of these damaging compounds. PMID:17685561

  1. CYP85A1 is required for the initiation of female gametogenesis in Arabidopsis thaliana

    PubMed Central

    Pérez-España, Victor Hugo; Sánchez-León, Nidia

    2011-01-01

    Brassinosteroids (BRs) are steroid-like hormones essential for plant growth and development. The most active forms of brassinosteroids are Brassinolide (BL) and Castasterone (CS), which are catalyzed by members of the CYP85A family of cytochrome P450 monooxygenases. In Arabidopsis thaliana there are two CYP85A gene members: CYP85A1 and CYP85A2. Unlike CYP85A1, CYP85A2 mediates the conversion of CS to BL. In contrast to mutations in CYP85A2 that result in severe dwarfism, cyp85a1 mutants do not show any obvious morphological phenotype during vegetative or floral development. By analyzing large-scale transcriptional activity in the ovule of Arabidopsis thaliana (Arabidopsis), we determined that CYP85A1 is abundantly expressed in wild-type, but not in sporocyteless (spl) ovules lacking a female gametophyte. Insertional T-DNA lines defective in the activity of CYP85A1 exhibit a semi-sterile phenotype, suggesting a role for the corresponding enzyme acting at the gametophytic level. The CYP85A1 mRNA is localized in the female gametophyte and its neighboring sporophytic cells; however, translational fusions of the CYP85A1 promoter to uidA (GUS) showed GUS expression restricted to the female gametophyte, suggesting that within the ovule the corresponding protein is mostly active in gametophytic cells. A cytological analysis of heterozygous cyp85a1/+ individuals showed that close to 50% of female gametophytes are arrested before the first nuclear mitotic division of the haploid functional megaspore. Our results indicate that BR biosynthesis is required for the initiation of megagametogenesis in Arabidopsis. PMID:21364326

  2. Regulation of translation by upstream translation initiation codons of surfactant protein A1 splice variants

    PubMed Central

    Tsotakos, Nikolaos; Silveyra, Patricia; Lin, Zhenwu; Thomas, Neal; Vaid, Mudit

    2014-01-01

    Surfactant protein A (SP-A), a molecule with roles in lung innate immunity and surfactant-related functions, is encoded by two genes in humans: SFTPA1 (SP-A1) and SFTPA2 (SP-A2). The mRNAs from these genes differ in their 5′-untranslated regions (5′-UTR) due to differential splicing. The 5′-UTR variant ACD′ is exclusively found in transcripts of SP-A1, but not in those of SP-A2. Its unique exon C contains two upstream AUG codons (uAUGs) that may affect SP-A1 translation efficiency. The first uAUG (u1) is in frame with the primary start codon (p), but the second one (u2) is not. The purpose of this study was to assess the impact of uAUGs on SP-A1 expression. We employed RT-qPCR to determine the presence of exon C-containing SP-A1 transcripts in human RNA samples. We also used in vitro techniques including mutagenesis, reporter assays, and toeprinting analysis, as well as in silico analyses to determine the role of uAUGs. Exon C-containing mRNA is present in most human lung tissue samples and its expression can, under certain conditions, be regulated by factors such as dexamethasone or endotoxin. Mutating uAUGs resulted in increased luciferase activity. The mature protein size was not affected by the uAUGs, as shown by a combination of toeprint and in silico analysis for Kozak sequence, secondary structure, and signal peptide and in vitro translation in the presence of microsomes. In conclusion, alternative splicing may introduce uAUGs in SP-A1 transcripts, which in turn negatively affect SP-A1 translation, possibly affecting SP-A1/SP-A2 ratio, with potential for clinical implication. PMID:25326576

  3. CYP85A1 is required for the initiation of female gametogenesis in Arabidopsis thaliana.

    PubMed

    Pérez-España, Victor Hugo; Sánchez-León, Nidia; Vielle-Calzada, Jean-Philippe

    2011-03-01

    Brassinosteroids (BRs) are steroid-like hormones essential for plant growth and development. The most active forms of brassinosteroids are Brassinolide (BL) and Castasterone (CS), which are catalyzed by members of the CYP85A family of cytochrome P450 monooxygenases. In Arabidopsis thaliana there are two CYP85A gene members: CYP85A1 and CYP85A2. Unlike CYP85A1, CYP85A2 mediates the conversion of CS to BL. In contrast to mutations in CYP85A2 that result in severe dwarfism, cyp85a1 mutants do not show any obvious morphological phenotype during vegetative or floral development. By analyzing large-scale transcriptional activity in the ovule of Arabidopsis thaliana (Arabidopsis), we determined that CYP85A1 is abundantly expressed in wild-type but not in sporocyteless (spl) ovules lacking a female gametophyte. Insertional T-DNA lines defective in the activity of CYP85A1 exhibit a semi-sterile phenotype, suggesting a role for the corresponding enzyme acting at the gametophytic level. The CYP85A1 mRNA is localized in the female gametophyte and its neighboring sporophytic cells; however, translational fusions of the CYP85A1 promoter to uidA (GUS) showed GUS expression restricted to the female gametophyte, suggesting that within the ovule the corresponding protein is mostly active in gametophytic cells. A cytological analysis of heterozygous cyp85a1/+ individuals showed that close to 50% of female gametophytes are arrested before the first nuclear mitotic division of the haploid functional megaspore. Our results indicate that BR biosynthesis is required for the initiation of megagametogenesis in Arabidopsis. PMID:21364326

  4. A2B adenosine receptor dampens hypoxia-induced vascular leak

    PubMed Central

    Eckle, Tobias; Faigle, Marion; Grenz, Almut; Laucher, Stefanie; Thompson, Linda F.

    2008-01-01

    Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine receptors (ARs: A1AR/A2AAR/A2BAR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR−/−-mice subjected to ambient hypoxia (8% oxygen, 4 hours; eg, lung: 2.1 ± 0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR−/−-, A2AAR−/−-, or A3AR−/−-deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583 [2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)-. phenyl]pyridin-2-ylsulfanyl]acetamide]) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (eg, lung: 2.0 ± 0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacologic and genetic evidence for vascular A2BAR signaling as central control point of hypoxia-associated vascular leak. PMID:18056839

  5. A ~0.1 bar Rule for Tropopause Temperature Minima in Thick Atmospheres of Planets and Large Moons

    NASA Astrophysics Data System (ADS)

    Robinson, T. D.; Catling, D. C.

    2013-12-01

    infrared optical depth of the tropopause minimum is ~0.1 for a very wide range of plausible atmospheric compositions. This optical depth is special as it marks the transition into an upper region of an atmosphere that is very transparent to thermal radiation. Here, shortwave absorption can dominate the temperature profile and, thus, create an inversion and corresponding temperature minimum. These general findings imply that the common 0.1 bar tropopause levels seen in the solar system atmospheres are more universal. Thus, we hypothesize that many exoplanet atmospheres with stratospheric inversions will possess a 0.1 bar tropopause temperature minimum.

  6. Human Pulmonary Surfactant Protein SP-A1 Provides Maximal Efficiency of Lung Interfacial Films.

    PubMed

    Lopez-Rodriguez, Elena; Pascual, Alicia; Arroyo, Raquel; Floros, Joanna; Perez-Gil, Jesus

    2016-08-01

    Pulmonary surfactant is a lipoprotein complex that reduces surface tension to prevent alveolar collapse and contributes to the protection of the respiratory surface from the entry of pathogens. Surfactant protein A (SP-A) is a hydrophilic glycoprotein of the collectin family, and its main function is related to host defense. However, previous studies have shown that SP-A also aids in the formation and biophysical properties of pulmonary surfactant films at the air-water interface. Humans, unlike rodents, have two genes, SFTPA1 and SFTPA2. The encoded proteins, SP-A1 and SP-A2, differ quantitatively or qualitatively in function. It has been shown that both gene products are necessary for tubular myelin formation, an extracellular structural form of lung surfactant. The goal of this study was to investigate potential differences in the biophysical properties of surfactants containing human SP-A1, SP-A2, or both. For this purpose, we have studied for the first time, to our knowledge, the biophysical properties of pulmonary surfactant from individual humanized transgenic mice expressing human SP-A1, SP-A2, or both SP-A1 and SP-A2, in the captive bubble surfactometer. We observed that pulmonary surfactant containing SP-A1 reaches lower surface tension after postexpansion interfacial adsorption than surfactants containing no SP-A or only SP-A2. Under interfacial compression-expansion cycling conditions, surfactant films containing SP-A1 also performed better, particularly with respect to the reorganization of the films that takes place during compression. On the other hand, addition of recombinant SP-A1 to a surfactant preparation reconstituted from the hydrophobic fraction of a porcine surfactant made it more resistant to inhibition by serum than the addition of equivalent amounts of SP-A2. We conclude that the presence of SP-A1 allows pulmonary surfactant to adopt a particularly favorable structure with optimal biophysical properties. PMID:27508436

  7. Conceptual design of a 0.1 W magnetic refrigerator for operation between 10 K and 2 K

    NASA Technical Reports Server (NTRS)

    Helvensteijn, Ben P. M.; Kashani, Ali

    1990-01-01

    The design of a magnetic refrigerator for space applications is discussed. The refrigerator is to operate in the temperature range of 10 K-2 K, at a 2 K cooling power of 0.10 W. As in other magnetic refrigerators operating in this temperature range GGG has been selected as the refrigerant. Crucial to the design of the magnetic refrigerator are the heat switches at both the hot and cold ends of the GGG pill. The 2 K heat switch utilizes a narrow He II filled gap. The 10 K heat switch is based on a narrow helium gas gap. For each switch, the helium in the gap is cycled by means of activated carbon pumps. The design concentrates on reducing the switching times of the pumps and the switches as a whole. A single stage system (one magnet; one refrigerant pill) is being developed. Continuous cooling requires the fully stationary system to have at least two stages running parallel/out of phase with each other. In order to conserve energy, it is intended to recycle the magnetic energy between the magnets. To this purpose, converter networks designed for superconducting magnetic energy storage are being studied.

  8. Experimental validation of a 0-D numerical model for phase change thermal management systems in lithium-ion batteries

    NASA Astrophysics Data System (ADS)

    Schweitzer, Ben; Wilke, Stephen; Khateeb, Siddique; Al-Hallaj, Said

    2015-08-01

    A lumped (0-D) numerical model has been developed for simulating the thermal response of a lithium-ion battery pack with a phase-change composite (PCC™) thermal management system. A small 10s4p battery pack utilizing PCC material was constructed and subjected to discharge at various C-rates in order to validate the lumped model. The 18650 size Li-ion cells used in the pack were electrically characterized to determine their heat generation, and various PCC materials were thermally characterized to determine their apparent specific heat as a function of temperature. Additionally, a 2-D FEA thermal model was constructed to help understand the magnitude of spatial temperature variation in the pack, and to understand the limitations of the lumped model. Overall, good agreement is seen between experimentally measured pack temperatures and the 0-D model, and the 2-D FEA model predicts minimal spatial temperature variation for PCC-based packs at C-rates of 1C and below.

  9. Search for Invisible Decays of a Light Scalar in Radiative Transitions Y(3S)->gamma A0

    SciTech Connect

    Aubert, B

    2008-11-05

    We search for a light scalar particle produced in single-photon decays of the {Upsilon}(3S) resonance through the process {Upsilon}(3S) {yields} {gamma} + A{sup 0}, A{sup 0} {yields} invisible. Such an object appears in Next-to-Minimal Supersymmetric extensions of the Standard Model, where a light CP-odd Higgs boson naturally couples strongly to b-quarks. If, in addition, there exists a light, stable neutralino, decays of A{sup 0} could be preferentially to an invisible final state. We search for events with a single high-energy photon and a large missing mass, consistent with a 2-body decay of {Upsilon}(3S). We find no evidence for such processes in a sample of 122 x 10{sup 6} {Upsilon}(3S) decays collected by the BABAR collaboration at the PEP-II B-factory, and set 90% C.L. upper limits on the branching fraction {Beta}({Upsilon}(3S) {yields} {gamma}A{sup 0}) x {Beta}(A{sup 0} {yields} invisible) at (0.7-31) x 10{sup -6} in the mass range m{sub A{sup 0}} {le} 7.8 GeV. The results are preliminary.

  10. Design of a 0.18 μm CMOS multi-band compatible low power GNSS receiver RF frontend

    NASA Astrophysics Data System (ADS)

    Bing, Li; Yiqi, Zhuang; Qiang, Long; Zhao, Jin; Zhenrong, Li; Gang, Jin

    2011-03-01

    This paper presents the design and implementation of a fully integrated multi-band RF receiver frontend for GNSS applications on L-band. A single RF signal channel with a low-IF architecture is adopted for multi-band operation on the RF section, which mainly consists of a low noise amplifier (LNA), a down-converter, polyphase filters and summing circuits. An improved cascode source degenerated LNA with a multi-band shared off-chip matching network and band switches is implemented in the first amplifying stage. Also, a re-designed wideband double balance mixer is implemented in the down conversion stage, which provides better gain, noise figure and linearity performances. Using a TSMC 0.18 μm 1P4M RF CMOS process, a compact 1.27 GHz/1.575 GHz dual-band GNSS frontend is realized in the proposed low-IF topology. The measurements exhibit the gains of 45 dB and 43 dB, and noise figures are controlled at 3.35 dB and 3.9 dB of the two frequency bands, respectively. The frontend model consumes about 11.8-13.5 mA current on a 1.8 V power supply. The core occupies 1.91 × 0.53 mm2 while the total die area with ESD is 2.45 × 2.36 mm2.

  11. A 0.18 μm CMOS transmit physical coding sublayer IC for 100G Ethernet

    NASA Astrophysics Data System (ADS)

    Weihua, Ruan; Qingsheng, Hu

    2016-03-01

    This paper presents a transmit physical coding sublayer (PCS) circuit for 100G Ethernet. Based on the 4 × 25 Gb/s architecture according to the IEEE P802.3ba and IEEE P802.3bmTM/D1.1 standards, this PCS circuit is designed using a semi-custom design method and consists of 4 modules including 64B/66B encoder, scrambler, multiple lanes distribution and 66 : 8 gearbox. By using the pipeline structure and several optimization techniques, the working speed of the circuit is increased significantly. The parallel scrambling combined with logic optimization also improve the performance. In addition, a kind of phase-independent structure is employed in the design of the gearbox to ensure it can work stably and reliably at high frequency. This PCS circuit has been fabricated based on 0.18 μm CMOS technology and the total area is 1.7 × 1.7 mm2. Measured results show that the circuit can work properly at 100 Gb/s and the power consumption is about 284 mW with a 1.8 V supply. Project supported by the National Natural Science Foundation of China (No. 6504000129) and the National Basic Research Program of China (No. 6504000052).

  12. A 2 X 2 achievement goal framework.

    PubMed

    Elliot, A J; McGregor, H A

    2001-03-01

    A 2 x 2 achievement goal framework comprising mastery-approach, mastery-avoidance, performance-approach, and performance-avoidance goals was proposed and tested in 3 studies. Factor analytic results supported the independence of the 4 achievement goal constructs. The goals were examined with respect to several important antecedents (e.g., motive dispositions, implicit theories, socialization histories) and consequences (e.g., anticipatory test anxiety, exam performance, health center visits), with particular attention allocated to the new mastery-avoidance goal construct. The results revealed distinct empirical profiles for each of the achievement goals; the pattern for mastery-avoidance goals was, as anticipated, more negative than that for mastery-approach goals and more positive than that for performance-avoidance goals. Implications of the present work for future theoretical development in the achievement goal literature are discussed. PMID:11300582

  13. La cometa 2001 A2 (LINEAR)

    NASA Astrophysics Data System (ADS)

    Milani, Giannantonio; Ligustri, Rolando; Facchini, Mauro; Tirelli, Diego

    2002-05-01

    The Comet C/2001 A2 (LINEAR) was expected as a relatively faint object for early summer 2001, but in March an outburst increased its brightness by more than 5 magnitudes with the development both of a diffuse coma and of a plasma tail. A dust tail was really evident only after perihelion. The comet was observed actively by the northern hemisphere before and after the perihelion passage, while in the southern hemisphere it was an easy naked eye object around the epoch of the perihelion passage. The behaviour of the light curve is dominated by the presence of several outbursts that are also related to the partial fragmentation of the nucleus. This had a strong influence in the development end extension of the coma and the tail. A relevant jet activity, documented by several observers,was detected within the coma in July.

  14. Polymorphisms of UGT1A1*6, UGT1A1*27 & UGT1A1*28 in three major ethnic groups from Malaysia

    PubMed Central

    Teh, L. K.; Hashim, H.; Zakaria, Z. A.; Salleh, M. Z.

    2012-01-01

    Background & objectives: Genetic polymorphisms of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) have been associated with a wide variation of responses among patients prescribed with irinotecan. Lack of this enzyme is known to be associated with a high incidence of severe toxicity. The objective of this study was to investigate the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28), which are associated with reduced enzyme activity and increased irinotecan toxicity, in the three main ethnic groups in Malaysia (Malays, Chinese and Indians). Methods: A total of 306 healthy unrelated volunteers were screened for UGT1A1*28, UGT1A1*6 and UGT1A1*27. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1*6, UGT1A1*27 and UGT1A1*28. Direct DNA sequencing was performed to validate the results of randomly selected samples. Results: Malays and Indian have two-fold higher frequency of homozygous of UGT1A1*28 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A1*6 and UGT1A1*27 showed no significant differences among them. UGT1A1*27 which has not been detected in Caucasian and African American population, was found in the Malaysian Malays (3.33%) and Malaysian Chinese (2.0%). Interpretation & conclusions: There was interethnic variability in the frequency of UGT1A1*28 in the Malaysian population. Our results suggest that genotyping of UGT1A1*6, UGT1A1*28 and UGT1A1*27 need to be performed before patients are prescribed with irinotecan due to their high prevalence of allelic variant which could lead to adverse drug reaction. PMID:22960892

  15. Localization of the oncogene c-erbA2 to human chromosome 3.

    PubMed

    Rider, S H; Gorman, P A; Shipley, J M; Moore, G; Vennstrom, B; Solomon, E; Sheer, D

    1987-05-01

    The human c-erbA1 gene has been previously mapped to chromosome 17. We have now mapped c-erbA2 to the short arm of chromosome 3, using a human genomic probe in Southern analysis of DNA from a panel of human/mouse somatic cell hybrids. In situ hybridization using the same probe on metaphase chromosomes has enabled fine chromosome mapping of c-erbA2 to the chromosome region 3p21-pter. PMID:3674756

  16. Raman microscope and quantum yield studies on the primary photochemistry of A2-visual pigments.

    PubMed Central

    Barry, B; Mathies, R A; Pardoen, J A; Lugtenburg, J

    1987-01-01

    The 77-K resonance Raman vibrational spectrum of intact goldfish rod photoreceptors containing 3,4-dehydro (A2) retinal is dominated by scattering from the 9-cis component of the steady state at all excitation wavelengths. Intact goldfish photoreceptors were regenerated with an A1-retinal chromophore to determine whether this behavior is caused by the protein or the chromophore. The resulting Raman spectrum was typical of an A1-pigment exhibiting significant scattering from all three components of the steady state: rhodopsin, bathorhodopsin, and isorhodopsin. Furthermore, regeneration of bovine opsin with A2-retinal produces a characteristic "A2-Raman spectrum" that is dominated by scattering from the 9-cis pigment. We conclude that the differences between the Raman spectra of the A1-and A2-pigments are caused by some intrinsic difference in the photochemical properties of the retinal chromophores. To quantitate these observations, the 77-K adsorption spectra and the photochemical quantum yields (phi) of the native A2-goldfish and the regenerated A2-bovine pigments were measured. In the goldfish A2-pigment, the value of phi 4 (9-cis----trans) is 0.05; phi 3 (trans----9-cis) is 0.10; and phi 2 (trans----11-cis) is 0.35. By contrast, in the bovine A1-pigment, these quantum yields are 0.10, 0.053, and 0.50, respectively. The reduced value of phi 4 and the increased value of phi 3 in the goldfish pigment confirms that the 9-cis isomer is photochemically more stable in A2-pigments. PMID:3676440

  17. Cloning and expression of Che a 1, the major allergen of Chenopodium album in Escherichia coli.

    PubMed

    Vahedi, Fatemeh; Sankian, Mojtaba; Moghadam, Malihe; Mohaddesfar, Maryam; Ghobadi, Sirous; Varasteh, Abdol Reza

    2011-04-01

    Chenopodium album is a weedy annual plant in the genus Chenopodium. C. album pollen represents a predominant allergen source in Iran. The main C. album pollen allergens have been described as Che a 1, Che a 2, and Che a 3. The aim of this work was to clone the Che a 1 in Escherichia coli to establish a system for overproduction of the recombinant Che a 1 (rChe a 1). In order to clone this allergen, the pollens were subjected to RNA extraction. A full-length fragment encoding Che a 1 was prepared by polymerase chain reaction amplification of the first-strand cDNA synthesized from extracted RNA. Cloning was carried out by inserting the cDNA into the pET21b+ vector, thereafter the construct was transformed into E. coli Top10 cells and expression of the protein was induced by IPTG. The rChe a 1 was purified using histidine tag in recombinant protein by means of Ni-NTA affinity chromatography. IgE immunoblotting, ELISA, and inhibition ELISA were done to evaluate IgE binding of the purified protein. In conclusion, the cDNA for the major allergen of the C. album pollen, Che a 1, was successfully cloned and rChe a 1 was purified. Inhibition assays demonstrated allergic subjects sera reacted with rChe a 1 similar to natural Che a 1 in crude extract of C. album pollen. This study is the first report of using the E. coli as a prokaryotic system for Che a 1 cloning and production of rChe a 1. PMID:20872185

  18. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Amount allocated. 1.666(a)-1 Section 1.666(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED... Beginning Before January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign...

  19. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Amount allocated. 1.666(a)-1 Section 1.666(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED... Beginning Before January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign...

  20. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Amount allocated. 1.666(a)-1 Section 1.666(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED... January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign trust created by a...

  1. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Amount allocated. 1.666(a)-1 Section 1.666(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED... Beginning Before January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign...

  2. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Amount allocated. 1.666(a)-1 Section 1.666(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED... Beginning Before January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign...

  3. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 9 2012-07-01 2012-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  4. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  5. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  6. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  7. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  8. Ligand Targeting of EphA2 Enhances Keratinocyte Adhesion and Differentiation via Desmoglein 1

    PubMed Central

    Lin, Samantha; Gordon, Kristin; Kaplan, Nihal

    2010-01-01

    EphA2 is a receptor tyrosine kinase that is engaged and activated by membrane-linked ephrin-A ligands residing on adjacent cell surfaces. Ligand targeting of EphA2 has been implicated in epithelial growth regulation by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2)-mitogen activated protein kinase (MAPK) pathway. Although contact-dependent EphA2 activation was required for dampening Erk1/2-MAPK signaling after a calcium switch in primary human epidermal keratinocytes, the loss of this receptor did not prevent exit from the cell cycle. Incubating keratinocytes with a soluble ephrin-A1-Fc peptide mimetic to target EphA2 further increased receptor activation leading to its down-regulation. Moreover, soluble ligand targeting of EphA2 restricted the lateral expansion of epidermal cell colonies without limiting proliferation in these primary cultures. Rather, ephrin-A1-Fc peptide treatment promoted epidermal cell colony compaction and stratification in a manner that was associated with increased keratinocyte differentiation. The ligand-dependent increase in keratinocyte adhesion and differentiation relied largely upon the up-regulation of desmoglein 1, a desmosomal cadherin that maintains the integrity and differentiated state of suprabasal keratinocytes in the epidermis. These data suggest that keratinocytes expressing EphA2 in the basal layer may respond to ephrin-A1–based cues from their neighbors to facilitate entry into a terminal differentiation pathway. PMID:20861311

  9. Striatal Pre- and Postsynaptic Profile of Adenosine A2A Receptor Antagonists

    PubMed Central

    Quiroz, César; Beaumont, Vahri; Goldberg, Steven R.; Lluís, Carme; Cortés, Antoni; Franco, Rafael; Casadó, Vicent; Canela, Enric I.; Ferré, Sergi

    2011-01-01

    Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential

  10. Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.

    PubMed

    Rombo, Diogo M; Newton, Kathryn; Nissen, Wiebke; Badurek, Sylvia; Horn, Jacqueline M; Minichiello, Liliana; Jefferys, John G R; Sebastiao, Ana M; Lamsa, Karri P

    2015-05-01

    Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2A R activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2A R's facilitatory effect on cortical network activity. PMID:25402014

  11. Amino acid sequence requirements in the hinge of human immunoglobulin A1 (IgA1) for cleavage by streptococcal IgA1 proteases.

    PubMed

    Batten, Margaret R; Senior, Bernard W; Kilian, Mogens; Woof, Jenny M

    2003-03-01

    The amino acid sequence requirements in the hinge of human immunoglobulin A1 (IgA1) for cleavage by IgA1 proteases of different species of Streptococcus were investigated. Recombinant IgA1 antibodies were generated with point mutations at proline 227 and threonine 228, the residues lying on either side of the peptide bond at which all streptococcal IgA1 proteases cleave wild-type human IgA1. The amino acid substitutions produced no major effect upon the structure of the mutant IgA1 antibodies or their functional ability to bind to Fcalpha receptors. However, the substitutions had a substantial effect upon sensitivity to cleavage with some streptococcal IgA1 proteases, with, in some cases, a single point mutation rendering the antibody resistant to a particular IgA1 protease. This effect was least marked with the IgA1 protease from Streptococcus pneumoniae, which showed no absolute requirement for either proline or threonine at residues 227 to 228. By contrast, the IgA1 proteases of Streptococcus oralis, Streptococcus sanguis, and Streptococcus mitis had an absolute requirement for proline at 227 but not for threonine at 228, which could be replaced by valine. There was evidence in S. mitis that proteases from different strains may have different amino acid requirements for cleavage. Remarkably, some streptococcal proteases appeared able to cleave the hinge at a distant alternative site if substitution prevented efficient cleavage of the original site. Hence, this study has identified key residues required for the recognition of the IgA1 hinge as a substrate by streptococcal IgA1 proteases, and it marks a preliminary step towards development of specific enzyme inhibitors. PMID:12595464

  12. Diagnostics for a 1.2 kA, 1 MeV, electron induction injector

    NASA Astrophysics Data System (ADS)

    Houck, T. L.; Anderson, D. E.; Eylon, S.; Henestroza, E.; Lidia, S. M.; Vanecek, D. L.; Westenskow, G. A.; Yu, S. S.

    1998-12-01

    We are constructing a 1.2 kA, 1 MeV, electron induction injector as part of the RTA program, a collaborative effort between LLNL and LBNL to develop relativistic klystrons for Two-Beam Accelerator applications. The RTA injector will also be used in the development of a high-gradient, low-emittance, electron source and beam diagnostics for the second axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT) Facility. The electron source will be a 3.5″-diameter, thermionic, flat-surface, m-type cathode with a maximum shroud field stress of approximately 165 kV/cm. Additional design parameters for the injector include a pulse length of over 150 ns flat top (1% energy variation), and a normalized edge emittance of less than 200 π-mm-mr. Precise measurement of the beam parameters is required so that performance of the RTA injector can be confidently scaled to the 4 kA, 3 MeV, and 2-microsecond pulse parameters of the DARHT injector. Planned diagnostics include an isolated cathode with resistive divider for direct measurement of current emission, resistive wall and magnetic probe current monitors for measuring beam current and centroid position, capacitive probes for measuring A-K gap voltage, an energy spectrometer, and a pepperpot emittance diagnostic. Details of the injector, beam line, and diagnostics are presented.

  13. Recent improvements in the development of A2B adenosine receptor agonists

    PubMed Central

    Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Romagnoli, Romeo; Preti, Delia

    2009-01-01

    Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary

  14. Recent improvements in the development of A2B adenosine receptor agonists

    PubMed Central

    Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Romagnoli, Romeo; Preti, Delia

    2008-01-01

    Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary

  15. History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents.

    PubMed

    Preti, Delia; Baraldi, Pier Giovanni; Moorman, Allan R; Borea, Pier Andrea; Varani, Katia

    2015-07-01

    Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD. PMID:25821194

  16. Phospholipase A2 as a mechanosensor.

    PubMed Central

    Lehtonen, J Y; Kinnunen, P K

    1995-01-01

    Osmotic swelling of large unilamellar vesicles (LUVs) causes membrane stretching and thus reduces the lateral packing of lipids. This is demonstrated to modulate strongly the catalytic activity of phospholipase A2 (PLA2) toward a fluorescent phospholipid, 1-palmitoyl-2-[(6-pyren-1-yl)]decanoyl-sn-glycero-3-phosphocholine (PPDPC) residing in LUVs composed of different unsaturated and saturated phosphatidylcholines. The magnitude of the osmotic pressure gradient delta omega required for maximal PLA2 activity as well as the extent of activation depend on the degree of saturation of the membrane phospholipid acyl chains. More specifically, delta omega needed for maximal hydrolytic activity increases in the sequence DOPC < SOPC < DMPC in accordance with the increment in the intensity of chain-chain van der Waals interactions. Previous studies on the hydrolysis of substrate monolayers by C. adamanteus and N. naja PLA2 revealed maximal hydrolytic rates for these two enzymes to be achieved at lipid packing densities corresponding to surface pressures of 12 and 18 mN m-1, respectively. In keeping with the above the magnitudes of delta omega producing maximal activity of Crotalus adamanteus and Naja naja toward PPDPC/DMPC LUVs were 40 and 20 mOsm/kg, respectively. Our findings suggest a novel possibility of regulating the activity of PLA2 and perhaps also other lipid packing density-dependent enzymes in vivo by osmotic forces applied on cellular membranes. Importantly, our results reveal serendipitously that the responsiveness of membranes to osmotic stress is modulated by the acyl chain composition of the lipids. PMID:7612831

  17. Improvement of Cold Tolerance by Selective A1 Adenosine Receptor Antagonists in Rats

    PubMed Central

    Lee, T. F.; Li, D. J.; Jacobson, K. A.; Wang, L. C. H.

    2015-01-01

    Previously we have shown that the improvement of cold tolerance by theophylline is due to antagonism at adenosine receptors rather than inhibition of phosphodiesterase. Since theophylline is a nonselective adenosine receptor antagonist for both A1 and A2 receptors, the present study investigated the adenosine receptor subtype involved in theophylline’s action. Acute systemic injection of selective A1 receptor antagonists (1,3-dialkyl-8-aryl or 1,3-dialkyl-8-cyclopentyl xanthine derivatives) significantly increased both the total and maximal heat production as well as cold tolerance. In contrast, injection of a relatively selective A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (compound No. 19), failed to significantly alter the thermogenic response of the rat under cold exposure. Further, the relative effectiveness of these compounds in increasing total thermogenesis was positively correlated with their potency in blocking the A1 adenosine receptor (r= .52, p<0.01), but not in A2 adenosine receptor (r= .20, p<0.2). It is likely that the thermally beneficial effects of adenosine A1 antagonists are due to their attenuation of the inhibitory effects of endogenously released adenosine on lipolysis and glucose utilization, resulting in increased substrate mobilization and utilization for enhanced thermogenesis. PMID:2263650

  18. Adenosine A2A receptor dynamics studied with the novel fluorescent agonist Alexa488-APEC

    PubMed Central

    Brand, Frank; Klutz, Athena; Jacobson, Kenneth A.; Fredholm, Bertil B.; Schulte, Gunnar

    2009-01-01

    G protein-coupled receptors, such as the adenosine A2A receptor, are dynamic proteins, which undergo agonist-dependent redistribution from the cell surface to intracellular membranous compartments, such as endosomes. In order to study the kinetics of adenosine A2A receptor redistribution in living cells, we synthesized a novel fluorescent agonist, Alexa488-APEC. Alexa488-APEC binds to adenosine A2A (Ki = 149 ± 27 nM) as well as A3 receptors (Ki= 240 ± 160 nM) but not to adenosine A1 receptors. Further, we characterized the dose-dependent increase in Alexa488-APEC-induced cAMP production as well as cAMP response element binding (CREB) protein phosphorylation, verifying the ligand’s functionality at adenosine A2A but not A2B receptors. In live cell imaging studies, Alexa488-APEC induced adenosine A2A receptor internalization, which was blocked by the competitive reversible antagonist ZM 241385 and hyperosmolaric sucrose. Further, internalized adenosine A2A receptors co-localized with clathrin and Rab5, indicating that agonist stimulation promotes adenosine A2A receptor uptake through a clathrin-dependent mechanism to Rab5-positive endosomes. The basic characterization of Alexa488-APEC provided here showed that it provides a usefultool for tracing adenosine A2A receptors in vitro. PMID:18603240

  19. Nucleus tractus solitarii A(2a) adenosine receptors inhibit cardiopulmonary chemoreflex control of sympathetic outputs.

    PubMed

    Minic, Zeljka; O'Leary, Donal S; Scislo, Tadeusz J

    2014-02-01

    Previously we have shown that stimulation of inhibitory A1 adenosine receptors located in the nucleus tractus solitarii (NTS) attenuates cardiopulmonary chemoreflex (CCR) evoked inhibition of renal, adrenal and lumbar sympathetic nerve activity and reflex decreases in arterial pressure and heart rate. Activation of facilitatory A2a adenosine receptors, which dominate over A1 receptors in the NTS, contrastingly alters baseline activity of regional sympathetic outputs: it decreases renal, increases adrenal and does not change lumbar nerve activity. Considering that NTS A2a receptors may facilitate release of inhibitory transmitters we hypothesized that A2a receptors will act in concert with A1 receptors differentially inhibiting regional sympathetic CCR responses (adrenal>lumbar>renal). In urethane/chloralose anesthetized rats (n=38) we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of serotonin 5HT3 receptor agonist, phenylbiguanide, (1-8μg/kg) before and after selective stimulation, blockade or combined blockade and stimulation of NTS A2a adenosine receptors (microinjections into the NTS of CGS-21680 0.2-20pmol/50nl, ZM-241385 40pmol/100nl or ZM-241385+CGS-21680, respectively). We found that stimulation of A2a adenosine receptors uniformly inhibited the regional sympathetic and hemodynamic reflex responses and this effect was abolished by the selective blockade of NTS A2a receptors. This indicates that A2a receptor triggered inhibition of CCR responses and the contrasting shifts in baseline sympathetic activity are mediated via different mechanisms. These data implicate that stimulation of NTS A2a receptors triggers unknown inhibitory mechanism(s) which in turn inhibit transmission in the CCR pathway when adenosine is released into the NTS during severe hypotension. PMID:24216055

  20. Crystallization and preliminary X-ray analysis of alginate lyases A1-II and A1-II′ from Sphingomonas sp. A1

    SciTech Connect

    Yamasaki, Masayuki; Ogura, Kohei; Moriwaki, Satoko; Hashimoto, Wataru; Murata, Kousaku; Mikami, Bunzo

    2005-03-01

    The crystallization and preliminary characterization of the family PL-7 alginate lyases A1-II and A1-II′ from Sphingomonas sp. A1 are presented. Alginate lyases depolymerize alginate, a heteropolysaccharide consisting of α-l-guluronate and β-d-mannuronate, through a β-elimination reaction. The alginate lyases A1-II (25 kDa) and A1-II′ (25 kDa) from Sphingomonas sp. A1, which belong to polysaccharide lyase family PL-7, exhibit 68% homology in primary structure but have different substrate specificities. To determine clearly the structural basis for substrate recognition in the depolymerization mechanism by alginate lyases, both proteins were crystallized at 293 K using the vapour-diffusion method. A crystal of A1-II belonged to space group P2{sub 1} and diffracted to 2.2 Å resolution, with unit-cell parameters a = 51.3, b = 30.1, c = 101.6 Å, β = 100.2°, while a crystal of A1-II′ belonged to space group P2{sub 1}2{sub 1}2{sub 1} and diffracted to 1.0 Å resolution, with unit-cell parameters a = 34.6, b = 68.5, c = 80.3 Å.