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Sample records for 1b 1d 1d1

  1. 75 FR 27411 - Airworthiness Directives; Turbomeca Arriel 1B, 1D, 1D1, and 1S1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    ... (that incorporate Turbomeca Modification (mod) TU 148), Arriel 1D, 1D1, and 1S1 turboshaft engines that do not incorporate mod TU 347. That AD also requires initial and repetitive replacements of 2nd stage... incorporate mod TU 148), 1D, 1D1, and 1S1 turboshaft engines that do not incorporate mod TU 347. We...

  2. The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin.

    PubMed

    de Rezende, Marcos Gonçalves; Garcia-Leal, Cybele; Graeff, Frederico Guilherme; Del-Ben, Cristina Marta

    2013-12-01

    This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test. The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo. The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance. Sumatriptan decreased plasma levels of prolactin. A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment. Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state. As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion.

  3. Interaction of environmental contaminants with zebrafish organic anion transporting polypeptide, Oatp1d1 (Slco1d1)

    SciTech Connect

    Popovic, Marta; Zaja, Roko; Fent, Karl; Smital, Tvrtko

    2014-10-01

    Polyspecific transporters from the organic anion transporting polypeptide (OATP/Oatp) superfamily mediate the uptake of a wide range of compounds. In zebrafish, Oatp1d1 transports conjugated steroid hormones and cortisol. It is predominantly expressed in the liver, brain and testes. In this study we have characterized the transport of xenobiotics by the zebrafish Oatp1d1 transporter. We developed a novel assay for assessing Oatp1d1 interactors using the fluorescent probe Lucifer yellow and transient transfection in HEK293 cells. Our data showed that numerous environmental contaminants interact with zebrafish Oatp1d1. Oatp1d1 mediated the transport of diclofenac with very high affinity, followed by high affinity towards perfluorooctanesulfonic acid (PFOS), nonylphenol, gemfibrozil and 17α-ethinylestradiol; moderate affinity towards carbaryl, diazinon and caffeine; and low affinity towards metolachlor. Importantly, many environmental chemicals acted as strong inhibitors of Oatp1d1. A strong inhibition of Oatp1d1 transport activity was found by perfluorooctanoic acid (PFOA), chlorpyrifos-methyl, estrone (E1) and 17β-estradiol (E2), followed by moderate to low inhibition by diethyl phthalate, bisphenol A, 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4 tetrahydronapthalene and clofibrate. In this study we identified Oatp1d1 as a first Solute Carrier (SLC) transporter involved in the transport of a wide range of xenobiotics in fish. Considering that Oatps in zebrafish have not been characterized before, our work on zebrafish Oatp1d1 offers important new insights on the understanding of uptake processes of environmental contaminants, and contributes to the better characterization of zebrafish as a model species. - Highlights: • We optimized a novel assay for determination of Oatp1d1 interactors • Oatp1d1 is the first SLC characterized fish xenobiotic transporter • PFOS, nonylphenol, diclofenac, EE2, caffeine are high affinity Oatp1d1substrates • PFOA, chlorpyrifos

  4. The organic anion transport polypeptide 1d1 (Oatp1d1) mediates hepatocellular uptake of phalloidin and microcystin into skate liver

    SciTech Connect

    Meier-Abt, F.; Hammann-Haenni, A.; Stieger, B.; Ballatori, N.; Boyer, J.L. . E-mail: james.boyer@yale.edu

    2007-02-01

    Organic anion transporting polypeptides (rodent Oatp; human OATP) mediate cellular uptake of numerous organic compounds including xenobiotic toxins into mammalian hepatocytes. In the little skate Leucoraja erinacea a liver-specific Oatp (Oatp1d1, also called sOatp) has been identified and suggested to represent an evolutionarily ancient precursor of the mammalian liver OATP1B1 (human), Oatp1b2 (rat), and OATP1B3 (human). The present study tested whether Oatp1d1 shares functional transport activity of the xenobiotic oligopeptide toxins phalloidin and microcystin with the mammalian liver Oatps/OATPs. The phalloidin analogue [{sup 3}H]-demethylphalloin was taken up into skate hepatocytes with high affinity (Km {approx} 0.4 {mu}M), and uptake could be inhibited by phalloidin and a variety of typical Oatp/OATP substrates such as bromosulfophthalein, bile salts, estrone-3-sulfate, cyclosporine A and high concentrations of microcystin-LR (Ki {approx} 150 {mu}M). When expressed in Xenopus laevis oocytes Oatp1d1 increased uptake of demethylphalloin (Km {approx} 2.2 {mu}M) and microcystin-LR (Km {approx} 27 {mu}M) 2- to 3-fold over water-injected oocytes, whereas the alternative skate liver organic anion transporter, the dimeric Ost{alpha}/{beta}, exhibited no phalloidin and only minor microcystin-LR transport. Also, the closest mammalian Oatp1d1 orthologue, the human brain and testis OATP1C1, did not show any phalloidin transport activity. These results demonstrate that the evolutionarily ancient Oatp1d1 is able to mediate uptake of cyclic oligopeptide toxins into skate liver. The findings support the notion that Oatp1d1 is a precursor of the liver-specific mammalian Oatps/OATPs and that its transport properties are closely associated with certain forms of toxic liver injury such as for example protein phosphatase inhibition by the water-borne toxin microcystin.

  5. 1D-1D Coulomb drag in a 6 Million Mobility Bi-layer Heterostructure

    NASA Astrophysics Data System (ADS)

    Bilodeau, Simon; Laroche, Dominique; Xia, Jian-Sheng; Lilly, Mike; Reno, John; Pfeiffer, Loren; West, Ken; Gervais, Guillaume

    We report Coulomb drag measurements in vertically-coupled quantum wires. The wires are fabricated in GaAs/AlGaAs bilayer heterostructures grown from two different MBE chambers: one at Sandia National Laboratories (1.2M mobility), and the other at Princeton University (6M mobility). The previously observed positive and negative drag signals are seen in both types of devices, demonstrating the robustness of the result. However, attempts to determine the temperature dependence of the drag signal in the 1D regime proved challenging in the higher mobility heterostructure (Princeton), in part because of difficulties in aligning the wires within the same transverse subband configuration. Nevertheless, this work, performed at the Microkelvin laboratory of the University of Florida, is an important proof-of-concept for future investigations of the temperature dependence of the 1D-1D drag signal down to a few mK. Such an experiment could confirm the Luttinger charge density wave interlocking predicted to occur in the wires. Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under Contract DE-AC04-94AL8500.

  6. Structure and Catalytic Mechanism of Human Steroid 5-Reductase (AKR1D1)

    SciTech Connect

    Costanzo, L.; Drury, J; Christianson, D; Penning, T

    2009-01-01

    Human steroid 5{beta}-reductase (aldo-keto reductase (AKR) 1D1) catalyzes reduction of {Delta}{sup 4}-ene double bonds in steroid hormones and bile acid precursors. We have reported the structures of an AKR1D1-NADP{sup +} binary complex, and AKR1D1-NADP{sup +}-cortisone, AKR1D1-NADP{sup +}-progesterone and AKR1D1-NADP{sup +}-testosterone ternary complexes at high resolutions. Recently, structures of AKR1D1-NADP{sup +}-5{beta}-dihydroprogesterone complexes showed that the product is bound unproductively. Two quite different mechanisms of steroid double bond reduction have since been proposed. However, site-directed mutagenesis supports only one mechanism. In this mechanism, the 4-pro-R hydride is transferred from the re-face of the nicotinamide ring to C5 of the steroid substrate. E120, a unique substitution in the AKR catalytic tetrad, permits a deeper penetration of the steroid substrate into the active site to promote optimal reactant positioning. It participates with Y58 to create a 'superacidic' oxyanion hole for polarization of the C3 ketone. A role for K87 in the proton relay proposed using the AKR1D1-NADP{sup +}-5{beta}-dihydroprogesterone structure is not supported.

  7. Analysis of the rotational structure in the high-resolution infrared spectra of trans-hexatriene-1,1-d2 and -cis-1-d1

    NASA Astrophysics Data System (ADS)

    Craig, Norman C.; Fuson, Hannah A.; Tian, Hengfeng; Blake, Thomas A.

    2012-09-01

    Mixtures of trans-hexatriene-1,1-d2, -cis-1-d1, and -trans-1-d1 have been synthesized. Anharmonic frequencies and harmonic intensities were predicted with the B3LYP/cc-pVTZ model for the out-of-plane (a″) modes of the three isotopologues. Assignments are proposed for most of the a″ vibrational modes above 500 cm-1. Ground state (GS) rotational constants have been determined for the 1,1-d2 and cis-1-d1 species from the analysis of rotational structure of C-type bands in the high-resolution (0.0015 cm-1) infrared spectra in a mixture of the three isotopologues. The GS constants for the 1,1-d2 species are A0 = 0.8018850(6), B0 = 0.0418540(6), and C0 = 0.0397997(4) cm-1. The GS constants for the cis-1-d1 species are A0 = 0.809388(1), B0 = 0.043532(2), and C0 = 0.041320(1) cm-1. Small inertial defects confirm planarity for both species. These ground state rotational constants are intended for use in determining a semiexperimental equilibrium structure and evaluating the influence of chain length on π-electron delocalization in polyenes.

  8. Calibration of a 1D/1D urban flood model using 1D/2D model results in the absence of field data.

    PubMed

    Leandro, J; Djordjević, S; Chen, A S; Savić, D A; Stanić, M

    2011-01-01

    Recently increased flood events have been prompting researchers to improve existing coupled flood-models such as one-dimensional (1D)/1D and 1D/two-dimensional (2D) models. While 1D/1D models simulate sewer and surface networks using a one-dimensional approach, 1D/2D models represent the surface network by a two-dimensional surface grid. However their application raises two issues to urban flood modellers: (1) stormwater systems planning/emergency or risk analysis demands for fast models, and the 1D/2D computational time is prohibitive, (2) and the recognized lack of field data (e.g. Hunter et al. (2008)) causes difficulties for the calibration/validation of 1D/1D models. In this paper we propose to overcome these issues by calibrating a 1D/1D model with the results of a 1D/2D model. The flood-inundation results show that: (1) 1D/2D results can be used to calibrate faster 1D/1D models, (2) the 1D/1D model is able to map the 1D/2D flood maximum extent well, and the flooding limits satisfactorily in each time-step, (3) the 1D/1D model major differences are the instantaneous flow propagation and overestimation of the flood-depths within surface-ponds, (4) the agreement in the volume surcharged by both models is a necessary condition for the 1D surface-network validation and (5) the agreement of the manholes discharge shapes measures the fitness of the calibrated 1D surface-network.

  9. The autophagy machinery restrains iNKT cell activation through CD1D1 internalization.

    PubMed

    Keller, Christian W; Loi, Monica; Ewert, Svenja; Quast, Isaak; Theiler, Romina; Gannagé, Monique; Münz, Christian; De Libero, Gennaro; Freigang, Stefan; Lünemann, Jan D

    2017-03-15

    Invariant natural killer T (iNKT) cells are innate T cells with powerful immune regulatory functions that recognize glycolipid antigens presented by the CD1D protein. While iNKT-cell-activating glycolipids are currently being explored for their efficacy to improve immunotherapy against infectious diseases and cancer, little is known about the mechanisms that control CD1D antigen presentation and iNKT cell activation in vivo. CD1D molecules survey endocytic pathways to bind lipid antigens in MHC class II containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4(+) T cell immunity. Here, we report that mice with dendritic cell (DC)-specific deletion of the essential autophagy gene Atg5 showed better CD1D1-restricted glycolipid presentation in vivo. These effects led to enhanced iNKT cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake or costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1D1 molecules via the adaptor protein complex 2 (AP2) and, thus, increased surface expression of stimulatory CD1D1-glycolipid complexes. These findings indicate that the autophagic machinery assists in the recruitment of AP2 to CD1D1 molecules resulting in attenuated iNKT cell activation, in contrast to the supporting role of macroautophagy in CD4(+) T cell stimulation.

  10. Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking.

    PubMed

    Zhou, Zhou; Menzel, Franziska; Benninghoff, Tim; Chadt, Alexandra; Du, Chen; Holman, Geoffrey D; Al-Hasani, Hadi

    2017-01-01

    The Rab-GTPase-activating proteins (GAPs) TBC1D1 and TBC1D4 play important roles in the insulin-stimulated translocation of the glucose transporter GLUT4 from intracellular vesicles to the plasma membrane in muscle cells and adipocytes. We identified Rab28 as a substrate for the GAP domains of both TBC1D1 and TBC1D4 in vitro. Rab28 is expressed in adipose cells and skeletal muscle, and its GTP-binding state is acutely regulated by insulin. We found that in intact isolated mouse skeletal muscle, siRNA-mediated knockdown of Rab28 decreases basal glucose uptake. Conversely, in primary rat adipose cells, overexpression of Rab28-Q72L, a constitutively active mutant, increases basal cell surface levels of an epitope-tagged HA-GLUT4. Our results indicate that Rab28 is a novel GTPase involved in the intracellular retention of GLUT4 in insulin target cells.

  11. Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice

    PubMed Central

    Hargett, Stefan R.; Walker, Natalie N.; Hussain, Syed S.; Hoehn, Kyle L.

    2015-01-01

    Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling. PMID:26015432

  12. 75 FR 11072 - Airworthiness Directives; Turbomeca Arriel 1B, 1D, 1D1, and 1S1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-10

    ... initial and repetitive relative position checks of the gas generator 2nd stage turbine blades on Turbomeca... blades since we issued AD 2008-07-01. We are proposing this AD to prevent the failure of 2nd stage turbine blades, which could result in an uncommanded in-flight engine ] shutdown, and a subsequent...

  13. Analysis of Rotational Structure in the High-Resolution Infrared Spectra of the TRANS-HEXATRIENE-1,1-D2 and -CIS-1-D1 Species

    NASA Astrophysics Data System (ADS)

    Craig, Norman C.; Fuson, Hannah A.; Tian, Hengfeng; Blake, Thomas A.

    2011-06-01

    Hexatriene-1,1-D2 with some admixture of the cis-1-D1 and trans-1-D1 species was synthesized by reaction of 2,4-pentadienal and (methyl-D3)-triphenylphosphonium iodide (Wittig reagent). The trans isomer was isolated by preparative gas chromatography, and the high-resolution (0.0015 Cm-1) infrared spectrum was recorded on a Bruker IFS 125HR instrument. The rotational structure in two C-type bands for the 1,1-D2 species was analyzed. For this species the bands at 902.043 and 721.864 Cm-1 yielded composite ground state rotational constants of A0 = 0.801882(1), B0 = 0.041850(2), and C0 = 0.039804(1) Cm-1. For the cis-1-D1 species the C-type band at 803.018 Cm-1 gave A0 = 0.809384(2), B0 = 0.043530(3), and C0 = 0.041321(2) Cm-1. By iodine-catalyzed isomerization, we have obtained some of the much less favored cis isomer and hope to obtain microwave spectra for its three deuterium-substituted species. The rotational constants reported here contribute to data needed for determining a semi-experimental structure for trans-hexatriene, which should show that the structural consequences of pi-electron delocalization increase with the chain length of polyenes.

  14. SCCRO3 (DCUN1D3) Antagonizes the Neddylation and Oncogenic Activity of SCCRO (DCUN1D1)*

    PubMed Central

    Huang, Guochang; Stock, Cameron; Bommeljé, Claire C.; Weeda, Víola B.; Shah, Kushyup; Bains, Sarina; Buss, Elizabeth; Shaha, Manish; Rechler, Willi; Ramanathan, Suresh Y.; Singh, Bhuvanesh

    2014-01-01

    The activity of cullin-RING type ubiquitination E3 ligases is regulated by neddylation, a process analogous to ubiquitination that culminates in covalent attachment of the ubiquitin-like protein Nedd8 to cullins. As a component of the E3 for neddylation, SCCRO/DCUN1D1 plays a key regulatory role in neddylation and, consequently, cullin-RING ligase activity. The essential contribution of SCCRO to neddylation is to promote nuclear translocation of the cullin-ROC1 complex. The presence of a myristoyl sequence in SCCRO3, one of four SCCRO paralogues present in humans that localizes to the membrane, raises questions about its function in neddylation. We found that although SCCRO3 binds to CAND1, cullins, and ROC1, it does not efficiently bind to Ubc12, promote cullin neddylation, or conform to the reaction processivity paradigms, suggesting that SCCRO3 does not have E3 activity. Expression of SCCRO3 inhibits SCCRO-promoted neddylation by sequestering cullins to the membrane, thereby blocking its nuclear translocation. Moreover, SCCRO3 inhibits SCCRO transforming activity. The inhibitory effects of SCCRO3 on SCCRO-promoted neddylation and transformation require both an intact myristoyl sequence and PONY domain, confirming that membrane localization and binding to cullins are required for in vivo functions. Taken together, our findings suggest that SCCRO3 functions as a tumor suppressor by antagonizing the neddylation activity of SCCRO. PMID:25349211

  15. Detection of SNPs in the TBC1D1 gene and their association with carcass traits in chicken.

    PubMed

    Wang, Yan; Xu, Heng-Yong; Gilbert, Elizabeth R; Peng, Xing; Zhao, Xiao-Ling; Liu, Yi-Ping; Zhu, Qing

    2014-09-01

    TBC1D1 plays an important role in numerous fundamental physiological processes including muscle metabolism, regulation of whole body energy homeostasis and lipid metabolism. The objective of the present study was to identify single nucleotide polymorphisms (SNPs) in chicken TBC1D1 using 128 Erlang mountainous chickens and to determine if these SNPs are associated with carcass traits. The approach consisted of sequencing TBC1D1 using a panel of DNA from different individuals, revealing twenty-two SNPs. Among these SNPs, two polymorphisms (g.69307744C>T and g.69307608T>G) of block 1, four polymorphisms (g.69322320C>T, g.69322314G>A, g.69317290A>G and g.69317276T>C) of block 2 and four polymorphisms of block 3 (g.69349746G>A, g.69349736C>G, g.69349727C>T and g.69349694C>T) exhibited a high degree of linkage disequilibrium in all test populations. An association analysis was performed between the twenty-two SNPs and seven performance traits. SNPs g.69307744C>T, g.69340192G>A and g.69355665T>C were demonstrated to have a strong effect on liveweight (BW), carcass weight (CW), semi-eviscerated weight (SEW) and eviscerated weight (EW) and g.69340070C>T polymorphism was related to BW, SEW and BMW in chicken populations. However, for the other SNPs, there were no significant correlations between different genotypes and carcass traits. Meanwhile, haplotype CT-TG of block 1 and combined genotype AG-TT-AC-CT of block 3 were significantly associated with BW, CW, SEW and EW. Overall, our results provide evidence that polymorphisms in TBC1D1 are associated with carcass traits and would be a useful candidate gene in selection programs for improving carcass traits.

  16. 5β-Reduced steroids and human Δ(4)-3-ketosteroid 5β-reductase (AKR1D1).

    PubMed

    Chen, Mo; Penning, Trevor M

    2014-05-01

    5β-Reduced steroids are non-planar steroids that have a 90° bend in their structure to create an A/B cis-ring junction. This novel property is required for bile-acids to act as emulsifiers, but in addition 5β-reduced steroids have remarkable physiology and may act as potent tocolytic agents, endogenous cardiac glycosides, neurosteroids, and can act as ligands for orphan and membrane bound receptors. In humans there is only a single 5β-reductase gene AKR1D1, which encodes Δ(4)-3-ketosteroid-5β-reductase (AKR1D1). This enzyme is a member of the aldo-keto reductase superfamily, but possesses an altered catalytic tetrad, in which Glu120 replaces the conserved His residue. This predominant liver enzyme generates all 5β-dihydrosteroids in the C19-C27 steroid series. Mutations exist in the AKR1D1 gene, which result in loss of protein stability and are causative in bile-acid deficiency.

  17. Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders

    PubMed Central

    Goto, Masahide; Mizuno, Makoto; Matsumoto, Ayumi; Yang, Zhiliang; Jimbo, Eriko F.; Tabata, Hidenori; Yamagata, Takanori; Nagata, Koh-ichi

    2017-01-01

    In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous one c.1499 G > A (p.R500H). We then analyzed the role of Nr1d1 in the development of the cerebral cortex in mice. Acute knockdown of mouse Nr1d1 with in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis. This aberrant phenotype was rescued by wild type Nr1d1, but not by the c.1499 G > A mutant. Time-lapse imaging revealed characteristic abnormal migration phenotypes in Nr1d1-deficient cortical neurons. When Nr1d1 was knocked down, axon extension and dendritic arbor formation of cortical neurons were also suppressed while proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected. Taken together, Nr1d1 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation. These results suggest that functional defects in NR1D1 may be related to ASD etiology and pathophysiology. PMID:28262759

  18. 75 FR 16664 - Airworthiness Directives; Turbomeca ARRIEL 1B, 1D, 1D1, 2B, and 2B1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-02

    ... Mandatory Service Bulletin (MSB) A292 72 0827 for Arriel 1 engines and A292 72 2833 for Arriel 2 engines... referenced Turbom ca MSB. --Additional testing and analysis had been carried out by Turbom ca which allows... installed, as listed by serial number (S/N) in Figure 1 of Turbomeca Alert Mandatory Service Bulletin...

  19. Nuclear receptor Rev-erb alpha (Nr1d1) functions in concert with Nr2e3 to regulate transcriptional networks in the retina.

    PubMed

    Mollema, Nissa J; Yuan, Yang; Jelcick, Austin S; Sachs, Andrew J; von Alpen, Désirée; Schorderet, Daniel; Escher, Pascal; Haider, Neena B

    2011-03-08

    The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene Rev-erb alpha/Nr1d1 has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of Rev-erb alpha/Nr1d1 in the retina, we evaluated the effects of loss of Nr1d1 to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene Nr2e3 in the developing and mature retina. Knock-down of Nr1d1 expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include: Nr2c1, Recoverin, Rgr, Rarres2, Pde8a, and Nupr1. We examined the cyclic expression of Nr1d1 and Nr2e3 over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for Nr1d1, in conjunction with its cofactor Nr2e3, in regulating transcriptional networks critical for photoreceptor development and function.

  20. The circadian clock regulates autophagy directly through the nuclear hormone receptor Nr1d1/Rev-erbα and indirectly via Cebpb/(C/ebpβ) in zebrafish

    PubMed Central

    Huang, Guodong; Zhang, Fanmiao; Ye, Qiang; Wang, Han

    2016-01-01

    ABSTRACT Autophagy is a highly conserved intracellular degradation system, and recently was shown to display circadian rhythms in mice. The mechanisms underlying circadian regulation of autophagy, however, are still unclear. Here, we observed that numbers of autophagosomes and autolysosomes exhibit daily rhythms in the zebrafish liver, and cebpb/(c/ebpβ) and various autophagy genes are rhythmically expressed in zebrafish larvae but significantly upregulated in per1b and TALEN-generated nr1d1/rev-erbα mutant fish, indicating that both Per1b and Nr1d1 play critical roles in autophagy rhythms. Luciferase reporter and ChIP assays show that the circadian clock directly regulates autophagy genes through Nr1d1, and also regulates transcription of cebpb through Per1b. We also found that fasting leads to altered expression of both circadian clock genes and autophagy genes in zebrafish adult peripheral organs. Further, transcriptome analysis reveals multiple functions of Nr1d1 in zebrafish. Taken together, these findings provide evidence for how the circadian clock regulates autophagy, imply that nutritional signaling affects both circadian regulation and autophagy activities in peripheral organs, and shed light on how circadian gene mutations act through autophagy to contribute to common metabolic diseases such as obesity. PMID:27171500

  1. Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise

    PubMed Central

    Vendelbo, M. H.; Møller, A. B.; Treebak, J. T.; Gormsen, L. C.; Goodyear, L. J.; Wojtaszewski, J. F. P.; Jørgensen, J. O. L.; Møller, N.

    2014-01-01

    Background: phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. Objective: to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. Design: eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. Results: phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser341 and Ser704 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr642 and Ser588 on AS160 or Ser237 and Thr596 on TBC1D1. Conclusions: AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr642 and Ser588. Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle. PMID:24876356

  2. Morphodynamics and sediment tracers in 1-D (MAST-1D): 1-D sediment transport that includes exchange with an off-channel sediment reservoir

    NASA Astrophysics Data System (ADS)

    Lauer, J. Wesley; Viparelli, Enrica; Piégay, Hervé

    2016-07-01

    Bed material transported in geomorphically active gravel bed rivers often has a local source at nearby eroding banks and ends up sequestered in bars not far downstream. However, most 1-D numerical models for gravel transport assume that gravel originates from and deposits on the channel bed. In this paper, we present a 1-D framework for simulating morphodynamic evolution of bed elevation and size distribution in a gravel-bed river that actively exchanges sediment with its floodplain, which is represented as an off-channel sediment reservoir. The model is based on the idea that sediment enters the channel at eroding banks whose elevation depends on total floodplain sediment storage and on the average elevation of the floodplain relative to the channel bed. Lateral erosion of these banks occurs at a specified rate that can represent either net channel migration or channel widening. Transfer of material out of the channel depends on a typical bar thickness and a specified lateral exchange rate due either to net channel migration or narrowing. The model is implemented using an object oriented framework that allows users to explore relationships between bank supply, bed structure, and lateral change rates. It is applied to a ∼50-km reach of the Ain River, France, that experienced significant reduction in sediment supply due to dam construction during the 20th century. Results are strongly sensitive to lateral exchange rates, showing that in this reach, the supply of sand and gravel at eroding banks and the sequestration of gravel in point bars can have strong influence on overall reach-scale sediment budgets.

  3. MicroRNA-218 inhibits EMT, migration and invasion by targeting SFMBT1 and DCUN1D1 in cervical cancer.

    PubMed

    Jiang, Zhaojing; Song, Qiancheng; Zeng, Rong; Li, Jing; Li, Jingyu; Lin, Xiaochun; Chen, Xing; Zhang, Jiren; Zheng, Yanfang

    2016-07-19

    Repeated infection with high-risk HPV is a major cause for the development and metastasis of human cervical cancer, even though the mechanism of the metastasis is still not completely understood. Here, we reported that miR-218 (microRNA-218) was downregulated in cervical cancer tissues, especially in metastatic cancer tissues. We found that miR-218 expression was associated with clinicopathological characteristics of patients with cervical cancer. MiR-218 overexpression inhibited Epithelial-Mesenchymal Transition (EMT), migration and invasiveness of cervical cancer cells in vitro. Moreover, miR-218 repressed the expression of SFMFBT1 (Scm-like with four MBT domains 1) and DCUN1D1 (defective in cullin neddylation 1, domain containing 1) by direct binding to the 3'UTRs of the mRNAs. The overexpression of SFMBT1 induced EMT and increased the migration and invasiveness of cervical cancer cells, while the overexpression of DCUN1D1 increased the migration and invasiveness of these cells, but did not induce EMT. An inverse correlation was observed between the expression of miR-218 and DCUN1D1 protein in cervical cancer tissues. Importantly, HPV16 E6 downregulated the expression of miR-218 in cervical cancer, while miR-218 rescued the promotion effect of HPV16 E6 on the expression of SFMBT1 and DCUN1D1. Taken together, our results revealed that HPV16 E6 promoted EMT and invasion in cervical cancer via the repression of miR-218, while miR-218 inhibited EMT and invasion in cervical cancer by targeting SFMBT1 and DCUN1D1.

  4. MicroRNA-218 inhibits EMT, migration and invasion by targeting SFMBT1 and DCUN1D1 in cervical cancer

    PubMed Central

    Li, Jing; Li, Jingyu; Lin, Xiaochun; Chen, Xing; Zhang, Jiren; Zheng, Yanfang

    2016-01-01

    Repeated infection with high-risk HPV is a major cause for the development and metastasis of human cervical cancer, even though the mechanism of the metastasis is still not completely understood. Here, we reported that miR-218 (microRNA-218) was downregulated in cervical cancer tissues, especially in metastatic cancer tissues. We found that miR-218 expression was associated with clinicopathological characteristics of patients with cervical cancer. MiR-218 overexpression inhibited Epithelial-Mesenchymal Transition (EMT), migration and invasiveness of cervical cancer cells in vitro. Moreover, miR-218 repressed the expression of SFMFBT1 (Scm-like with four MBT domains 1) and DCUN1D1 (defective in cullin neddylation 1, domain containing 1) by direct binding to the 3′UTRs of the mRNAs. The overexpression of SFMBT1 induced EMT and increased the migration and invasiveness of cervical cancer cells, while the overexpression of DCUN1D1 increased the migration and invasiveness of these cells, but did not induce EMT. An inverse correlation was observed between the expression of miR-218 and DCUN1D1 protein in cervical cancer tissues. Importantly, HPV16 E6 downregulated the expression of miR-218 in cervical cancer, while miR-218 rescued the promotion effect of HPV16 E6 on the expression of SFMBT1 and DCUN1D1. Taken together, our results revealed that HPV16 E6 promoted EMT and invasion in cervical cancer via the repression of miR-218, while miR-218 inhibited EMT and invasion in cervical cancer by targeting SFMBT1 and DCUN1D1. PMID:27285984

  5. Engineered Solution-Liquid-Solid Growth of a "Treelike" 1D/1D TiO2 Nanotube-CdSe Nanowire Heterostructure: Photoelectrochemical Conversion of Broad Spectrum of Solar Energy.

    PubMed

    Mukherjee, Bratindranath; Sarker, Swagotom; Crone, Eric; Pathak, Pawan; Subramanian, Vaidyanathan R

    2016-12-07

    This work presents a hitherto unreported approach to assemble a 1D oxide-1D chalcogenide heterostructured photoactive film. As a representative system, bismuth (Bi) catalyzed 1D CdSe nanowires are directly grown on anodized 1D TiO2 nanotube (T_NT). A combination of the reductive successive-ionic-layer-adsorption-reaction (R-SILAR) and the solution-liquid-solid (S-L-S) approach is implemented to fabricate this heterostructured assembly, reported in this 1D/1D form for the first time. XRD, SEM, HRTEM, and elemental mapping are performed to systematically characterize the deposition of bismuth on T_NT and the growth of CdSe nanowires leading to the evolution of the 1D/1D heterostructure. The resulting "treelike" photoactive architecture demonstrates UV-visible light-driven electron-hole pair generation. The photoelectrochemical results highlight: (i) the formation of a stable n-n heterojunction between TiO2 nanotube and CdSe nanowire, (ii) an excellent correlation between the absorbance vis-à-vis light conversion efficiency (IPCE), and (iii) a photocurrent density of 3.84 mA/cm(2). This proof-of-concept features the viability of the approach for designing such complex 1D/1D oxide-chalcogenide heterostructures that can be of interest to photovoltaics, photocatalysis, environmental remediation, and sensing.

  6. Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease.

    PubMed

    Cruz, Nelly M; Yuan, Yang; Leehy, Barrett D; Baid, Rinku; Kompella, Uday; DeAngelis, Margaret M; Escher, Pascal; Haider, Neena B

    2014-01-01

    Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.

  7. Crystal Structure of Human Liver delta {4}-3-Ketosteroid 5 beta-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

    SciTech Connect

    Di Costanzo,L.; Drury, J.; Penning, T.; Christianson, D.

    2008-01-01

    AKR1D1 (steroid 5{beta}-reductase) reduces all 4-3-ketosteroids to form 5{beta}-dihydrosteroids, a first step in the clearance of steroid hormones and an essential step in the synthesis of all bile acids. The reduction of the carbon-carbon double bond in an a,{beta}-unsaturated ketone by 5{beta}-reductase is a unique reaction in steroid enzymology because hydride transfer from NADPH to the {beta}-face of a 4-3-ketosteroid yields a cis-A/B-ring configuration with an {approx}90 bend in steroid structure. Here, we report the first x-ray crystal structure of a mammalian steroid hormone carbon-carbon double bond reductase, human 4-3-ketosteroid 5{beta}-reductase (AKR1D1), and its complexes with intact substrates. We have determined the structures of AKR1D1 complexes with NADP+ at 1.79- and 1.35- Angstroms resolution (HEPES bound in the active site), NADP+ and cortisone at 1.90- Angstroms resolution, NADP+ and progesterone at 2.03- Angstroms resolution, and NADP+ and testosterone at 1.62- Angstroms resolution. Complexes with cortisone and progesterone reveal productive substrate binding orientations based on the proximity of each steroid carbon-carbon double bond to the re-face of the nicotinamide ring of NADP+. This orientation would permit 4-pro-(R)-hydride transfer from NADPH. Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr58 and Glu120. The Y58F and E120A mutants are devoid of activity, supporting a role for this dyad in the catalytic mechanism. Intriguingly, testosterone binds nonproductively, thereby rationalizing the substrate inhibition observed with this particular steroid. The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed.

  8. Crystal Structure of Human Liver [delta][superscript 4]-3-Ketosteroid 5[beta]-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

    SciTech Connect

    Di Costanzo, Luigi; Drury, Jason E.; Penning, Trevor M.; Christianson, David W.

    2008-07-15

    AKR1D1 (steroid 5{beta}-reductase) reduces all {Delta}{sup 4}-3-ketosteroids to form 5{beta}-dihydrosteroids, a first step in the clearance of steroid hormones and an essential step in the synthesis of all bile acids. The reduction of the carbon-carbon double bond in an {alpha}{beta}-unsaturated ketone by 5{beta}-reductase is a unique reaction in steroid enzymology because hydride transfer from NADPH to the {beta}-face of a {Delta}{sup 4}-3-ketosteroid yields a cis-A/B-ring configuration with an {approx}90{sup o} bend in steroid structure. Here, we report the first x-ray crystal structure of a mammalian steroid hormone carbon-carbon double bond reductase, human {Delta}{sup 4}-3-ketosteroid 5{beta}-reductase (AKR1D1), and its complexes with intact substrates. We have determined the structures of AKR1D1 complexes with NADP{sup +} at 1.79- and 1.35-{angstrom} resolution (HEPES bound in the active site), NADP{sup +} and cortisone at 1.90-{angstrom} resolution, NADP{sup +} and progesterone at 2.03-{angstrom} resolution, and NADP{sup +} and testosterone at 1.62-{angstrom} resolution. Complexes with cortisone and progesterone reveal productive substrate binding orientations based on the proximity of each steroid carbon-carbon double bond to the re-face of the nicotinamide ring of NADP{sup +}. This orientation would permit 4-pro-(R)-hydride transfer from NADPH. Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr{sup 58} and Glu{sup 120}. The Y58F and E120A mutants are devoid of activity, supporting a role for this dyad in the catalytic mechanism. Intriguingly, testosterone binds nonproductively, thereby rationalizing the substrate inhibition observed with this particular steroid. The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed.

  9. Leptin Reduces the Expression and Increases the Phosphorylation of the Negative Regulators of GLUT4 Traffic TBC1D1 and TBC1D4 in Muscle of ob/ob Mice

    PubMed Central

    Sáinz, Neira; Rodríguez, Amaia; Catalán, Victoria; Becerril, Sara; Ramírez, Beatriz; Lancha, Andoni; Burgos-Ramos, Emma; Gómez-Ambrosi, Javier; Frühbeck, Gema

    2012-01-01

    Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P = 0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4. PMID:22253718

  10. Methylation of Exons 1D, 1F, and 1H of the Glucocorticoid Receptor Gene Promoter and Exposure to Adversity in Pre-School Aged Children

    PubMed Central

    Tyrka, Audrey R.; Parade, Stephanie H.; Eslinger, Nicole M.; Marsit, Carmen J.; Lesseur, Corina; Armstrong, David A.; Philip, Noah S.; Josefson, Brittney; Seifer, Ronald

    2016-01-01

    Epigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR) which is a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n=74 with child welfare documentation of moderate-severe maltreatment in the past six months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1D, 1F, and 1H of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1D and 1F in the promoter of NR3C1. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the bio-behavioral effects of adverse exposures in young children. PMID:25997773

  11. Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects.

    PubMed

    Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Hoffmann, Hanne M; Fuentes, Silvia; Rosell-Vilar, Santi; Gasperini, Paola; Rodríguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carme; Ferré, Sergi; Ortiz, Jordi; Canela, Enric; McCormick, Peter J

    2014-03-05

    The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.

  12. 75 FR 2067 - Airworthiness Directives; Turbomeca S.A. Model Arriel 1B, 1D, and 1D1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-14

    ... incorporating Turbom ca modification TU 232. You may obtain further information by examining the MCAI in the AD... (P/N 0 292 70 779 0) with Pinions incorporating Turbom ca modification TU 232 in accordance...

  13. A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.

    PubMed

    Morgan, Neil V; Hartley, Jane L; Setchell, Kenneth D R; Simpson, Michael A; Brown, Rachel; Tee, Louise; Kirkham, Sian; Pasha, Shanaz; Trembath, Richard C; Maher, Eamonn R; Gissen, Paul; Kelly, Deirdre A

    2013-05-16

    Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.

  14. Spatially branched hierarchical ZnO nanorod-TiO2 nanotube array heterostructures for versatile photocatalytic and photoelectrocatalytic applications: towards intimate integration of 1D-1D hybrid nanostructures

    NASA Astrophysics Data System (ADS)

    Xiao, Fang-Xing; Hung, Sung-Fu; Tao, Hua Bing; Miao, Jianwei; Yang, Hong Bin; Liu, Bin

    2014-11-01

    Hierarchically ordered ZnO nanorods (NRs) decorated nanoporous-layer-covered TiO2 nanotube array (ZnO NRs/NP-TNTAs) nanocomposites have been prepared by an efficient, two-step anodization route combined with an electrochemical deposition strategy, by which monodispersed one-dimensional (1D) ZnO NRs were uniformly grown on the framework of NP-TNTAs. The crystal phases, morphologies, optical properties, photocatalytic as well as photoelectrocatalytic performances of the well-defined ZnO NRs/NP-TNTAs heterostructures were systematically explored to clarify the structure-property correlation. It was found that the ZnO NRs/NP-TNTAs heterostructure exhibits significantly enhanced photocatalytic and photoelectrocatalytic performances, along with favorable photostability toward degradation of organic pollutants under UV light irradiation, as compared to the single component counterparts. The remarkably enhanced photoactivity of ZnO NRs/NP-TNTAs heterostructure is ascribed to the intimate interfacial integration between ZnO NRs and NP-TNTAs substrate imparted by the unique spatially branched hierarchical structure, thereby contributing to the efficient transfer and separation of photogenerated electron-hole charge carriers. Moreover, the specific active species during the photocatalytic process was unambiguously determined and photocatalytic mechanism was tentatively presented. It is anticipated that our work could provide new insights for the construction of various hierarchical 1D-1D hybrid nanocomposites for extensive photocatalytic applications.Hierarchically ordered ZnO nanorods (NRs) decorated nanoporous-layer-covered TiO2 nanotube array (ZnO NRs/NP-TNTAs) nanocomposites have been prepared by an efficient, two-step anodization route combined with an electrochemical deposition strategy, by which monodispersed one-dimensional (1D) ZnO NRs were uniformly grown on the framework of NP-TNTAs. The crystal phases, morphologies, optical properties, photocatalytic as well as

  15. Conversion of Human Steroid 5[beta]-Reductase (AKR1D1) into 3[beta]-Hydroxysteroid Dehydrogenase by Single Point Mutation E120H: Example of Perfect Enzyme Engineering

    SciTech Connect

    Chen, Mo; Drury, Jason E.; Christianson, David W.; Penning, Trevor M.

    2012-10-10

    Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5{beta}-reduction of {Delta}{sup 4}-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His120 (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5{beta}-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5{alpha}-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3{beta}-HSD as opposed to a 3{alpha}-HSD. The catalytic efficiency achieved for 3{beta}-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5{beta}-dihydrotestosterone, and {Delta}{sup 4}-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the {Delta}{sup 4}-double bond and confers 3{beta}-HSD activity on the 5{beta}-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its {alpha}-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.

  16. Analysis of the rotational structure in the high-resolution infrared spectra of cis,cis- and trans,trans-1,4-difluorobutadiene-1-d1 and trans,trans-1,4-difluorobutadiene-1,4-d2

    SciTech Connect

    Craig, Norman C.; Chen, Yihui; Lu, Yuhua; Neese, Christopher F.; Nemchick, Deacon J.; Blake, Thomas A.

    2013-06-01

    Samples of cis,cis- and trans,trans-1,4-difluorobutadiene-1- d1 and of trans,trans-1,4-difluorobutadiene-1,4-d2 have been synthesized, and high-resolution (≤0.0018 cm-1) infrared spectra of these substances have been recorded in the gas phase. Analysis of the rotational structure, mostly in C-type bands, has yielded ground state rotational constants. For the two 1-d1 species more than one band has been analyzed. For the 1,4-d2 species only one band was available for analysis. However, good agreement between the experimental centrifugal distortion constants and those predicted with a B3LYP/cc-pVTZ model give strong support to the analysis of the very dense spectrum. The ground state rotational constants are a contribution to finding semiexperimental equilibrium structures of the two nonpolar isomers of 1,4- difluorobutadiene.

  17. Interaction of ApoA-IV with NR4A1 and NR1D1 Represses G6Pase and PEPCK Transcription: Nuclear Receptor-Mediated Downregulation of Hepatic Gluconeogenesis in Mice and a Human Hepatocyte Cell Line

    PubMed Central

    Li, Xiaoming; Xu, Min; Wang, Fei; Ji, Yong; DavidsoN, W. Sean; Li, Zongfang; Tso, Patrick

    2015-01-01

    We have previously shown that the nuclear receptor, NR1D1, is a cofactor in ApoA-IV-mediated downregulation of gluconeogenesis. Nuclear receptor, NR4A1, is involved in the transcriptional regulation of various genes involved in inflammation, apoptosis, and glucose metabolism. We investigated whether NR4A1 influences the effect of ApoA-IV on hepatic glucose metabolism. Our in situ proximity ligation assays and coimmunoprecipitation experiments indicated that ApoA-IV colocalized with NR4A1 in human liver (HepG2) and kidney (HEK-293) cell lines. The chromatin immunoprecipitation experiments and luciferase reporter assays indicated that the ApoA-IV and NR4A1 colocalized at the RORα response element of the human G6Pase promoter, reducing its transcriptional activity. Our RNA interference experiments showed that knocking down the expression of NR4A1 in primary mouse hepatocytes treated with ApoA-IV increased the expression of NR1D1, G6Pase, and PEPCK, and that knocking down NR1D1 expression increased the level of NR4A1. We also found that ApoA-IV induced the expression of endogenous NR4A1 in both cultured primary mouse hepatocytes and in the mouse liver, and decreased glucose production in primary mouse hepatocytes. Our findings showed that ApoA-IV colocalizes with NR4A1, which suppresses G6Pase and PEPCK gene expression at the transcriptional level, reducing hepatic glucose output and lowering blood glucose. The ApoA-IV-induced increase in NR4A1 expression in hepatocytes mediates further repression of gluconeogenesis. Our findings suggest that NR1D1 and NR4A1 serve similar or complementary functions in the ApoA-IV-mediated regulation of gluconeogenesis. PMID:26556724

  18. 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.

  19. α-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK

    PubMed Central

    Enriori, Pablo J.; Jensen, Thomas Elbenhardt; Garcia-Rudaz, Cecilia; Litwak, Sara A.; Raun, Kirsten; Wojtaszewski, Jørgen; Wulff, Birgitte Schjellerup; Cowley, Michael A.

    2016-01-01

    The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in α-MSH-stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate α-MSH stimulation in both wild type and AMPK deficient mice. We found that α-MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that α-MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation. PMID:27467141

  20. Analysis of the Rotational Structure in the High-Resolution Infrared Spectra of cis,cis- and trans,trans-1,4-DIFLUOROBUTADIENE-1-d_{1} and trans,trans-1,4-DIFLUOROBUTADIENE-1,4-d_{2}

    NASA Astrophysics Data System (ADS)

    Craig, Norman C.; Chen, Yihui; Lu, Yuhua; Neese, Christopher F.; Nemchick, Deacon J.; Blake, Thomas A.

    2013-06-01

    Samples of cis,cis- and trans,trans-1,4-difluorobutadiene-1-d_{1} (DFBD) and trans,trans-DFBD-1,4-d_{2} have been synthesized and investigated with high-resolution (0.0015 cm^{-1}) infrared spectroscopy. For the first two species the rotational structure in more than one band has been analyzed. For the 1,4-d_{2} species the spectrum of only one C-type band was available in an isotopic mixture. Ground state rotational constants are reported for all three molecules. It is proposed that quartic centrifugal distortion constants computed with a B3LYP/cc-pVTZ model can be used to assess the quality of observed rotational constants. The favorable comparison of predicted and observed ground state rotational constants for all four ^{13}C species of cis,trans-DFBD, which is MW active, demonstrates that the ground state rotational constants for the ^{13}C species of the cis,cis and trans,trans isomers can be successfully predicted with high accuracy. Rotational constants for a full set of isotopologues will be used to determine accurate semiexperimental equilibrium structures of the cis,cis and trans,trans species of DFBD. N. C. Craig, C. M. Oertel, D. C. Oertel, M. J. Tubergen, R. J. Lavrich, A. M Chaka J. Phys. Chem. A 106, 4230-4235 (2002).

  1. 76 FR 49300 - Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-10

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF THE TREASURY Internal Revenue Service 26 CFR Part 1 RIN 1545-BF83 Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY: Internal Revenue Service (IRS), Treasury....

  2. Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle.

    PubMed

    Winter, Lilli; Kuznetsov, Andrey V; Grimm, Michael; Zeöld, Anikó; Fischer, Irmgard; Wiche, Gerhard

    2015-08-15

    Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion-fission machinery and manifesting with upregulated mitochondrial fusion-associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways.

  3. MetaboQuant: a tool combining individual peak calibration and outlier detection for accurate metabolite quantification in 1D (1)H and (1)H-(13)C HSQC NMR spectra.

    PubMed

    Klein, Matthias S; Oefner, Peter J; Gronwald, Wolfram

    2013-05-01

    Solution nuclear magnetic resonance (NMR) spectroscopy is widely used to analyze complex mixtures of organic compounds such as biological fluids and tissue extracts. Targeted profiling approaches with reliable compound quantitifcation are hampered, however, by signal overlap and other interferences. Here, we present a tool named MetaboQuant for automated compound quantification from pre-processed 1D and 2D heteronuclear single quantum coherence (HSQC) NMR spectral data and concomitant validation of results. Performance of MetaboQuant was tested on a urinary spike-in data set and compared with other quantification strategies. The use of individual calibration factors in combination with the validation algorithms of MetaboQuant raises the reliability of the quantification results. MetaboQuant can be downloaded at http://genomics.uni-regensburg.de/site/institute/software/metaboquant/ as stand-alone software for Windows or run on other operating systems from within Matlab. Separate software for peak fitting and integration is necessary in order to use MetaboQuant.

  4. Predominance of bovine viral diarrhea virus 1b and 1d subtypes during eight years of survey in Poland.

    PubMed

    Kuta, A; Polak, M P; Larska, M; Żmudziński, J F

    2013-10-25

    The genetic diversity of bovine viral diarrhea virus (BVDV) was determined from 65 animals persistently infected with BVDV and diagnosed between 2004 and 2011 in Poland. The samples originated from 28 herds in 12 provinces, where over 90% of the whole cattle population of Poland is reared. Phylogenetic analysis based on the fragments of two genomic regions of BVDV namely, 5'-untranslated region (5'-UTR) and N(pro) was performed. All the BVDV isolates belonged to BVDV-1 species and were further divided into four subtypes. There were 31 viruses of BVDV-1b subtype (47.6%) present in 12 herds, 24 of BVDV-1d subtype (36.9%) in 9 herds, 8 of BVDV-1f subtype (12.3%) in 5 herds and 2 BVDV-1g subtype (3.0%) in 2 herds. Neither BVDV-1a subtype, nor BVDV-2 species or any atypical bovine pestivirus were found among isolates tested. Despite increasing import of live cattle in the recent years, genetic diversity of Polish BVDV isolates was rather low.

  5. Characterization of 5-HT receptors mediating constriction of porcine carotid arteriovenous anastomoses; involvement of 5-HT1B/1D and novel receptors

    PubMed Central

    De Vries, Peter; Villalón, Carlos M; Heiligers, Jan P C; Saxena, Pramod R

    1998-01-01

    It was previously shown that porcine cranial arteriovenous anastomoses (AVAs) constrict to 5-hydroxytryptamine (5-HT), ergotamine, dihydroergotamine, as well as sumatriptan and that sumatriptan acts exclusively via 5-HT1B/1D receptors. The present study was devoted to establish the contribution of 5-HT1B/1D receptors in the constriction of AVAs elicited by 5-HT (in presence of 0.5 mg kg−1 ketanserin), ergotamine and dihydroergotamine in anaesthetized pigs.Intracarotid infusion of 5-HT (2 μg kg−1 min−1) and intravenous doses of ergotamine (2.5–20 μg kg−1) and dihydroergotamine (3–100 μg kg−1) reduced AVA and increased nutrient blood flows and vascular conductances. The vasodilator response to 5-HT, observed mainly in the skin and ear, was much more prominent than that of the ergot alkaloids.Treatment with the 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg−1, i.v.) significantly attenuated both ergot-induced AVA constriction and arteriolar dilatation, whereas GR127935 only slightly affected the carotid vascular effects of 5-HT.The results suggest that 5-HT constricts carotid AVAs primarily via receptors, which seem to differ from those (5-HT1B/1D) stimulated by sumatriptan. The ergot alkaloids produce AVA constriction for a substantial part via 5-HT1B/1D receptors, but also stimulate unidentified receptors. Both these non-5-HT1B/1D receptors may be targets for the development of novel antimigraine drugs.The moderate vasodilator response to the ergot derivatives seems to be mediated, at least in part, by 5-HT1B/1D receptors, whereas the arteriolar dilatation caused by 5-HT may be mediated by other, possibly 5-HT7 receptors. PMID:9605562

  6. Applications of organocatalytic asymmetric synthesis to drug prototypes--dual action and selective inhibitors of n-nitric oxide synthase with activity against the 5-HT1D/1B subreceptors.

    PubMed

    Hanessian, Stephen; Stoffman, Eli; Mi, Xueling; Renton, Paul

    2011-03-04

    The scope of MacMillan's organocatalytic asymmetric conjugate addition reaction of indoles and electron-rich aromatics to α,β-unsaturated aldehydes has been extended to the use of 3-amino crotonaldehydes as substrates. The aromatics used include indoles as well as an aniline and a furan. The scope and effect of the groups on nitrogen (R, R') has also been studied. The method has been applied to the concise synthesis of an advanced precursor to S-(+)-1, a drug prototype for the treatment of migraine headaches.

  7. Effects of the 5-HT receptor antagonists GR127935 (5-HT1B/1D) and MDL100907 (5-HT2A) in the consolidation of learning.

    PubMed

    Meneses, A; Terrón, J A; Hong, E

    1997-12-01

    We have previously reported that 5-HT1B/1D and 5-HT2A/2B/2C receptors play a role in learning and memory. The present investigation was devoted to analyze further in the autoshaping learning task: (1) the effects of the 5-HT1A/1B/1D receptor agonist, GR46611, the 5-HT1B/1D receptor antagonist, GR127935, and the selective 5-HT2A receptor antagonist, MDL100907. Consistent with a role of 5-HT1B/1D receptors in learning, the post-training injection of GR46611 (1-10 mg/kg) decreased the consolidation of learning whereas GR127935 (10 mg/kg) increased it; the effects of both drugs were reversed by PCA pretreatment. GR127935 abolished the decrease induced by GR46611, TFMPP and mCPP, whereas MDL100907 (0.1-3.0 mg/kg) had no effect by itself but abolished the effects of DOI, ketanserin and TFMPP and moderately inhibited the effects elicited by mCPP, 1-NP and mesulergine. Neither did GR127935 nor MDL100907 significantly modify the increase in the consolidation of learning induced by 8-OH-DPAT. Thus, the present findings suggest that stimulation of presynaptic 5-HT1B/1D receptors impairs the consolidation of learning whilst stimulation of 5-HT2A/2C receptors enhances it; the blockade of 5-HT2A receptors has no effects. In addition, 5-HT2 receptors seem to modulate this cognitive stage.

  8. Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors

    PubMed Central

    Muñoz-Islas, E; Gupta, S; Jiménez-Mena, L R; Lozano-Cuenca, J; Sánchez-López, A; Centurión, D; Mehrotra, S; MaassenVanDenBrink, A; Villalón, C M

    2006-01-01

    Background and purpose: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT1B/1D water-soluble), donitriptan (5-HT1B/1D lipid-soluble), PNU-142633 (5-HT1D water-soluble) and PNU-109291 (5-HT1D lipid-soluble) on vasodilator responses to capsaicin, α-CGRP and acetylcholine in dog external carotid artery. Experimental approach: 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. Key results: Intracarotid infusions of capsaicin, α-CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT1B), but not of BRL15572 (5-HT1D), abolished the inhibition by donitriptan. Conclusions and implications: Our results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT1B, rather than 5-HT1D, receptors, probably by a central mechanism. PMID:16880765

  9. Role of 5-HT5A and 5-HT1B/1D receptors in the antinociception produced by ergotamine and valerenic acid in the rat formalin test.

    PubMed

    Vidal-Cantú, Guadalupe C; Jiménez-Hernández, Mildred; Rocha-González, Héctor I; Villalón, Carlos M; Granados-Soto, Vinicio; Muñoz-Islas, Enriqueta

    2016-06-15

    Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15nmol) or valerenic acid (1nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1nmol); (ii) SB-699551 (selective 5-HT5A; up to 10nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1nmol). Likewise, antinociception by intraplantar ergotamine (15nmol) and valerenic acid (10nmol) was: (i) partially blocked by methiothepin (1nmol), SB-699551 (10nmol) or SB-224289 (1nmol); and (ii) abolished by BRL-15572 (1nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain.

  10. Protein kinase mediated upregulation of endothelin A, endothelin B and 5-hydroxytryptamine 1B/1D receptors during organ culture in rat basilar artery

    PubMed Central

    Hansen-Schwartz, Jacob; Svensson, Carl-Lennart; Xu, Cang-Bao; Edvinsson, Lars

    2002-01-01

    Organ culture has been shown to upregulate both endothelin (ET) and 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptors in rat cerebral arteries. The purpose of the present study was to investigate the involvement of protein kinases, especially protein kinases C (PKC) and A (PKA) in this process. The effect of inhibiting protein kinases during organ culture with staurosporine (unspecific protein kinase inhitor), RO 31-7549 (specific inhibitor of classical PKC's) and H 89 (specific inhibitor of PKA) was examined using in vitro pharmacological examination of cultured vessel segments with ET-1 (unspecific ETA and ETB agonist), S6c (specific ETB agonist) and 5-CT (5-HT1 agonist). Levels of mRNA coding for the ETA, ETB, 5-HT1B and 5-HT1D receptors were analysed using real-time RT–PCR. Classical PKC's are critically involved in the appearance of the ETB receptor; co-culture with RO 31-7549 abolished the contractile response (6.9±1.8%) and reduced the ETB receptor mRNA by 44±4% as compared to the cultured control. Correlation between decreased ETB receptor mRNA and abolished contractile function indicates upstream involvement of PKC. Inhibition of PKA generally had an enhancing effect on the induced changes giving rise to a 7–25% increase in Emax in response to ET-1, S6c and 5-CT as compared to the cultured control. Staurosporine inhibited the culture induced upregulation of the response of both the ETA and the 5-HT1B/1D receptors, but had no significant effect on the mRNA levels of these receptors. This lack of correlation indicates an additional downstream involvement of protein kinases. PMID:12183337

  11. Signalling pathways activated by 5-HT(1B)/5-HT(1D) receptors in native smooth muscle and primary cultures of rabbit renal artery smooth muscle cells.

    PubMed

    Hinton, J M; Hill, P; Jeremy, J; Garland, C

    2000-01-01

    The potential of primary cultures of rabbit renal artery vascular smooth muscle cells (VSMCs) was assessed as a means to investigate the signalling pathways linked to 5-hydroxytryptamine (5-HT) 5-HT(1B)/5-HT(1D) receptors in native arteries. In renal artery segments denuded of endothelium, incubated with ketanserin and prazosin (each 1 microM), and prestimulated with 20 mM K(+) Krebs buffer, 5-HT and CP 93,129, a 5-HT(1B) receptor agonist, evoked concentration-dependent contractions. GR 127935, a 5-HT(1B)/5-HT(1D) receptor antagonist, significantly antagonised 5-HT-evoked contractions at nanomolar concentrations. Reverse transcription polymerase chain reaction (RT-PCR) of mRNA from smooth muscle cells from the isolated renal artery and from primary cultures of VSMCs from the same artery expressed mRNA transcripts for the 5-HT(1B) receptor and the 5-HT(1D) receptor in both preparations. The sequence of the PCR fragments corresponded to the known sequence for these receptors. Application of 5-HT evoked a concentration-dependent, pertussis toxin (PTx)-sensitive reduction in cyclic AMP in both cultured cells and intact artery (cyclic AMP concentration reduced by 65.53 +/- 3.33 and 52.65 +/- 5.34% from basal with 10 microM 5-HT, respectively). The effect of 10 microM 5-HT on cAMP was increased in the presence of 20 mM K(+) (reduced by 82.50 +/- 2.50 and 87.54 +/- 3.97%, respectively). In intact arteries, contraction through 5-HT(1B)/5-HT(1D) receptors was significantly attenuated by inhibitors of phosphatidylinositol 3-kinase (wortmannin) and activated mitogen-activated protein kinase (MAPK), MEK (U0126). In the cultured VSMCs, activated MAPK was identified by immunocytochemistry and immunoblotting after stimulation with 5-HT, but only if 20 mM K(+) was present at the onset of stimulation. These data provide the first direct evidence that 5-HT(1B)/5-HT(1B) receptors are linked to the activation of MAPK and indicate that primary cultures of renal VSMCs could provide a

  12. Investigation of the role of 5-HT1B and 5-HT1D receptors in the sumatriptan-induced constriction of porcine carotid arteriovenous anastomoses

    PubMed Central

    Vries, Peter De; Willems, Edwin W; Heiligers, Jan P C; Villalón, Carlos M; Saxena, Pramod R

    1999-01-01

    It has previously been shown that the antimigraine drug sumatriptan constricts porcine carotid arteriovenous anastomoses via 5-HT1-like receptors, identical to 5-HT1B/1D receptors. The recent availability of silent antagonists selective for the 5-HT1B (SB224289) and 5-HT1D (BRL15572) receptor led us to further analyse the nature of receptors involved.In pentobarbitone-anaesthetized, bilaterally vagosympathectomized pigs, sumatriptan (30, 100 and 300 μg kg−1, i.v.) dose-dependently decreased carotid arteriovenous anastomotic conductance by up to 70±5%.The dose-related decreases in carotid arteriovenous anastomotic conductance by sumatriptan (30, 100 and 300 μg kg−1, i.v.) remained unchanged in animals treated (i.v.) with 1 mg kg−1 of BRL15572 (maximum decrease: 72±3%), but were significantly attenuated by 1 mg kg−1 (maximum decrease: 30±11%) and abolished by 3 mg kg−1 (maximum decrease: 3±7%) of SB224289. The highest dose of SB224289 did not attenuate the hypertension, tachycardia or increases in carotid blood flow induced by bolus injections of noradrenaline (0.1–3 μg kg−1, i.v.).The results indicate that sumatriptan constricts porcine carotid arteriovenous anastomoses primarily via 5-HT1B, but not via 5-HT1D receptors. PMID:10385240

  13. Autoradiographic Mapping of 5-HT(1B/1D) Binding Sites in the Rhesus Monkey Brain Using [carbonyl-C]zolmitriptan.

    PubMed

    Lindhe, Orjan; Almqvist, Per; Kågedal, Matts; Gustafsson, Sven-Åke; Bergström, Mats; Nilsson, Dag; Antoni, Gunnar

    2011-01-01

    Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [(11)C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [(11)C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [(11)C]zolmitriptan as a radioligand. In saturation studies, [(11)C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95-5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT(1) receptor antagonists, [(11)C]zolmitriptan binding was blocked by selective 5-HT(1B) and 5-HT(1D) ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT(1A) receptor antagonist.

  14. Evidence for 5-HT1B/1D and 5-HT2A receptors mediating constriction of the canine internal carotid circulation

    PubMed Central

    Centurión, David; Ortiz, Mario I; Sánchez-López, Araceli; De Vries, Peter; Saxena, Pramod R; Villalón, Carlos M

    2001-01-01

    The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1–10 μg min−1), sumatriptan (0.3–10 μg min−1; 5-HT1B/1D), 5-methoxytryptamine (1–100 μg min−1; 5-HT1, 5-HT2, 5-HT4, 5-ht6 and 5-HT7) or DOI (0.31–10 μg min−1; 5-HT2), but not 5-carboxamidotryptamine (0.01–0.3 μg min−1; 5-HT1, 5-ht5A and 5-HT7), 1-(m-chlorophenyl)-biguanide (mCPBG; 1–1000 μg min−1; 5-HT3) or cisapride (1–1000 μg min−1; 5-HT4), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 μg kg−1; 5-HT2A/2B/2C) in combination with tropisetron (3000 μg kg−1; 5-HT3/4) or the cyclo-oxygenase inhibitor, indomethacin (5000 μg kg−1), but were abolished by the 5-HT1B/1D receptor antagonist, GR127935 (30 μg kg−1). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 μg kg−1) or ketanserin (100 μg kg−1; 5-HT2A), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT1B/1D and 5-HT2A receptors

  15. Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: role of 5-HT1B/1D receptors and α2-adrenoceptors

    PubMed Central

    Villalón, Carlos M; De Vries, Peter; Rabelo, Gonzalo; Centurión, David; Sánchez-López, Araceli; Saxena, Pramod

    1999-01-01

    The antimigraine drugs methysergide, ergotamine and dihydroergotamine (DHE) produce selective vasoconstriction in the external carotid bed of vagosympathectomized dogs anaesthetized with pentobarbital and artificially respired, but the receptors involved have not yet been completely characterized. Since the above drugs display affinity for several binding sites, including α-adrenoceptors and several 5-HT1 and 5-HT2 receptor subtypes, this study has analysed the mechanisms involved in the above responses. Intracarotid (i.c.) infusions during 1 min of methysergide (31–310 μg min−1), ergotamine (0.56–5.6 μg min−1) or DHE (5.6–31 μg min−1) dose-dependently reduced external carotid blood flow (ECBF) by up to 46±4, 37±4 and 49±5%, respectively. Blood pressure and heart rate remained unchanged. The reductions in ECBF by methysergide were abolished and even reversed to increases in animals pre-treated with GR127935 (10 μg kg−1, i.v.). The reductions in ECBF by ergotamine and DHE remained unchanged in animals pre-treated (i.v.) with prazosin (300 μg kg−1), but were partly antagonized in animals pre-treated with either GR127935 (10 or 30 μg kg−1) or yohimbine (1000 μg kg−1). Pre-treatment with a combination of GR127935 (30 μg kg−1) and yohimbine (1000 μg kg−1) abolished the responses to both ergotamine and DHE. The above doses of antagonists were shown to produce selective antagonism at their respective receptors. These results suggest that the external carotid vasoconstrictor responses to methysergide primarily involve 5-HT1B/1D receptors, whereas those to ergotamine and DHE are mediated by 5-HT1B/1D receptors as well as α2-adrenoceptors. PMID:10188968

  16. Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats.

    PubMed

    Avila-Rojas, Sabino Hazael; Velázquez-Lagunas, Isabel; Salinas-Abarca, Ana Belen; Barragán-Iglesias, Paulino; Pineda-Farias, Jorge Baruch; Granados-Soto, Vinicio

    2015-10-05

    Serotonin (5-HT) participates in pain modulation by interacting with different 5-HT receptors. The role of 5-HT5A receptor in neuropathic pain has not previously studied. The purpose of this study was to investigate: A) the role of 5-HT5A receptors in rats subjected to spinal nerve injury; B) the expression of 5-HT5A receptors in dorsal spinal cord and dorsal root ganglia (DRG). Neuropathic pain was induced by L5/L6 spinal nerve ligation. Tactile allodynia in neuropathic rats was assessed with von Frey filaments. Western blot methodology was used to determine 5-HT5A receptor protein expression. Intrathecal administration (on day 14th) of 5-HT (10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) reversed nerve injury-induced tactile allodynia. Intrathecal non-selective (methiothepin, 0.1-0.8 nmol) and selective (SB-699551, 1-10 nmol) 5-HT5A receptor antagonists reduced, by ~60% and ~25%, respectively, the antiallodynic effect of 5-HT (100 nmol) or 5-CT (0.3 nmol). Moreover, both selective 5-HT1A and 5-HT1B/1D receptor antagonists, WAY-100635 (0.3-1 nmol) and GR-127935 (0.3-1 nmol), respectively, partially diminished the antiallodynic effect of 5-HT or 5-CT by about 30%. Injection of antagonists, by themselves, did not affect allodynia. 5-HT5A receptors were expressed in the ipsilateral dorsal lumbar spinal cord and DRG and L5/L6 spinal nerve ligation did not modify 5-HT5A receptor protein expression in those sites. Results suggest that 5-HT5A receptors reduce pain processing in the spinal cord and that 5-HT and 5-CT reduce neuropathic pain through activation of 5-HT5A and 5-HT1A/1B/1D receptors. These receptors could be an important part of the descending pain inhibitory system.

  17. Receptor specificity and trigemino-vascular inhibitory actions of a novel 5-HT1B/1D receptor partial agonist, 311C90 (zolmitriptan)

    PubMed Central

    Martin, G R; Robertson, A D; MacLennan, S J; Prentice, D J; Barrett, V J; Buckingham, J; Honey, A C; Giles, H; Moncada, S

    1997-01-01

    311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone) is a novel 5-HT1B/1D receptor agonist with proven efficacy in the acute treatment of migraine. Here, we describe the receptor specificity of the drug and its actions on trigeminal-evoked plasma protein extravasation into the dura mater of the anaesthetized guinea-pig. At the ‘5-HT1B-like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A50]=6.79±0.06) partial agonist achieving 77±4% of the maximum effect to 5-hydroxytryptamine (5-HT). In the same experiments, sumatriptan (p[A50]=6.48±0.04) was half as potent as 311C90 and produced 97±2% of the 5-HT maximum effect. Studies in which receptor inactivation methods were used to estimate the affinity (pKA) and efficacy relative to 5-HT (τrel.) for each agonist confirmed that 311C90 exhibits higher affinity than sumatriptan (pKA=6.63±0.04 and 6.16±0.03, respectively) and that both drugs are partial agonists relative to 5-HT (τrel=0.61±0.03 and 0.63±0.10, respectively, compared to 5-HT=1.0). Consistent with its effects in rabbit saphenous vein, 311C90 also produced concentration-dependent contractions of primate basilar artery and human epicardial coronary artery rings. In basilar artery, agonist potency (p[A50]=6.92±0.07) was similar to that demonstrated in rabbit saphenous vein, again being 2–3 fold higher than for sumatriptan (p[A50]=6.46±0.03). Both agonists produced about 50% of the maximum response obtained with 5-HT in the same preparations. In rings of human coronary artery, the absolute potency of 311C90 and sumatriptan was higher than in primate basilar artery (p[A50]=7.3±0.1 and 6.7±0.1, respectively), but maximum effects relative to 5-HT were lower (37±8% and 35±7%, respectively). In both types of vessel, the inability of 5-HT1B/1D agonists to achieve the same maximum as the endogenous agonist 5-HT is explained by the additional presence of 5-HT2A

  18. Differential regulation of expression of the MHC class II molecules RT1.B and RT1.D on rat B lymphocytes: effects of interleukin-4, interleukin-13 and interferon-gamma.

    PubMed Central

    Roos, A; Schilder-Tol, E J; Chand, M A; Claessen, N; Lakkis, F G; Pascual, D W; Weening, J J; Aten, J

    1998-01-01

    Susceptibility to induction of both T helper 1- (Th1) and Th2-mediated autoimmunity is multifactorial and involves genetic linkage to the major histocompatibility complex (MHC) class II haplotype. Brown Norway (BN) rats exposed to mercuric chloride develop a Th2-dependent systemic autoimmunity, whereas Lewis rats, which are highly susceptible to Th1-mediated autoimmunity, develop immune suppression after mercuric chloride exposure. Exposure to mercuric chloride is known to enhance B-lymphocyte expression of the MHC class II molecule RT1.B, predominantly in BN rats. We demonstrate that, in contrast, expression of RT1.D was unmodified on these B cells, whereas both RT1.B and RT1.D were up-regulated on epithelial cells. Regulation of B-cell MHC class II isotype expression was further studied in vitro, using BN rat lymph node (LN) cells. Interleukin-4 (IL-4) strongly enhanced B-cell expression of RT1.B (2.8-fold), whereas RT1.D expression was only slightly, although significantly, modified (1.2-fold). B cells from Lewis rats showed a similar IL-4-induced enhancement of RT1.B expression (2.5-fold), whereas, in contrast, RT1.D expression was unmodified. Exposure of LN cells from BN rats to interferon-gamma induced a moderate increase of B-cell MHC class II expression, predominantly of RT1.B. Strong and rapid enhancement of B-cell RT1.D expression was observed after stimulation by phorbol 12-myristate 13-acetate and ionomycin. Rat IL-13 did not modify B-cell MHC class II expression; however, it induced typical morphological changes in peritoneal macrophages. These experiments demonstrate isotype-specific and strain-dependent regulation of MHC class II expression on rat B lymphocytes, which may be of pathophysiological relevance for the strain-dependent susceptibility for Th1- or Th2-mediated autoimmunity. Images Figure 1 Figure 5 PMID:9536116

  19. The 5-HT1-like receptors mediating inhibition of sympathetic vasopressor outflow in the pithed rat: operational correlation with the 5-HT1A, 5-HT1B and 5-HT1D subtypes

    PubMed Central

    Villalón, Carlos M; Centurión, David; Rabelo, Gonzalo; de Vries, Peter; Saxena, Pramod R; Sánchez-López, Araceli

    1998-01-01

    It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT1-like receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors.Intravenous (i.v.) continuous infusions of 5-HT and the 5-HT1 receptor agonists, 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP 93,129 (5-HT1B) and sumatriptan (5-HT1B/1D), resulted in a dose-dependent inhibition of sympathetically-induced vasopressor responses.The sympatho-inhibitory responses induced by 5-HT, 8-OH-DPAT, indorenate, CP 93,129 or sumatriptan were analysed before and after i.v. treatment with blocking doses of the putative 5-HT receptor antagonists, WAY 100635 (5-HT1A), cyanopindolol (5-HT1A/1B) or GR 127935 (5-HT1B/1D). Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished.In additional experiments, the inhibition induced by 5-HT was not modified after 5-HT7 receptor blocking doses of mesulergine.The above results suggest that the 5-HT1-like receptors, which inhibit the sympathetic vasopressor outflow in pithed rats, display the pharmacological profile of the 5-HT1A, 5-HT1B and 5-HT1D, but not that of 5-HT7, receptors. PMID:9692787

  20. The GR127935-sensitive 5-HT1 receptors mediating canine internal carotid vasoconstriction: resemblance to the 5-HT1B, but not to the 5-HT1D or 5-ht1F, receptor subtype

    PubMed Central

    Centurión, David; Sánchez-López, Araceli; De Vries, Peter; Saxena, Pramod R; Villalón, Carlos M

    2001-01-01

    This study has further investigated the pharmacological profile of the GR127935-sensitive 5-HT1 receptors mediating vasoconstriction in the internal carotid bed of anaesthetized vagosympathectomized dogs. One-minute intracarotid infusions of the agonists 5-hydroxytryptamine (5-HT; 0.1–10 μg min−1; endogenous ligand) and sumatriptan (0.3–10 μg min−1; 5-HT1B/1D), but not PNU-142633 (1–1000 μg min−1; 5-HT1D) or LY344864 (1–1000 μg min−1; 5-ht1F), produced dose-dependent decreases in internal carotid blood flow without changing blood pressure or heart rate. The responses to 5-HT were apparently resistant to blockade by i.v. administration of the antagonists SB224289 (300 μg kg−1; 5-HT1B), BRL15572 (300 μg kg−1; 5-HT1D) or ritanserin (100 μg kg−1; 5-HT2). In contrast, the responses to sumatriptan were antagonized by SB224289, but not by BRL15572. In the animals receiving SB224289, but not those receiving BRL15572, the subsequent administration of ritanserin abolished the 5-HT-induced vasoconstriction and unmasked a vasodilator component. Similarly, in ritanserin-treated animals, the subsequent administration of SB224289, but not BRL15572, completely blocked the 5-HT-induced vasoconstriction, revealing vasodilatation. In animals receiving initially BRL15572, the subsequent administration of SB224289 did not affect (except at 10 μg min−1) the vasoconstrictor responses to 5-HT. Notably, in animals pretreated with 1000 μg kg−1 of mesulergine, a 5-HT2/7 receptor antagonist, 5-HT produced a dose-dependent vasoconstriction, which was practically abolished by SB224289. After BRL15572, no further blockade was produced and the subsequent administration of ritanserin was similarly inactive. These results suggest that the GR127935-sensitive 5-HT1 receptors mediating canine internal carotid vasoconstriction resemble the 5-HT1B but not the 5-HT1D or 5-ht1F, receptor subtype. PMID:11226129

  1. Ethanol and Mesolimbic Serotonin/Dopamine Interactions Via 5-HT1B Receptors

    DTIC Science & Technology

    2006-03-01

    5 - HT3 receptor antagonist antagonized systemic ethanol- induced increases of DA release in the VTA [10] or the NACC [9]. Moreover, the...experiments with a selective 5 -HT1B receptor antagonist such as SB 216641 are required to strengthen this conclusion. The future experiments will be... receptor antagonist ), but not BRL 15572 (a 5 -HT1D/1A receptor antagonist ) or WAY 100635 (a 5 -HT1A receptor antagonist ). Administration

  2. Robust algorithms for automated chemical shift calibration of 1D 1H NMR spectra of blood serum.

    PubMed

    Pearce, Jake T M; Athersuch, Toby J; Ebbels, Timothy M D; Lindon, John C; Nicholson, Jeremy K; Keun, Hector C

    2008-09-15

    In biofluid NMR spectroscopy, the frequency of each resonance is typically calibrated by addition of a reference compound such as 3-(trimethylsilyl)-propionic acid- d 4 (TSP) to the sample. However biofluids such as serum cannot be referenced to TSP, due to shifts resonance caused by binding to macromolecules in solution. In order to overcome this limitation we have developed algorithms, based on analysis of derivative spectra, to locate and calibrate (1)H NMR spectra to the alpha-glucose anomeric doublet. We successfully used these algorithms to calibrate 77 serum (1)H NMR spectra and demonstrate the greater reproducibility of the calculated chemical-shift corrections ( r = 0.97) than those generated by manual alignment ( r = 0.8-0.88). Hence we show that these algorithms provide robust and reproducible methods of calibrating (1)H NMR of serum, plasma, or any biofluid in which glucose is abundant. Precise automated calibration of complex biofluid NMR spectra is an important tool in large-scale metabonomic or metabolomic studies, where hundreds or even thousands of spectra may be analyzed in high-resolution by pattern recognition analysis.

  3. TES Level 1B

    Atmospheric Science Data Center

    2014-12-08

    TES Level 1B data files contain radiometric calibrated spectral radiances and their ... and some engineering data are also provided. A Level 1B data file contains data from a single TES orbit for one focal ... as the Aura orbit number at the time of the South Pole apex crossing. version id represents the version identification number, ...

  4. Using 1-D 1H and 2-D 1H J-resolved NMR metabolomics to understand the effects of anemia in channel catfish (Ictalurus punctatus)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Anemia is a widespread hematological disorder in vertebrates. In channel catfish (Ictalurus punctatus), anemia is a persistent problem in culture environments, however, its causes and physiological impacts are not well understood. To better understand the symptoms and characterize associated biomark...

  5. A synaptic device built in one diode-one resistor (1D-1R) architecture with intrinsic SiOx-based resistive switching memory

    NASA Astrophysics Data System (ADS)

    Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Pan, Chih-Hung; Chang, Kuan-Chang; Tsai, Tsung-Ming; Chang, Ting-Chang; Sze, Simon M.; Lee, Jack C.

    2016-04-01

    We realize a device with biological synaptic behaviors by integrating silicon oxide (SiOx) resistive switching memory with Si diodes to further minimize total synaptic power consumption due to sneak-path currents and demonstrate the capability for spike-induced synaptic behaviors, representing critical milestones for the use of SiO2-based materials in future neuromorphic computing applications. Biological synaptic behaviors such as long-term potentiation, long-term depression, and spike-timing dependent plasticity are demonstrated systemically with comprehensive investigation of spike waveform analyses and represent a potential application for SiOx-based resistive switching materials. The resistive switching SET transition is modeled as hydrogen (proton) release from the (SiH)2 defect to generate the hydrogenbridge defect, and the RESET transition is modeled as an electrochemical reaction (proton capture) that re-forms (SiH)2. The experimental results suggest a simple, robust approach to realize programmable neuromorphic chips compatible with largescale complementary metal-oxide semiconductor manufacturing technology.

  6. Triton 2 (1B)

    NASA Technical Reports Server (NTRS)

    Clark, Michelle L.; Meiss, A. G.; Neher, Jason R.; Rudolph, Richard H.

    1994-01-01

    The goal of this project was to perform a detailed design analysis on a conceptually designed preliminary flight trainer. The Triton 2 (1B) must meet the current regulations in FAR Part 23. The detailed design process included the tasks of sizing load carrying members, pulleys, bolts, rivets, and fuselage skin for the safety cage, empennage, and control systems. In addition to the regulations in FAR Part 23, the detail design had to meet established minimums for environmental operating conditions and material corrosion resistance.

  7. 5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats.

    PubMed

    García-Pedraza, José-Ángel; García, Mónica; Martín, María-Luisa; Morán, Asunción

    2015-09-01

    Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release.

  8. Strv1-b Flight Experiment

    NASA Technical Reports Server (NTRS)

    1992-01-01

    The Space Technology Research Vehicle (STRV-1b) is discussed. The STRV-1b is a small (100 watt) satellite flown by the British Defense Research Agency (DRA). The mission goal is to fly new and emerging space technologies at a more reasonable cost in a short-term timeframe. The STRV-1b's orbit can be described as a geosynchronous transfer orbit (GTO) with a perigee of 200 km, an apogee of 36,000 km (geosynchronous earth orbit (GEO)), and a period of 10.5 hours. The Phillips Laboratory plans to use the STRV-1b to test up to 20 advanced experimental photovoltaic cells. The discussion is presented in vugraph form.

  9. Interferon Beta-1b Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS, a disease in which ... interferon beta-1b injection at around the same time of day each time you inject it. Follow ...

  10. Pharmacological evidence that 5-HT1D activation induces renal vasodilation by NO pathway in rats.

    PubMed

    García-Pedraza, José-Ángel; García, Mónica; Martín, María-Luisa; Morán, Asunción

    2015-06-01

    5-HT is a powerful vasoconstrictor substance in renal vasculature (mainly by 5-HT₂ activation). Nevertheless, 5-HT is notable for its dual cardiovascular effects, producing both vasodilator and vasoconstrictor actions. This study aimed to investigate whether, behind the predominant serotonergic vasoconstrictor action, THE 5-HT system may exert renal vasodilator actions, and, if so, characterize the 5-HT receptors and possible indirect pathways. Renal perfusion pressure (PP), systemic blood pressure (SBP) and heart rate (HR) measurement in in situ autoperfused rat kidney was determined in phenylephrine infused rats. Intra arterial (i.a.) bolus administration of 5-HT (0.00000125-0.1 μg/kg) decreased renal PP in the presence of a phenylephrine continuous infusion (phenylephrine-infusion group), without modifying SBP or HR. These vasodilator responses were potentiated by 5-HT₂ antagonism (ritanserin, 1 mg/kg i.v.), whereas the responses were abolished by 5-HT₁ /₇ antagonist (methiothepin, 100 μg/kg i.v.) or 5-HT1D antagonist (LY310762, 1 mg/kg i.v.). The i.a. administration (0.00000125 to 0.1 μg/kg) of 5-CT or L-694,247 (5-HT1D agonist) mimicked 5-HT vasodilator effect, while other agonists (1-PBG, α-methyl-5-HT, AS-19 (5-HT₇), 8-OH-DPAT (5-HT1A) or CGS-12066B (5-HT1B)) did not alter baseline haemodynamic variables. L-694,247 vasodilation was abolished by i.v. bolus of antagonists LY310762 (5-HT1D, 1 mg/kg) or L-NAME (nitric oxide, 10 mg/kg), but not by i.v. bolus of indomethacin (cyclooxygenase, 2 mg/kg) or glibenclamide (ATP-dependent K(+) channel, 20 mg/kg). These outcomes suggest that 5-HT1D activation produces a vasodilator effect in the in situ autoperfused kidney of phenylephrine-infusion rats mediated by the NO pathway.

  11. Toward Structural Correctness: Aquatolide and the Importance of 1D Proton NMR FID Archiving.

    PubMed

    Pauli, Guido F; Niemitz, Matthias; Bisson, Jonathan; Lodewyk, Michael W; Soldi, Cristian; Shaw, Jared T; Tantillo, Dean J; Saya, Jordy M; Vos, Klaas; Kleinnijenhuis, Roel A; Hiemstra, Henk; Chen, Shao-Nong; McAlpine, James B; Lankin, David C; Friesen, J Brent

    2016-02-05

    The revision of the structure of the sesquiterpene aquatolide from a bicyclo[2.2.0]hexane to a bicyclo[2.1.1]hexane structure using compelling NMR data, X-ray crystallography, and the recent confirmation via full synthesis exemplify that the achievement of "structural correctness" depends on the completeness of the experimental evidence. Archived FIDs and newly acquired aquatolide spectra demonstrate that archiving and rigorous interpretation of 1D (1)H NMR data may enhance the reproducibility of (bio)chemical research and curb the growing trend of structural misassignments. Despite being the most accessible NMR experiment, 1D (1)H spectra encode a wealth of information about bonds and molecular geometry that may be fully mined by (1)H iterative full spin analysis (HiFSA). Fully characterized 1D (1)H spectra are unideterminant for a given structure. The corresponding FIDs may be readily submitted with publications and collected in databases. Proton NMR spectra are indispensable for structural characterization even in conjunction with 2D data. Quantum interaction and linkage tables (QuILTs) are introduced for a more intuitive visualization of 1D J-coupling relationships, NOESY correlations, and heteronuclear experiments. Overall, this study represents a significant contribution to best practices in NMR-based structural analysis and dereplication.

  12. Toward Structural Correctness: Aquatolide and the Importance of 1D Proton NMR FID Archiving

    PubMed Central

    2016-01-01

    The revision of the structure of the sesquiterpene aquatolide from a bicyclo[2.2.0]hexane to a bicyclo[2.1.1]hexane structure using compelling NMR data, X-ray crystallography, and the recent confirmation via full synthesis exemplify that the achievement of “structural correctness” depends on the completeness of the experimental evidence. Archived FIDs and newly acquired aquatolide spectra demonstrate that archiving and rigorous interpretation of 1D 1H NMR data may enhance the reproducibility of (bio)chemical research and curb the growing trend of structural misassignments. Despite being the most accessible NMR experiment, 1D 1H spectra encode a wealth of information about bonds and molecular geometry that may be fully mined by 1H iterative full spin analysis (HiFSA). Fully characterized 1D 1H spectra are unideterminant for a given structure. The corresponding FIDs may be readily submitted with publications and collected in databases. Proton NMR spectra are indispensable for structural characterization even in conjunction with 2D data. Quantum interaction and linkage tables (QuILTs) are introduced for a more intuitive visualization of 1D J-coupling relationships, NOESY correlations, and heteronuclear experiments. Overall, this study represents a significant contribution to best practices in NMR-based structural analysis and dereplication. PMID:26812443

  13. Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors.

    PubMed

    Murray, Katherine C; Stephens, Marilee J; Rank, Michelle; D'Amico, Jessica; Gorassini, Monica A; Bennett, David J

    2011-08-01

    Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT(1B) or 5-HT(1F) receptor agonists, including zolmitriptan (5-HT(1B/1D/1F)) and LY344864 (5-HT(1F)), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC(50)) and potency (-log EC(50)). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT(1B) and 5-HT(1F) receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT(1B) receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT(1B) agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT(1B) receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at -73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT(1B/1F) agonists, such as zolmitriptan, can restore inhibition

  14. Relation between high-pressure spectroscopy and fn-1d1 excited-state geometry: A comparison between theoretical and experimental results in SrF2:Sm2+

    NASA Astrophysics Data System (ADS)

    Pascual, José Luis; Barandiarán, Zoila; Seijo, Luis

    2007-09-01

    In this paper, we present the results of ab initio model potential embedded-cluster calculations of Sm2+ impurities in SrF2 in order to study the behavior of the electronic transitions of the dopant ion under high hydrostatic pressure. We find that the impurity-ligand bond length shortens upon f→d(eg) excitation and, as a consequence, the f→d(eg) transition energy decreases with increasing applied pressure. On the other hand, the bond lengths do not appreciably change upon f→f excitation and the energies of the f→f transitions are almost constant with pressure. These trends are in agreement with spectroscopic measurements under pressure in the title material, which gives credit to the computed bond length changes upon excitation, in contradiction with the widespread assumption of bond length lengthening upon f→d excitations. Spectroscopic experiments under high pressure are shown to be able to provide the sign of bond length changes in electronic transitions, constituting a simpler alternative to difficult excited-state x-ray absorption fine structure experiments.

  15. Ruthenium and osmium complexes of hemilabile chiral monophosphinite ligands derived from 1D-pinitol or 1D-chiro-inositol as catalysts for asymmetric hydrogenation reactions.

    PubMed

    Slade, Angela T; Lensink, Cornelis; Falshaw, Andrew; Clark, George R; Wright, L James

    2014-12-07

    The monophosphinite ligands, 1D-1,2;5,6-di-O-cyclopentylidene-3-O-methyl-4-O-diphenylphosphino-chiro-inositol (D-P1), 1D-1,2;5,6-di-O-isopropylidene-3-O-methyl-4-O-diphenylphosphino-chiro-inositol (D-P2), 1D-1,2;5,6-di-O-cyclohexylidene-3-O-methyl-4-O-diphenylphosphino-chiro-inositol (D-P3), and 1D-1,2;5,6-di-O-cyclopentylidene-3-O-ethyl-4-O-diphenylphosphino-chiro-inositol (D-P4), can be conveniently prepared from the chiral natural products 1D-pinitol or 1D-chiro-inositol. On treatment of toluene solutions of RuCl2(PPh3)3 with two mole equivalents of the ligands D-PY (Y = 1-4) the complexes RuCl2(D-P1)2 (1), RuCl2(D-P2)2 (4), RuCl2(D-P3)2 (5), or RuCl2(D-P4)2 (6), respectively, are formed. Similarly, treatment of OsCl2(PPh3)3 with D-P1 gives OsCl2(D-P1)2 (7). The single crystal X-ray structure determination of 1 reveals that each D-P1 ligand coordinates to ruthenium through phosphorus and the oxygen atom of the methoxyl group. Treatment of 1 with excess LiBr or LiI results in metathesis of the chloride ligands and RuBr2(D-P1)2 (2) or RuI2(D-P1)2 (3), respectively, are formed. Exposure of a solution of 1 to carbon monoxide results in the very rapid formation of RuCl2(CO)2(D-P1)2 (8), thereby demonstrating the ease with which the oxygen donors are displaced from the metal and hence the hemilabile nature of the two bidentate D-P1 ligands in 1. Preliminary studies indicate that 1-7 act as catalysts for the asymmetric hydrogenation reactions of acetophenone and 3-quinuclidinone to give the corresponding alcohols in generally high conversions but low enantiomeric excesses.

  16. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  17. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  18. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  19. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  20. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  1. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  2. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  3. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Enforcement hotline. 1b.21 Section 1b.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.21 Enforcement hotline. (a)...

  4. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  5. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Enforcement hotline. 1b.21 Section 1b.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.21 Enforcement hotline. (a)...

  6. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  7. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  8. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Formal investigations. 1b.5 Section 1b.5 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.5 Formal investigations....

  9. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Formal investigations. 1b.5 Section 1b.5 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.5 Formal investigations....

  10. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  11. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  12. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Policy. 1b.2 Section 1b.2 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.2 Policy. (a) All policies and programs of... compliance with Executive Order 12114, “Environmental Effects Abroad of Major Federal Actions.”...

  13. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Formal investigations. 1b.5 Section 1b.5 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.5 Formal investigations....

  14. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  15. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  16. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  17. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  18. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  19. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  20. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  1. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Formal investigations. 1b.5 Section 1b.5 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.5 Formal investigations....

  2. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  3. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  4. 18 CFR 1b.12 - Transcripts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Transcripts. 1b.12 Section 1b.12 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.12 Transcripts. Transcripts, if any,...

  5. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  6. 18 CFR 1b.19 - Submissions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Submissions. 1b.19 Section 1b.19 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.19 Submissions. In the event...

  7. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  8. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  9. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  10. 18 CFR 1b.2 - Scope.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Scope. 1b.2 Section 1b.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.2 Scope. This part applies to...

  11. 18 CFR 1b.14 - Subpoenas.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Subpoenas. 1b.14 Section 1b.14 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.14 Subpoenas. (a) Service of a...

  12. 18 CFR 1b.6 - Preliminary investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Preliminary investigations. 1b.6 Section 1b.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.6 Preliminary investigations....

  13. 18 CFR 1b.5 - Formal investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Formal investigations. 1b.5 Section 1b.5 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.5 Formal investigations....

  14. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Enforcement hotline. 1b..., DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.21 Enforcement hotline. (a) The Hotline Staff may provide information to the public and give informal staff opinions. The opinions...

  15. DSCOVR_EPIC_L1B

    Atmospheric Science Data Center

    2017-01-04

    DSCOVR_EPIC_L1B Full sun-light Earth images, georectified to the same ... 551NM 680NM 688NM 764NM 780NM DSCOVR EPIC IMAGERY L1B LAGRANGE Order Data:  Earthdata ...   Order Data Readme Files:  EPIC Data Format Control Book SCAR-B Block:  ...

  16. Unambiguous metabolite identification in high-throughput metabolomics by hybrid 1D 1 H NMR/ESI MS 1 approach: Hybrid 1D 1 H NMR/ESI MS 1 metabolomics method

    SciTech Connect

    Walker, Lawrence R.; Hoyt, David W.; Walker, S. Michael; Ward, Joy K.; Nicora, Carrie D.; Bingol, Kerem

    2016-09-16

    We present a novel approach to improve accuracy of metabolite identification by combining direct infusion ESI MS1 with 1D 1H NMR spectroscopy. The new approach first applies standard 1D 1H NMR metabolite identification protocol by matching the chemical shift, J-coupling and intensity information of experimental NMR signals against the NMR signals of standard metabolites in metabolomics library. This generates a list of candidate metabolites. The list contains false positive and ambiguous identifications. Next, we constrained the list with the chemical formulas derived from high-resolution direct infusion ESI MS1 spectrum of the same sample. Detection of the signals of a metabolite both in NMR and MS significantly improves the confidence of identification and eliminates false positive identification. 1D 1H NMR and direct infusion ESI MS1 spectra of a sample can be acquired in parallel in several minutes. This is highly beneficial for rapid and accurate screening of hundreds of samples in high-throughput metabolomics studies. In order to make this approach practical, we developed a software tool, which is integrated to Chenomx NMR Suite. The approach is demonstrated on a model mixture, tomato and Arabidopsis thaliana metabolite extracts, and human urine.

  17. FOLH1B — EDRN Public Portal

    Cancer.gov

    FOLH1B, or PSMAL, is a cytoplasmic protein. It has been found in the kidney and liver, and has not been detected in the prostate. GO annotations related to this gene include metallopeptidase activity and dipeptidase activity.

  18. Could the 5-HT1B receptor inverse agonism affect learning consolidation?

    PubMed

    Meneses, A

    2001-03-01

    Diverse evidence indicates that, the 5-HT system might play a role in learning and memory, since it occurs in brain areas mediating such processes and 5-HT drugs modulate them. Hence in this work, in order to explore further 5-HT involvement on learning and memory 5-HT1B receptors' role is investigated. Evidence indicates that SB-224289 (a 5-HT1B receptor inverse agonist) post-training injection facilitated learning consolidation in an associative autoshaping learning task, this effect was partially reversed by GR 127935 (a 5-HT1B/1D receptor antagonist), but unaffected by MDL 100907 (a 5-HT2A receptor antagonist) or ketanserin (a 5-HT1D/2A/7 receptor antagonist) at low doses. Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT1A/1B/1D receptor agonist), mCPP (a 5-HT2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose). SB-224289 did not alter the 8-OH-DPAT (a 5-HT1A/7 receptor agonist) learning facilitatory effect. SB-224289 eliminated the deficit learning produced by the anticholinergic muscarinic scopolamine or the glutamatergic antagonist dizocilpine. Administration of both, GR 127935 (5mg/kg) plus ketanserin (0.01 mg/kg) did not modify learning consolidation; nevertheless, when ketanserin dose was increased (0.1-1.0mg/kg) and SB-224289 dose was maintained constant, a learning facilitation effect was observed. Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose. Collectively, the data confirm and extend the earlier findings with GR 127935 and the effects of non-selective 5-HT(1B) receptor agonists. Clearly 5-HT1B agonists induced a learning deficit which can be reversed with SB-224289. Perhaps more importantly, SB-224289 enhances learning consolidation when given alone and can reverse the deficits

  19. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Enforcement hotline. 1b... or writing to the Hotline at the telephone number and address in paragraph (f) of this section. The... matter. A caller may terminate use of the Hotline procedure at any time. (f) The Hotline may be...

  20. 18 CFR 1b.21 - Enforcement hotline.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Enforcement hotline. 1b... or writing to the Hotline at the telephone number and address in paragraph (f) of this section. The... matter. A caller may terminate use of the Hotline procedure at any time. (f) The Hotline may be...

  1. 7 CFR 1b.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.1 Purpose. (a) This part supplements the regulations for implementation of the National Environmental Policy Act (NEPA), for which regulations were published by the Council on Environmental Quality (CEQ) in 40 CFR parts 1500 through 1508. This...

  2. Experimental Reproduction of Type 1B Chondrules

    NASA Technical Reports Server (NTRS)

    Lofgren, G. E.; Le, L.

    2002-01-01

    We have replicated type 1B chondrule textures and compositions with crystallization experiments in which UOC material was melted at 1400 deg.C and cooled at 5-1000 deg.C/hr using graphite crucibles in evacuated silica tubes to provide a reducing environment. Additional information is contained in the original extended abstract.

  3. Aldo-keto Reductase 1B15 (AKR1B15)

    PubMed Central

    Weber, Susanne; Salabei, Joshua K.; Möller, Gabriele; Kremmer, Elisabeth; Bhatnagar, Aruni; Adamski, Jerzy; Barski, Oleg A.

    2015-01-01

    Aldo-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues. PMID:25577493

  4. Crystal structure of TBC1D15 GTPase-activating protein (GAP) domain and its activity on Rab GTPases.

    PubMed

    Chen, Yan-Na; Gu, Xin; Zhou, X Edward; Wang, Weidong; Cheng, Dandan; Ge, Yinghua; Ye, Fei; Xu, H Eric; Lv, Zhengbing

    2017-04-01

    TBC1D15 belongs to the TBC (Tre-2/Bub2/Cdc16) domain family and functions as a GTPase-activating protein (GAP) for Rab GTPases. So far, the structure of TBC1D15 or the TBC1D15·Rab complex has not been determined, thus, its catalytic mechanism on Rab GTPases is still unclear. In this study, we solved the crystal structures of the Shark and Sus TBC1D15 GAP domains, to 2.8 Å and 2.5 Å resolution, respectively. Shark-TBC1D15 and Sus-TBC1D15 belong to the same subfamily of TBC domain-containing proteins, and their GAP-domain structures are highly similar. This demonstrates the evolutionary conservation of the TBC1D15 protein family. Meanwhile, the newly determined crystal structures display new variations compared to the structures of yeast Gyp1p Rab GAP domain and TBC1D1. GAP assays show that Shark and Sus GAPs both have higher catalytic activity on Rab11a·GTP than Rab7a·GTP, which differs from the previous study. We also demonstrated the importance of arginine and glutamine on the catalytic sites of Shark GAP and Sus GAP. When arginine and glutamine are changed to alanine or lysine, the activities of Shark GAP and Sus GAP are lost.

  5. MISR Level 1A CCD, 1B1, 1B2, and Browse Products

    Atmospheric Science Data Center

    2013-04-01

    ... 1B1 Radiance, CCD Science;  Local Mode Data (Hi-Res Target Scenes): Terrain/Ellipsoid-Projected Radiance, 1B1 Radiance ... transform fix. ROI Image Matching improvements to blunder detection algorithm and to Image Coordinate Correction. New ancillary ...

  6. PTP1B inhibitors from Saussrurea lappa.

    PubMed

    Li, S; An, T-Y; Li, J; Shen, Q; Lou, F-C; Hu, L-H

    2006-01-01

    A new lignan glycoside, named 1,5-dihydroxypinoresinol-4'-O-beta-d-glucopyranoside (1), has been isolated from the EtOH extract of the roots of Saussurea lappa, together with twenty known compounds: (+)-1-hydroxypinoresinol-1-O-beta-D-glucopyranoside (2), fraxiresinol-4'-O-beta-D-glucopyranoside (3), (-)-olivil-4''-O-beta-D-glucopyranoside (4), 4-allyl-2,6-dimethoxybenzene-1-O-beta-D-glucopyranoside, syringin, costunolide-15-O-beta-D-glucopyranoside, chlorogenic acid, aloe-emodin-8-O-beta-D-glucopyranoside (5), rhein-8-O-beta-D-glucopyranoside (6), chrysophanol (7), emodin, dehydrocostus lactone, costunolide, beta-costic acid, reynosin, arbusculin A, alpha-cyclocostunolide, beta-cyclocostunolide, santamarine and magnolialide. Three anthraquinones (5-7) showed moderate bioactivity against human Protein Tyrosine Phosphatase 1B (hPTP1B) in vitro.

  7. Identifying and structurally characterizing CD1b in Aotus nancymaae owl monkeys.

    PubMed

    Castillo, Fabio; Guerrero, Carlos; Trujillo, Esperanza; Delgado, Gabriela; Martinez, Pilar; Salazar, Luz M; Barato, Paola; Patarroyo, Manuel E; Parra-López, Carlos

    2004-10-01

    This study reports the molecular characterization and tissue expression of the non-human Aotus nancymaae primate CD1b isoform in the search for an experimental animal model to be used in evaluating the role of non-peptide antigen-presentation molecules in the immune response to infectious agents. CD1b expression on the surface of A. nancymaae peripheral blood monocyte-derived dendritic cells, shown by flow cytometry, was made possible by using human CD1b isoform antibodies. Studying the expression of CD1b-encoded transcripts revealed this molecule's broad distribution in several tissues. The A. nancymaae CD1b transcript-encoded amino-acid sequence showed 95.5% identity with the human sequence. Such high sequence homology was reflected in the identical structural conservation of how pockets A', C' and F' and tunnel T' conforming the antigen's binding site are organized, the similar arrangement of those amino-acids interacting with the T-cell receptor (TCR) during antigen presentation, and the conservation of YQNI-motif sequence in the cytoplasmatic tail (responsible for the molecule's intracellular trafficking in humans). Comparing the structure of human CD1a and CD1b and mouse CD1d proteins with CD1b structure in A. nancymaae obtained by minimization revealed that changes in the latter molecule's alpha1 and alpha2 domains imposed a narrowing of the antigen-binding groove in A. nancymaae CD1b. The high structural similarity between A. nancymaae CD1b and that from humans presented in this study leads to A. nancymaae being proposed as a suitable experimental animal model for analyzing CD1b in vivo, mainly in bacterial and parasite infections such as tuberculosis and malaria, respectively.

  8. EMODEL_1D v. 1.0

    SciTech Connect

    Aldridge, David F.

    2016-07-06

    Program EMODEL_1D is an electromagnetic earth model construction utility designed to generate a three-dimensional (3D) uniformly-gridded representation of one-dimensional (1D) layered earth model. Each layer is characterized by the isotropic EM properties electric permittivity ?, magnetic permeability ?, and current conductivity ?. Moreover, individual layers of the model may possess a linear increase/decrease of any or all of these properties with depth.

  9. Oleanane triterpenes as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Camellia japonica.

    PubMed

    Uddin, Mohammad Nasir; Sharma, Govinda; Yang, Jun-Li; Choi, Hong Seok; Lim, Seong-Il; Kang, Keon Wook; Oh, Won Keun

    2014-07-01

    Protein tyrosine phosphatase 1B (PTP1B) plays a key role in metabolic signaling, thereby making it an exciting drug target for type 2 diabetes and obesity. Besides, there is substantial evidence that shows its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. As part of our continuous research on PTP1B inhibitors from medicinal plants, four oleanane-type triterpenes were isolated from an EtOAc-soluble extract of fruit peels of Camellia japonica (Theaceae), together with 6 previously known compounds of this class. Their structures were determined on the basis of spectroscopic data analysis (UV, IR, (1)H and (13)CNMR, HMBC, HSQC, NOESY, and MS). All isolates were evaluated for their inhibitory effects on PTP1B, as well as their cytotoxic effects against human breast cancer cell lines MCF7, MCF7/ADR, and MDA-MB-231. Several compounds with OH-3 or/and COOH-28 functionalities showed strong PTP1B inhibitory activity (IC50 values ranging from 3.77±0.11 to 6.40±0.81 μM) as well as significant cytotoxicity (IC50 values ranging from 0.51±0.05 to 13.55±1.44 μM).

  10. Heat Capacity of 1D Molecular Chains

    NASA Astrophysics Data System (ADS)

    Bagatskii, M. I.; Barabashko, M. S.; Sumarokov, V. V.; Jeżowski, A.; Stachowiak, P.

    2017-04-01

    The heat capacity of 1D chains of nitrogen and methane molecules (adsorbed in the outer grooves of bundles of closed-cap single-walled carbon nanotubes) has been studied in the temperature ranges 2-40 and 2-60 K, respectively. The temperature dependence of the heat capacity of 1D chains of nitrogen molecules below 3 K is close to a linear. It was found that the rotational heat capacity of methane molecules is a significant part of the total heat capacity of the chains throughout the whole investigated temperature range, whereas in the case of nitrogen, the librations are significant only above 15 K. The dependence of the heat capacity for methane below 10 K indicates the presence of a Schottky anomaly caused by the tunneling between the lowest energy levels of the CH4 molecule rotational spectra. Characteristic features observed in the temperature dependence of the heat capacity of 1D methane crystals are also discussed.

  11. Upstream Design and 1D-CAE

    NASA Astrophysics Data System (ADS)

    Sawada, Hiroyuki

    Recently, engineering design environment of Japan is changing variously. Manufacturing companies are being challenged to design and bring out products that meet the diverse demands of customers and are competitive against those produced by rising countries(1). In order to keep and strengthen the competitiveness of Japanese companies, it is necessary to create new added values as well as conventional ones. It is well known that design at the early stages has a great influence on the final design solution. Therefore, design support tools for the upstream design is necessary for creating new added values. We have established a research society for 1D-CAE (1 Dimensional Computer Aided Engineering)(2), which is a general term for idea, methodology and tools applicable for the upstream design support, and discuss the concept and definition of 1D-CAE. This paper reports our discussion about 1D-CAE.

  12. Helical Floquet Channels in 1D Lattices

    NASA Astrophysics Data System (ADS)

    Budich, Jan Carl; Hu, Ying; Zoller, Peter

    2017-03-01

    We show how dispersionless channels exhibiting perfect spin-momentum locking can arise in a 1D lattice model. While such spectra are forbidden by fermion doubling in static 1D systems, here we demonstrate their appearance in the stroboscopic dynamics of a periodically driven system. Remarkably, this phenomenon does not rely on any adiabatic assumptions, in contrast to the well known Thouless pump and related models of adiabatic spin pumps. The proposed setup is shown to be experimentally feasible with state-of-the-art techniques used to control ultracold alkaline earth atoms in optical lattices.

  13. Withdrawal from chronic cocaine up-regulates 5-HT1B receptors in the rat brain.

    PubMed

    Przegaliński, Edmund; Czepiel, Klaudia; Nowak, Ewa; Dlaboga, Daniel; Filip, Małgorzata

    2003-11-20

    In the present study we examined the effect of prolonged treatment with cocaine (a sensitization and discrimination paradigm) on the expression of serotonin (5-HT)(1B) receptors in rat brain structures using a quantitative autoradiographic analysis. To estimate the distribution of 5-HT(1B) receptors in several brain coronal sections, we used [N-methyl-(3)H]GR 125743, a 5-HT(1B/1D) receptor antagonist, in the presence of ketanserin (a drug used to block 5-HT(1D) receptors). The binding of [N-methyl-(3)H]GR 125743 in the areas containing dopamine cell bodies (the ventral tegmental area, the substantia nigra) and terminals (the nucleus accumbens shell and core, but not in the caudate-putamen) and in the subiculum of the hippocampus was increased after withdrawal from repeated cocaine in both the discrimination and the sensitization paradigms, either being effective as confirmed by behavioral experiments. Neither acute cocaine injection nor the psychostimulant challenge following its repeated administration affected the binding of [N-methyl-(3)H]GR 125743 in the above brain areas. Our results indicate that withdrawal from chronic cocaine induces up-regulation of 5-HT(1B) receptors in a number of rat brain structures.

  14. TNFRSF1B — EDRN Public Portal

    Cancer.gov

    TNFRSF1B, also known as TNFr2, a single-pass type I member of the TNF-receptor superfamily, forms a heterocomplex with TNF-receptor 1 that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. Although the function of IAPs in TNF-receptor signalling is unknown, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest that TNFr2 plays a role in protecting neurons from apoptosis by stimulating antioxidative pathways.

  15. Skylab Saturn 1B flight manual

    NASA Technical Reports Server (NTRS)

    1972-01-01

    A Saturn 1B Flight Manual provides launch vehicle systems descriptions and predicted performance data for the Skylab missions. Vehicle SL-2 (SA-206) is the baseline for this manual; but, as a result of the great similarity, the material is representative of SL-3 and SL-4 launch vehicles, also. The Flight Manual is not a control document but is intended primarily as an aid to astronauts who are training for Skylab missions. In order to provide a comprehensive reference for that purpose, the manual also contains descriptions of the ground support interfaces, prelaunch operations, and emergency procedures. Mission variables and constraints are summarized, and mission control monitoring and data flow during launch preparation and flight are discussed.

  16. The Phytophthora sojae Avr1d gene encodes an RxLR-dEER effector with presence and absence polymorphisms among pathogen strains.

    PubMed

    Yin, Weixiao; Dong, Suomeng; Zhai, Luchong; Lin, Yachun; Zheng, Xiaobo; Wang, Yuanchao

    2013-08-01

    Soybean root and stem rot is caused by the oomycete pathogen Phytophthora sojae. The interaction between P. sojae and soybean fits the "gene-for-gene" hypothesis. Although more than 10 P. sojae avirulence (Avr) effectors have been genetically identified, nearly half of genetically defined avr genes have been cloned. In a previous bioinformatic and global transcriptional analysis, we identified a P. sojae RxLR effector, Avr1d, which was 125 amino acids in length. Mapping data demonstrated that Avr1d presence or absence in the genome was co-segregated with the Avr1d avirulence phenotype in F2 populations. Transient expression of the Avr1d gene using co-bombardment in soybean isogenic lines revealed that this gene triggered a hypersensitive response (HR) in the presence of Rps1d. Sequencing of Avr1d genes in different P. sojae strains revealed two Avr1d alleles. Although polymorphic, the two Avr1d alleles could trigger Rps1d-mediated HR. P. sojae strains carrying either of the alleles were avirulent on Rps1d soybean lines. Avr1d was upregulated during the germinating cyst and early infection stages. Furthermore, transient expression of Avr1d in Nicotiana benthamiana suppressed BAX-induced cell death and enhanced P. capsici infection. Avr1d also suppressed effector-triggered immunity induction by associating with Avr1b and Rps1b, suggestive of a role in suppressing plant immunity.

  17. GIFTS SM EDU Level 1B Algorithms

    NASA Technical Reports Server (NTRS)

    Tian, Jialin; Gazarik, Michael J.; Reisse, Robert A.; Johnson, David G.

    2007-01-01

    The Geosynchronous Imaging Fourier Transform Spectrometer (GIFTS) SensorModule (SM) Engineering Demonstration Unit (EDU) is a high resolution spectral imager designed to measure infrared (IR) radiances using a Fourier transform spectrometer (FTS). The GIFTS instrument employs three focal plane arrays (FPAs), which gather measurements across the long-wave IR (LWIR), short/mid-wave IR (SMWIR), and visible spectral bands. The raw interferogram measurements are radiometrically and spectrally calibrated to produce radiance spectra, which are further processed to obtain atmospheric profiles via retrieval algorithms. This paper describes the GIFTS SM EDU Level 1B algorithms involved in the calibration. The GIFTS Level 1B calibration procedures can be subdivided into four blocks. In the first block, the measured raw interferograms are first corrected for the detector nonlinearity distortion, followed by the complex filtering and decimation procedure. In the second block, a phase correction algorithm is applied to the filtered and decimated complex interferograms. The resulting imaginary part of the spectrum contains only the noise component of the uncorrected spectrum. Additional random noise reduction can be accomplished by applying a spectral smoothing routine to the phase-corrected spectrum. The phase correction and spectral smoothing operations are performed on a set of interferogram scans for both ambient and hot blackbody references. To continue with the calibration, we compute the spectral responsivity based on the previous results, from which, the calibrated ambient blackbody (ABB), hot blackbody (HBB), and scene spectra can be obtained. We now can estimate the noise equivalent spectral radiance (NESR) from the calibrated ABB and HBB spectra. The correction schemes that compensate for the fore-optics offsets and off-axis effects are also implemented. In the third block, we developed an efficient method of generating pixel performance assessments. In addition, a

  18. Protein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer’s Therapy?

    PubMed Central

    Vieira, Marcelo N. N.; Lyra e Silva, Natalia M.; Ferreira, Sergio T.; De Felice, Fernanda G.

    2017-01-01

    Despite significant advances in current understanding of mechanisms of pathogenesis in Alzheimer’s disease (AD), attempts at drug development based on those discoveries have failed to translate into effective, disease-modifying therapies. AD is a complex and multifactorial disease comprising a range of aberrant cellular/molecular processes taking part in different cell types and brain regions. As a consequence, therapeutics for AD should be able to block or compensate multiple abnormal pathological events. Here, we examine recent evidence that inhibition of protein tyrosine phosphatase 1B (PTP1B) may represent a promising strategy to combat a variety of AD-related detrimental processes. Besides its well described role as a negative regulator of insulin and leptin signaling, PTB1B recently emerged as a modulator of various other processes in the central nervous system (CNS) that are also implicated in AD. These include signaling pathways germane to learning and memory, regulation of synapse dynamics, endoplasmic reticulum (ER) stress and microglia-mediated neuroinflammation. We propose that PTP1B inhibition may represent an attractive and yet unexplored therapeutic approach to correct aberrant signaling pathways linked to AD. PMID:28197094

  19. Glass-based 1-D dielectric microcavities

    NASA Astrophysics Data System (ADS)

    Chiasera, Alessandro; Scotognella, Francesco; Valligatla, Sreeramulu; Varas, Stefano; Jasieniak, Jacek; Criante, Luigino; Lukowiak, Anna; Ristic, Davor; Gonçalves, Rogeria Rocha; Taccheo, Stefano; Ivanda, Mile; Righini, Giancarlo C.; Ramponi, Roberta; Martucci, Alessandro; Ferrari, Maurizio

    2016-11-01

    We have developed a reliable RF sputtering techniques allowing to fabricate glass-based one dimensional microcavities, with high quality factor. This property is strongly related to the modification of the density of states due to the confinement of the gain medium in a photonic band gap structure. In this short review we present some of the more recent results obtained by our team exploiting these 1D microcavities. In particular we present: (1) Er3+ luminescence enhancement of the 4I13/2 → 4I15/2 transition; (2) broad band filters based on disordered 1-D photonic structures; (3) threshold defect-mode lasing action in a hybrid structure.

  20. Centrosome Positioning in 1D Cell Migration

    NASA Astrophysics Data System (ADS)

    Adlerz, Katrina; Aranda-Espinoza, Helim

    During cell migration, the positioning of the centrosome and nucleus define a cell's polarity. For a cell migrating on a two-dimensional substrate the centrosome is positioned in front of the nucleus. Under one-dimensional confinement, however, the centrosome is positioned behind the nucleus in 60% of cells. It is known that the centrosome is positioned by CDC42 and dynein for cells moving on a 2D substrate in a wound-healing assay. It is currently unknown, however, if this is also true for cells moving under 1D confinement, where the centrosome position is often reversed. Therefore, centrosome positioning was studied in cells migrating under 1D confinement, which mimics cells migrating through 3D matrices. 3 to 5 μm fibronectin lines were stamped onto a glass substrate and cells with fluorescently labeled nuclei and centrosomes migrated on the lines. Our results show that when a cell changes directions the centrosome position is maintained. That is, when the centrosome is between the nucleus and the cell's trailing edge and the cell changes direction, the centrosome will be translocated across the nucleus to the back of the cell again. A dynein inhibitor did have an influence on centrosome positioning in 1D migration and change of directions.

  1. Practical route to the left wing of CTX1B and total syntheses of CTX1B and 54-deoxyCTX1B.

    PubMed

    Yamashita, Shuji; Takeuchi, Katsutoshi; Koyama, Takuya; Inoue, Masayuki; Hayashi, Yujiro; Hirama, Masahiro

    2015-02-02

    Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant-sensitive bisallylic ether moiety, by a 6-exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B.

  2. Kinetics and Mechanism of Protein Tyrosine Phosphatase 1B (PTP1B) Inactivation by Acrolein

    PubMed Central

    Seiner, Derrick R.; LaButti, Jason N.; Gates, Kent S.

    2010-01-01

    Human cells are exposed to the electrophilic α,β-unsaturated aldehyde acrolein from a variety of sources. Reaction of acrolein with functionally critical protein thiol residues can yield important biological consequences. Protein tyrosine phosphatases (PTPs) are an important class of cysteine-dependent enzymes whose reactivity with acrolein previously has not been well characterized. These enzymes catalyze the dephosphorylation of phosphotyrosine residues on proteins via a phosphocysteine intermediate. PTPs work in tandem with protein tyrosine kinases to regulate a number of critically important mammalian signal transduction pathways. We find that acrolein is a potent time-dependent inactivator of the enzyme PTP1B (kinact = 0.02 ± 0.005 s−1, KI = 2.3 ± 0.6 × 10−4 M). Enzyme activity does not return upon gel filtration of the inactivated enzyme and addition of the competitive phosphatase inhibitor vanadate slows inactivation of PTP1B by acrolein. Together these observations suggest that acrolein covalently modifies the active site of PTP1B. Mass spectrometric analysis reveals that acrolein modifies the catalytic cysteine residue at the active site of the enzyme. Aliphatic aldehydes such as glyoxal, acetaldehyde, and propanal are relatively weak inactivators of PTP1B under the conditions employed here. Similarly, unsaturated aldehydes such as crotonaldehyde and 3-methyl-2-butenal bearing substitution at the alkene terminus are poor inactivators of the enzyme. Overall, the data suggest that enzyme inactivation occurs via conjugate addition of the catalytic cysteine residue to the carbon-carbon double bond of acrolein. The results indicate that inactivation of PTPs should be considered as a possible contributor to the diverse biological activities of acrolein and structurally-related α,β-unsaturated aldehydes. PMID:17655273

  3. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  4. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  5. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  6. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.9 Confidentiality of...

  7. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  8. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  9. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.20 Request...

  10. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  11. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.9 Confidentiality of...

  12. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.20 Request...

  13. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  14. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  15. 7 CFR 1b.4 - Exclusion of agencies.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Exclusion of agencies. 1b.4 Section 1b.4 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.4 Exclusion of agencies. (a... activities that have been found to have no individual or cumulative effect on the human environment. The...

  16. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  17. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  18. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  19. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  20. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  1. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  2. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  3. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  4. 18 CFR 1b.3 - Scope of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Scope of investigations. 1b.3 Section 1b.3 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.3 Scope of investigations....

  5. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  6. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  7. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  8. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.18 Right to...

  9. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  10. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  11. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  12. 18 CFR 1b.16 - Rights of witnesses.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Rights of witnesses. 1b.16 Section 1b.16 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.16 Rights of witnesses. (a)...

  13. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  14. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  15. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  16. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.8 Requests for...

  17. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  18. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.10 By whom conducted....

  19. 18 CFR 1b.11 - Limitation on participation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Limitation on participation. 1b.11 Section 1b.11 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.11 Limitation...

  20. 18 CFR 1b.7 - Procedure after investigation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Procedure after investigation. 1b.7 Section 1b.7 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.7 Procedure after...

  1. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  2. 18 CFR 1b.9 - Confidentiality of investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Confidentiality of investigations. 1b.9 Section 1b.9 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... Freedom of Information Act disclosure are set forth in 18 CFR part 3b and § 1b.20. A request...

  3. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  4. 18 CFR 1b.4 - Types of investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Types of investigations. 1b.4 Section 1b.4 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.4 Types of...

  5. Multiple Intravenous Infusions Phase 1b

    PubMed Central

    Cassano-Piché, A; Fan, M; Sabovitch, S; Masino, C; Easty, AC

    2012-01-01

    Background Minimal research has been conducted into the potential patient safety issues related to administering multiple intravenous (IV) infusions to a single patient. Previous research has highlighted that there are a number of related safety risks. In Phase 1a of this study, an analysis of 2 national incident-reporting databases (Institute for Safe Medical Practices Canada and United States Food and Drug Administration MAUDE) found that a high percentage of incidents associated with the administration of multiple IV infusions resulted in patient harm. Objectives The primary objectives of Phase 1b of this study were to identify safety issues with the potential to cause patient harm stemming from the administration of multiple IV infusions; and to identify how nurses are being educated on key principles required to safely administer multiple IV infusions. Data Sources and Review Methods A field study was conducted at 12 hospital clinical units (sites) across Ontario, and telephone interviews were conducted with program coordinators or instructors from both the Ontario baccalaureate nursing degree programs and the Ontario postgraduate Critical Care Nursing Certificate programs. Data were analyzed using Rasmussen’s 1997 Risk Management Framework and a Health Care Failure Modes and Effects Analysis. Results Twenty-two primary patient safety issues were identified with the potential to directly cause patient harm. Seventeen of these (critical issues) were categorized into 6 themes. A cause-consequence tree was established to outline all possible contributing factors for each critical issue. Clinical recommendations were identified for immediate distribution to, and implementation by, Ontario hospitals. Future investigation efforts were planned for Phase 2 of the study. Limitations This exploratory field study identifies the potential for errors, but does not describe the direct observation of such errors, except in a few cases where errors were observed. Not all

  6. 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.

  7. GD1b-specific antibodies may bind to complex of GQ1b and GM1, causing ataxia.

    PubMed

    Yuki, Nobuhiro; Fukami, Yuki; Yanaka, Chiaki; Koike, Saiko; Hirata, Koichi

    2014-08-01

    Monospecific IgG antibodies to GD1b ganglioside (GD1b-specific antibodies) have been found in patients with acute ataxic neuropathy and Guillain-Barré syndrome, but the association of the GD1b-specific antibodies with specific neurological conditions has yet to be established. We tested sera from more than 10,000 patients with various neurological disorders, and found six sera, which contained IgG antibodies to GD1b, but not to LM1, GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, GT1b and GQ1b. All six patients who carried GD1b-specific antibodies presented with acute onset of ataxia and monophasic course of the illness, of whom five demonstrated cerebellar-like ataxia. Four patients had antecedent symptoms of upper respiratory tract infection. The six patients demonstrated areflexia, and four complained of distal numbness. All the six patients who had the GD1b-specific antibodies carried IgG antibodies to complex of GQ1b/GM1 and GT1a/GM1. GD1b-specific antibodies were significantly absorbed by GQ1b/GM1 and GT1a/GM1 and anti-GQ1b/GM1 and -GT1a/GM1 antibodies were absorbed by GD1b. In conclusion, the GD1b-specific antibodies, which recognizes GQ1b/GM1 or GT1a/GM1 complex, are associated with acute ataxia.

  8. Extrapolation of fractal dimensions of natural fracture networks in dolomites from 1-D to 2-D environment

    NASA Astrophysics Data System (ADS)

    Verbovšek, T.

    2009-04-01

    Fractal dimensions of fracture networks (D) are usually determined from 2-D objects, like the digitized fracture traces in outcrops. Sometimes, extrapolations to higher dimensions are required if the measurements (for example fracture traces in the boreholes or in the scanlines) are performed in 1-D environment (D1-D) and are later upscaled to higher dimensions (D2-D). For isotropic fractals this relation should be straight-forward according to the theory: D2-D = D1-D +1, as the intersection of a 2-D fractal with a plane results in a fractal with D1-D equal to D2-D minus one. Some authors have questioned this relation and proposed different empirical relationships. Still, there exist very few field studies of natural fracture networks to support or test such a relationship. The study was therefore focused on the analysis of 23 natural fracture networks in Triassic dolomites in Slovenia. The traces of these fractures were analyzed separately in both 1-D and 2-D environments, and relationships between the obtained fractal dimensions were determined. For 2-D data, the digitized images of fracture traces in 2048x2048 pixel resolution were analyzed by the box-counting method, considering truncation and censoring effects (the 'cut-off' method, using only the valid data right of the cut-off points) and also by considering the complete data range interval (the 'full' method). These values were consequently compared to 1-D values. Those were obtained by dissecting images in both x- and y-directions into 2048 smaller linear images of 1-pixel width, simulating the intersection with a plane. Such line images were then examined by the fracture line-counting method, a 1-D equivalent of the box-counting technique. Results show that the values of all fractal dimensions, regardless of the different fracture networks or the method used, lie in a very narrow data range, and the standard deviations are very small (up to 0.03). The small range can be attributed to a similar fracturing

  9. Kinetics of O(1D) + H2O and O(1D) + H2: absolute rate coefficients and O(3P) yields between 227 and 453 K.

    PubMed

    Vranckx, Stijn; Peeters, Jozef; Carl, Shaun

    2010-08-28

    The rate coefficients for the crucial atmospheric reactions of O((1)D) with H(2)O and H(2), k(1) and k(2), were measured over a wide temperature range using O((1)D) detection based on the chemiluminescence reaction of O((1)D) with C(2)H. Analyzing the decays of the chemiluminescence intensities yielded a value for k(1)(T) of (1.70 x 10(-10)exp[36 K/T]) cm(3) s(-1). Multiplying or dividing k(1)(T) by a factor f(T) = 1.04 exp(5.59(|1 K/T- 1/287|)), gives the 95% confidence limits; our new determination, in good agreement with previous studies, further reduces the uncertainty in k(1). An extended study of k(2) yielded a temperature independent rate constant of (1.35 +/- 0.05) x 10(-10) cm(3) s(-1). This precise value, based on an extended set of determinations with very low scatter, is significantly larger than the current recommendations, as were two other recent k(2) determinations. Secondly, the fractions of O((1)D) quenched to O((3)P) by H(2)O and H(2), k(1b)/k(1) and k(2b)/k(2), were precisely determined from fits to chemiluminescence decays. A temperature-independent value for k(1b)/k(1) of 0.010 +/- 0.003 was found. For the quenching fraction k(2b)/k(2) a value of 0.007 +/- 0.007 was obtained at room temperature. Both determinations are significantly smaller than values and upper limits from previous studies.

  10. 1D-VAR Retrieval Using Superchannels

    NASA Technical Reports Server (NTRS)

    Liu, Xu; Zhou, Daniel; Larar, Allen; Smith, William L.; Schluessel, Peter; Mango, Stephen; SaintGermain, Karen

    2008-01-01

    Since modern ultra-spectral remote sensors have thousands of channels, it is difficult to include all of them in a 1D-var retrieval system. We will describe a physical inversion algorithm, which includes all available channels for the atmospheric temperature, moisture, cloud, and surface parameter retrievals. Both the forward model and the inversion algorithm compress the channel radiances into super channels. These super channels are obtained by projecting the radiance spectra onto a set of pre-calculated eigenvectors. The forward model provides both super channel properties and jacobian in EOF space directly. For ultra-spectral sensors such as Infrared Atmospheric Sounding Interferometer (IASI) and the NPOESS Airborne Sounder Testbed Interferometer (NAST), a compression ratio of more than 80 can be achieved, leading to a significant reduction in computations involved in an inversion process. Results will be shown applying the algorithm to real IASI and NAST data.

  11. The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha1B-adrenoceptors.

    PubMed

    Nojimoto, F D; Mueller, A; Hebeler-Barbosa, F; Akinaga, J; Lima, V; Kiguti, L R de A; Pupo, A S

    2010-01-01

    Although it is long known that the tricyclic antidepressants amitriptyline, nortriptyline and imipramine inhibit the noradrenaline transporter and alpha(1)-adrenoceptors with similar affinities, which may lead to self-cancelling actions, the selectivity of these drugs for alpha(1)-adrenoceptor subtypes is unknown. The present study investigates the selectivity of amitriptyline, nortriptyline and imipramine for human recombinant and rat native alpha(1)-adrenoceptor subtypes. The selectivity of amitriptyline, nortriptyline and imipramine was investigated in HEK-293 cells expressing each of the human alpha(1)-subtypes and in rat native receptors from the vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)) through [(3)H]prazosin binding, and noradrenaline-induced intracellular Ca(2+) increases and contraction assays. Amitriptyline, nortriptyline and imipramine showed considerably higher affinities for alpha(1A)- (approximately 25- to 80-fold) and alpha(1D)-adrenoceptors (approximately 10- to 25-fold) than for alpha(1B)-adrenoceptors in both contraction and [(3)H]prazosin binding assays with rat native and human receptors, respectively. In addition, amitriptyline, nortriptyline and imipramine were substantially more potent in the inhibition of noradrenaline-induced intracellular Ca(2+) increases in HEK-293 cells expressing alpha(1A)- or a truncated version of alpha(1D)-adrenoceptors which traffics more efficiently towards the cell membrane than in cells expressing alpha(1B)-adrenoceptors. Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human alpha(1B)-adrenoceptors than of alpha(1A)- and alpha(1D)-adrenoceptors. The differential affinities for these receptors indicate that the alpha(1)-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the alpha(1B)-adrenoceptor. This may be important for the behavioural effects of these

  12. Selectivity and potency of microcystin congeners against OATP1B1 and OATP1B3 expressing cancer cells.

    PubMed

    Niedermeyer, Timo H J; Daily, Abigail; Swiatecka-Hagenbruch, Monika; Moscow, Jeffrey A

    2014-01-01

    Microcystins are potent phosphatase inhibitors and cellular toxins. They require active transport by OATP1B1 and OATP1B3 transporters for uptake into human cells, and the high expression of these transporters in the liver accounts for their selective hepatic toxicity. Several human tumors have been shown to have high levels of expression of OATP1B3 but not OATP1B1, the main transporter in liver cells. We hypothesized that microcystin variants could be isolated that are transported preferentially by OATP1B3 relative to OATP1B1 to advance as anticancer agents with clinically tolerable hepatic toxicity. Microcystin variants have been isolated and tested for cytotoxicity in cancer cells stably transfected with OATP1B1 and OATP1B3 transporters. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. As microcystin structure has a significant impact on transporter selectivity, it is potentially possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs.

  13. Amyloid-beta peptide binds to microtubule-associated protein 1B (MAP1B).

    PubMed

    Gevorkian, Goar; Gonzalez-Noriega, Alfonso; Acero, Gonzalo; Ordoñez, Jorge; Michalak, Colette; Munguia, Maria Elena; Govezensky, Tzipe; Cribbs, David H; Manoutcharian, Karen

    2008-05-01

    Extracellular and intraneuronal formation of amyloid-beta aggregates have been demonstrated to be involved in the pathogenesis of Alzheimer's disease. However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of targets have deleterious effects on cellular functions. In the present study we have shown for the first time that amyloid-beta 1-42 bound to a peptide comprising the microtubule binding domain of the heavy chain of microtubule-associated protein 1B by the screening of a human brain cDNA library expressed on M13 phage. This interaction may explain, in part, the loss of neuronal cytoskeletal integrity, impairment of microtubule-dependent transport and synaptic dysfunction observed previously in Alzheimer's disease.

  14. AMYLOID-β PEPTIDE BINDS TO MICROTUBULE-ASSOCIATED PROTEIN 1B (MAP1B)

    PubMed Central

    Gevorkian, Goar; Gonzalez-Noriega, Alfonso; Acero, Gonzalo; Ordoñez, Jorge; Michalak, Colette; Munguia, Maria Elena; Govezensky, Tzipe; Cribbs, David H.; Manoutcharian, Karen

    2008-01-01

    Extracellular and intraneuronal formation of amyloid-beta aggregates have been demonstrated to be involved in the pathogenesis of Alzheimer’s disease. However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of targets have deleterious effects on cellular functions. In the present study we have shown for the first time that amyloid-beta 1-42 bound to a peptide comprising the microtubule binding domain of the heavy chain of microtubule-associated protein 1B by the screening of a human brain cDNA library expressed on M13 phage. This interaction may explain, in part, the loss of neuronal cytoskeletal integrity, impairment of microtubule-dependent transport and synaptic dysfunction observed previously in Alzheimer’s disease. PMID:18079022

  15. Curated human hyperbilirubinemia data and the respective OATP1B1 and 1B3 inhibition predictions.

    PubMed

    Kotsampasakou, Eleni; Escher, Sylvia E; Ecker, Gerhard F

    2017-04-01

    Hyperbilirubinemia is a pathological condition, very often indicative of underlying liver condition that is characterized by excessive accumulation of conjugated or unconjugated bilirubin in sinusoidal blood. In literature there are several indications associating the inhibition of the basolateral hepatic transporters Organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and 1B3) with hyperbilirubinemia. In this article, we present a curated human hyperbilirubinemia dataset and the respective OATP1B1 and 1B3 inhibition predictions obtained from an effort to generate a classification model for hyperbilirubinemia. These data originate from the research article "Linking organic anion transporting polypeptide 1b1 and 1b3 (oatp1b1 and oatp1b3) interaction profiles to hepatotoxicity- the hyperbilirubinemia use case" (E. Kotsampasakou, S.E. Escher, G.F. Ecker, 2017) [1]. We further provide the full list of descriptors used for generating the hyperbilirubinemia classification models as well as the calculated descriptors for each compound of the dataset that was used to build the classification model.

  16. Overexpression and enhanced specific activity of aldoketo reductases (AKR1B1 & AKR1B10) in human breast cancers.

    PubMed

    Reddy, K Ashok; Kumar, P Uday; Srinivasulu, M; Triveni, B; Sharada, K; Ismail, Ayesha; Reddy, G Bhanuprakash

    2017-02-01

    The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors.

  17. Quinazoline derivatives as selective CYP1B1 inhibitors.

    PubMed

    Mohd Siddique, Mohd Usman; McCann, Glen J P; Sonawane, Vinay R; Horley, Neill; Gatchie, Linda; Joshi, Prashant; Bharate, Sandip B; Jayaprakash, Venkatesan; Sinha, Barij N; Chaudhuri, Bhabatosh

    2017-04-21

    CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid 'O' atom with 'N' atom led to the prediction that a 'quinazoline' scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells.

  18. ARID1B-mediated disorders: Mutations and possible mechanisms

    PubMed Central

    Sim, Joe C. H.; White, Susan M; Lockhart, Paul J.

    2015-01-01

    Summary Mutations in the gene encoding AT-rich interactive domain-containing protein 1B (ARID1B) were recently associated with multiple syndromes characterized by developmental delay and intellectual disability, in addition to nonsyndromic intellectual disability. While the majority of ARID1B mutations identified to date are predicted to result in haploinsufficiency, the underlying pathogenic mechanisms have yet to be fully understood. ARID1B is a DNA-binding subunit of the Brahma-associated factor chromatin remodelling complexes, which play a key role in the regulation of gene activity. The function of remodelling complexes can be regulated by their subunit composition, and there is some evidence that ARID1B is a component of the neuron-specific chromatin remodelling complex. This complex is involved in the regulation of stem/progenitor cells exiting the cell cycle and differentiating into postmitotic neurons. Recent research has indicated that alterations in the cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency in fibroblasts derived from affected individuals. This review describes studies linking ARID1B to neurodevelopmental disorders and it summarizes the function of ARID1B to provide insights into the pathogenic mechanisms underlying ARID1B-mediated disorders. In conclusion, ARID1B is likely to play a key role in neurodevelopment and reduced levels of wild-type protein compromise normal brain development. Additional studies are required to determine the mechanisms by which impaired neural development contributes to the intellectual disability and speech impairment that are consistently observed in individuals with ARID1B haploinsufficiency. PMID:25674384

  19. Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

    PubMed Central

    Jiang, Cheng-shi; Liang, Lin-fu; Guo, Yue-wei

    2012-01-01

    This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented. PMID:22941286

  20. Host range of the potential biopesticide Pea Albumin 1b (PA1b) is limited to insects.

    PubMed

    Rahioui, Isabelle; Eyraud, Vanessa; Karaki, Lamis; Sasse, Florenz; Carre-Pierrat, Maïté; Qin, An; Zheng, Ming H; Toepfer, Stefan; Sivignon, Catherine; Royer, Corinne; Da Silva, Pedro; Gressent, Frédéric

    2014-10-01

    The Pea Albumin 1 subunit b (PA1b) peptide is an entomotoxin extracted from legume seeds with lethal activity towards several insect pests. Its toxic activity occurs after the perception of PA1b by a plasmalemmic proton pump (V-ATPase) in the insects. Assays revealed that PA1b showed no activity towards mammalian cells displaying high V-ATPase activity. Similarly, PA1b displayed no binding activity and no biological activity towards other non-insect organisms. We demonstrate here that binding to labelled PA1b was found in all the insect families tested, regardless of the sensitivity or insensitivity of the individual species. The coleopteran Bruchidae, which are mainly legume seed pests, were found to be fully resistant. A number of insect species were seen to be insensitive to the toxin although they exhibited binding activity for the labelled PA1b. The fruit fly, Drosophila melanogaster (Diptera), was generally insensitive when maintained on an agar diet, but the fly appeared to be sensitive to PA1b in bioassays using a different diet. In conclusion, the PA1b toxin provides legumes with a major source of resistance to insects, and insects feeding on legume seeds need to overcome this plant resistance by disrupting the PA1b - V-ATPase interaction.

  1. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  2. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  3. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18...

  4. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... of facts or memoranda of law for the purpose of explaining said person's position or...

  5. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... investigations should set forth the alleged violation of law with supporting documentation and information...

  6. 18 CFR 1b.18 - Right to submit statements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Right to submit statements. 1b.18 Section 1b.18 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... of facts or memoranda of law for the purpose of explaining said person's position or...

  7. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... laws of the United States and the regulations of the Commission. Investigating Officers shall have...

  8. 18 CFR 1b.10 - By whom conducted.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false By whom conducted. 1b.10 Section 1b.10 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... laws of the United States and the regulations of the Commission. Investigating Officers shall have...

  9. 18 CFR 1b.8 - Requests for Commission investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Requests for Commission investigations. 1b.8 Section 1b.8 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... investigations should set forth the alleged violation of law with supporting documentation and information...

  10. Acute myelogenous leukemia and glycogen storage disease 1b.

    PubMed

    Pinsk, Maury; Burzynski, Jeffrey; Yhap, Margaret; Fraser, Robert B; Cummings, Brian; Ste-Marie, Micheline

    2002-12-01

    Glycogen storage disease 1b (GSD 1b) is caused by a deficiency of glucose-6-phosphate translocase and the intracellular accumulation of glycogen. The disease presents with failure to thrive, hepatomegaly, hypoglycemia, lactic acidosis, as well as neutropenia causing increased susceptibility to pyogenic infections. We present a case of a young woman with GSD 1b who developed acute myelogenous leukemia while on long-term granulocyte colony-stimulating factor therapy. The presence of two rare diseases in a single patient raises suspicion that GSD 1b and acute myelogenous leukemia are linked. Surveillance for acute myelogenous leukemia should become part of the long-term follow-up for GSD 1b.

  11. CYP1B1 and hormone-induced cancer.

    PubMed

    Gajjar, Ketan; Martin-Hirsch, Pierre L; Martin, Francis L

    2012-11-01

    Cancers in hormone-responsive tissues (e.g., breast, ovary, endometrium, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to date suggest that endogenous/exogenous oestrogen and environmental carcinogens may play a role in development and/or progression of hormone-induced cancers via oxidative oestrogen metabolism. Cytochrome P450 1B1 is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Although CYP1B1 is expressed in many cancers, particularly high levels of expression are observed in oestrogen-mediated disease. CYP1B1 is more readily found in tumour tissue compared to normal. Given the role of CYP1B1 in pro-carcinogen and oestrogen metabolism, polymorphisms in CYP1B1 could result in modifications in its enzyme activity and subsequently lead to hormone-mediated carcinogenesis. CYP1B1 may also be involved in progression of the disease by altering the tissue response to hormones and clinical response to chemotherapy. The exact mechanism behind these events is complex and unclear. Only a few functional single nucleotide polymorphisms of CYP1B1 are known to result in amino acid substitutions and have been extensively investigated. Studies examining the contribution of different CYP1B1 alleles to hormone-mediated cancer risks are inconsistent. The main focus of this review is to appraise the available studies linking the pathogenesis of the hormone-induced cancers to various CYP1B1 polymorphisms. Additionally, we explore the role of a neuronal protein, γ-synuclein, in CYP1B1-mediated pathogenesis.

  12. Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.

    PubMed

    Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D

    2016-08-01

    We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Cε, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 hyperalgesia. The prolongation of PGE2 hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.

  13. Characterization of 5-HT1D receptor binding sites in post-mortem human brain cortex.

    PubMed Central

    Martial, J; de Montigny, C; Cecyre, D; Quirion, R

    1991-01-01

    The present study provides further evidence for the presence of serotonin1D (5-HT1D) receptors in post-mortem human brain. Receptor binding parameters in temporal cortex homogenates were assessed using [3H]5-HT in the presence of 100 nM 8-OH-DPAT, 1 microM propranolol and 1 microM mesulergine to prevent labelling of the 5-HT1A, 5-HT1B and 5-HT1C sites, respectively. Under these conditions, [3H]5-HT apparently bound to a class of high affinity (Kd = 5.0 +/- 1.0 nM) low capacity (Bmax = 96 +/- 23 fmol/mg protein) sites. In competition experiments, 5-HT and 5-carboxyamidotryptamine (5-CT), as well as ergotamine, lysergic acid, sumatriptan and RU-24969 exhibited high affinity for these sites. This pharmacological profile is concordant with the ligand selectivity pattern reported for 5-HT1D receptors in other species and thus provides further evidence for its existence in human temporal cortex. In addition, the competition profile of some ligands, particularly of unlabelled 5-HT, 5-CT and ergotamine, revealed the existence of a lower affinity binding site. The latter suggests receptor heterogeneity or the presence of a lower affinity state of 5-HT1D receptors. PMID:1911737

  14. Synthesis and characterization of potent and selective mu-opioid receptor antagonists, [Dmt(1), D-2-Nal(4)]endomorphin-1 (Antanal-1) and [Dmt(1), D-2-Nal(4)]endomorphin-2 (Antanal-2).

    PubMed

    Fichna, Jakub; do-Rego, Jean-Claude; Chung, Nga N; Lemieux, Carole; Schiller, Peter W; Poels, Jeroen; Broeck, Jozef Vanden; Costentin, Jean; Janecka, Anna

    2007-02-08

    To synthesize potent antagonists of the mu-opioid receptor, we prepared a series of endomorphin-1 and endomorphin-2 analogues with 3-(1-naphthyl)-d-alanine (d-1-Nal) or 3-(2-naphthyl)-d-alanine (d-2-Nal) in position 4. Some of these analogues displayed weak antagonist properties. We tried to strengthen these properties by introducing the structurally modified tyrosine residue 2,6-dimethyltyrosine (Dmt) in place of Tyr1. Among the synthesized compounds, [Dmt1, d-2-Nal4]endomorphin-1, designated antanal-1, and [Dmt1, d-2-Nal4]endomorphin-2, designated antanal-2, turned out to be highly potent and selective mu-opioid receptor antagonists, as judged on the basis of two functional assays, the receptor binding assay and the hot plate test of analgesia. Interestingly, another analogue of this series, [Dmt1, d-1-Nal4]endomorphin-1, turned out to be a moderately potent mixed mu-agonist/delta-antagonist.

  15. Reduced ultrasonic vocalizations in vasopressin 1b knockout mice.

    PubMed

    Scattoni, M L; McFarlane, H G; Zhodzishsky, V; Caldwell, H K; Young, W S; Ricceri, L; Crawley, J N

    2008-03-05

    The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages.

  16. Transcription Factor GFI1B in Health and Disease

    PubMed Central

    Anguita, Eduardo; Candel, Francisco J.; Chaparro, Alberto; Roldán-Etcheverry, Juan J.

    2017-01-01

    Many human diseases arise through dysregulation of genes that control key cell fate pathways. Transcription factors (TFs) are major cell fate regulators frequently involved in cancer, particularly in leukemia. The GFI1B gene, coding a TF, was identified by sequence homology with the oncogene growth factor independence 1 (GFI1). Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain. Gfi1 is essential for neutrophil differentiation in mice. In humans, GFI1 mutations are associated with severe congenital neutropenia. Gfi1 is also required for B and T lymphopoiesis. However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages. Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function. Loss of Gfi1b in adult mice increases the absolute numbers of hematopoietic stem cells (HSCs) that are less quiescent than wild-type HSCs. In keeping with this key role in cell fate, GFI1B is emerging as a gene involved in cancer, which also includes solid tumors. In fact, abnormal activation of GFI1B and GFI1 has been related to human medulloblastoma and is also likely to be relevant in blood malignancies. Several pieces of evidence supporting this statement will be detailed in this mini review.

  17. Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana.

    PubMed

    Shah, Muhammad Raza; Ishtiaq; Hizbullah, Syed Muhammad; Habtemariam, Solomon; Zarrelli, Armando; Muhammad, Akhtar; Collina, Simona; Khan, Inamulllah

    2016-08-01

    Artemisia roxburghiana is used in traditional medicine for treating various diseases including diabetes. The present study was designed to evaluate the antidiabetic potential of active constituents by using protein tyrosine phosphatase 1B (PTP1B) as a validated target for management of diabetes. Various compounds were isolated as active principles from the crude methanolic extract of aerial parts of A. roxburghiana. All compounds were screened for PTP1B inhibitory activity. Molecular docking simulations were performed to investigate the mechanism behind PTP1B inhibition of the isolated compound and positive control, ursolic acid. Betulinic acid, betulin and taraxeryl acetate were the active PTP1B principles with IC50 values 3.49 ± 0.02, 4.17 ± 0.03 and 87.52 ± 0.03 µM, respectively. Molecular docking studies showed significant molecular interactions of the triterpene inhibitors with Gly220, Cys215, Gly218 and Asp48 inside the active site of PTP1B. The antidiabetic activity of A. roxburghiana could be attributed due to PTP1B inhibition by its triterpene constituents, betulin, betulinic acid and taraxeryl acetate. Computational insights of this study revealed that the C-3 and C-17 positions of the compounds needs extensive optimization for the development of new lead compounds.

  18. Identification of Novel Inhibitors of Organic Anion Transporting Polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) Using a Consensus Vote of Six Classification Models

    PubMed Central

    2015-01-01

    Organic anion transporting polypeptides 1B1 and 1B3 are transporters selectively expressed on the basolateral membrane of the hepatocyte. Several studies reveal that they are involved in drug–drug interactions, cancer, and hyperbilirubinemia. In this study, we developed a set of classification models for OATP1B1 and 1B3 inhibition based on more than 1700 carefully curated compounds from literature, which were validated via cross-validation and by use of an external test set. After combining several sets of descriptors and classifiers, the 6 best models were selected according to their statistical performance and were used for virtual screening of DrugBank. Consensus scoring of the screened compounds resulted in the selection and purchase of nine compounds as potential dual inhibitors and of one compound as potential selective OATP1B3 inhibitor. Biological testing of the compounds confirmed the validity of the models, yielding an accuracy of 90% for OATP1B1 and 80% for OATP1B3, respectively. Moreover, at least half of the new identified inhibitors are associated with hyperbilirubinemia or hepatotoxicity, implying a relationship between OATP inhibition and these severe side effects. PMID:26469880

  19. Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.

    PubMed

    Marada, Venkata V V R; Flörl, Saskia; Kühne, Annett; Burckhardt, Gerhard; Hagos, Yohannes

    2015-03-06

    Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.

  20. TCR bias and affinity define two compartments of the CD1b-glycolipid-specific T Cell repertoire.

    PubMed

    Van Rhijn, Ildiko; Gherardin, Nicholas A; Kasmar, Anne; de Jager, Wilco; Pellicci, Daniel G; Kostenko, Lyudmila; Tan, Li Lynn; Bhati, Mugdha; Gras, Stephanie; Godfrey, Dale I; Rossjohn, Jamie; Moody, D Branch

    2014-05-01

    Current views emphasize TCR diversity as a key feature that differentiates the group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 systems. Whereas TCR sequence motifs define CD1d-reactive NKT cells, the available data do not allow a TCR-based organization of the group 1 CD1 repertoire. The observed TCR diversity might result from donor-to-donor differences in TCR repertoire, as seen for MHC-restricted T cells. Alternatively, diversity might result from differing CD1 isoforms, Ags, and methods used to identify TCRs. Using CD1b tetramers to isolate clones recognizing the same glycolipid, we identified a previously unknown pattern of V gene usage (TRAV17, TRBV4-1) among unrelated human subjects. These TCRs are distinct from those present on NKT cells and germline-encoded mycolyl lipid-reactive T cells. Instead, they resemble the TCR of LDN5, one of the first known CD1b-reactive clones that was previously thought to illustrate the diversity of the TCR repertoire. Interdonor TCR conservation was observed in vitro and ex vivo, identifying LDN5-like T cells as a distinct T cell type. These data support TCR-based organization of the CD1b repertoire, which consists of at least two compartments that differ in TCR sequence motifs, affinity, and coreceptor expression.

  1. CYP1B1: a unique gene with unique characteristics.

    PubMed

    Faiq, Muneeb A; Dada, Rima; Sharma, Reetika; Saluja, Daman; Dada, Tanuj

    2014-01-01

    CYP1B1, a recently described dioxin inducible oxidoreductase, is a member of the cytochrome P450 superfamily involved in the metabolism of estradiol, retinol, benzo[a]pyrene, tamoxifen, melatonin, sterols etc. It plays important roles in numerous physiological processes and is expressed at mRNA level in many tissues and anatomical compartments. CYP1B1 has been implicated in scores of disorders. Analyses of the recent studies suggest that CYP1B1 can serve as a universal/ideal cancer marker and a candidate gene for predictive diagnosis. There is plethora of literature available about certain aspects of CYP1B1 that have not been interpreted, discussed and philosophized upon. The present analysis examines CYP1B1 as a peculiar gene with certain distinctive characteristics like the uniqueness in its chromosomal location, gene structure and organization, involvement in developmentally important disorders, tissue specific, not only expression, but splicing, potential as a universal cancer marker due to its involvement in key aspects of cellular metabolism, use in diagnosis and predictive diagnosis of various diseases and the importance and function of CYP1B1 mRNA in addition to the regular translation. Also CYP1B1 is very difficult to express in heterologous expression systems, thereby, halting its functional studies. Here we review and analyze these exceptional and startling characteristics of CYP1B1 with inputs from our own experiences in order to get a better insight into its molecular biology in health and disease. This may help to further understand the etiopathomechanistic aspects of CYP1B1 mediated diseases paving way for better research strategies and improved clinical management.

  2. [Solubilization Specificities Interferon beta-1b from Inclusion Bodies].

    PubMed

    Zhuravko, A S; Kononova, N V; Bobruskin, A I

    2015-01-01

    A new solubilization method of recombinant interferon beta-1b (IFNβ-1b) from the inclusion bodies was developed. This method allows to extract the target protein selectively in the solutions of different alcohols, such as ethanol, propanol and isopropanol. It was shown that the more effective IFNβ-1b solubilization was achieved in the 55% propanol solution. This method allowed to extract the target protein from inclusion bodies around 85-90%, and significantly reduced Escherichia coli content in the solubilizate, in comparison with standard methods.

  3. PROBING THE EARLIEST STAGE OF PROTOSTELLAR EVOLUTION-BARNARD 1-bN AND BARNARD 1-bS

    SciTech Connect

    Huang, Yun-Hsin; Hirano, Naomi

    2013-04-01

    Two submm/mm sources in the Barnard 1b (B1-b) core, B1-bN and B1-bS, have been observed with the Submillimeter Array (SMA) and the Submillimeter Telescope (SMT). The 1.1 mm continuum map obtained with the SMA reveals that the two sources contain spatially compact components, suggesting that they harbor protostars. The N{sub 2}D{sup +} and N{sub 2}H{sup +} J = 3-2 maps were obtained by combining the SMA and SMT data. The N{sub 2}D{sup +} map clearly shows two peaks at the continuum positions. The N{sub 2}H{sup +} map also peaks at the continuum positions, but is more dominated by the spatially extended component. The N{sub 2}D{sup +}/N{sub 2}H{sup +} ratio was estimated to be {approx}0.2 at the positions of both B1-bN and B1-bS. The derived N{sub 2}D{sup +}/N{sub 2}H{sup +} ratio is comparable to those of the prestellar cores in the late evolutionary stage and the class 0 protostars in the early evolutionary stage. Although B1-bN is bright in N{sub 2}H{sup +} and N{sub 2}D{sup +}, this source was barely seen in H{sup 13}CO{sup +}. This implies that the depletion of carbon-bearing molecules is significant in B1-bN. The chemical property suggests that B1-bN is in the earlier evolutionary stage as compared to B1-bS with the H{sup 13}CO{sup +} counterpart. The N{sub 2}H{sup +} and N{sub 2}D{sup +} lines show that the radial velocities of the two sources are different by {approx}0.9 km s{sup -1}. However, the velocity pattern along the line through B1-bN and B1-bS suggests that these two sources were not formed out of a single rotating cloud. It is likely that the B1-b core consists of two velocity components, each of which harbors a very young source.

  4. AKR1B10 — EDRN Public Portal

    Cancer.gov

    The AKR1B10 protein is a member of the aldo/keto reductase superfamily. This superfamily has more than 40 known enzymes and proteins. AKR1B10 acts as an all-trans-retinaldehyde reductase. It can efficiently reduce aliphatic and aromatic aldehydes, and is less active on hexoses (in vitro). It is highly expressed in adrenal gland, small intestine, and colon, and may play an important role in liver carcinogenesis.

  5. APOLLO SOYUZ TEST PROJECT [ASTP] MATING OF SATURN 1B

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The second stage of the Saturn 1B booster for the United States mission on the Apollo Soyuz Test Project was mated with the Saturn 1B first stage in the Kennedy Space Center's Vehicle Assembly Building today. Mating was completed at 9:50 a.m. The U. S. ASTP launch with mission commander Thomas Stafford, command module pilot Vance Brand and docking module pilot Donald Slayton is scheduled at 3:50 p.m. EDT July 15.

  6. PTP1B inhibitors from stems of Angelica keiskei (Ashitaba).

    PubMed

    Li, Jin-Long; Gao, Li-Xin; Meng, Fan-Wang; Tang, Chun-Lan; Zhang, Ru-Jun; Li, Jing-Ya; Luo, Cheng; Li, Jia; Zhao, Wei-Min

    2015-01-01

    Three new chalcones, xanthoangelols K-M (1-3), together with 19 known compounds were isolated from the stems of Angelica keiskei Koidzumi, a well-known rejuvenated and anti-diabetic plant originated from Japan. The structures of compounds 1-3 were elucidated on the basis of spectroscopic data and Mosher's method. All compounds were evaluated for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Among them, six chalcones, xanthoangelol K (1), xanthoangelol (4), xanthoangelol F (5), 4-hydroxyderricin (6), xanthoangelol D (7), xanthoangelol E (8), and a coumarin, methoxsalen (17), showed strong PTP1B inhibitory effect with IC50 values of 0.82, 1.97, 1.67, 2.47, 3.97, 1.43, and 2.53μg/mL, respectively. A kinetic study revealed that compound 1 inhibited PTP1B with characteristics typical of a competitive inhibitor. Molecular docking simulations elucidated that ring B of 1 may anchor in a pocket of PTP1B and the molecule is stabilized by hydrogen bonds with Arg47, Asp48, and π-π interaction with Phe182 of PTP1B.

  7. Linking organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3) interaction profiles to hepatotoxicity - The hyperbilirubinemia use case.

    PubMed

    Kotsampasakou, Eleni; Escher, Sylvia E; Ecker, Gerhard F

    2017-03-30

    Hyperbilirubinemia is a pathological condition of excessive accumulation of conjugated or unconjugated bilirubin in blood. It has been associated with neurotoxicity and non-neural organ dysfunctions, while it can also be a warning of liver side effects. Hyperbilirubinemia can either be a result of overproduction of bilirubin due to hemolysis or dyserythropoiesis, or the outcome of impaired bilirubin elimination due to liver transporter malfunction or inhibition. There are several reports in literature that inhibition of organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) might lead to hyperbilirubinemia. In this study we created a set of classification models for hyperbilirubinemia, which, besides physicochemical descriptors, also include the output of classification models of human OATP1B1 and 1B3 inhibition. Models were based on either human data derived from public toxicity reports or animal data extracted from the eTOX database VITIC. The generated models showed satisfactory accuracy (68%) and area under the curve (AUC) for human data and 71% accuracy and 70% AUC for animal data. However, our results did not indicate strong association between OATP inhibition and hyperbilirubinemia, neither for humans nor for animals.

  8. CYP1B1-mediated Pathobiology of Primary Congenital Glaucoma.

    PubMed

    Faiq, Muneeb A; Dada, Rima; Qadri, Rizwana; Dada, Tanuj

    2015-01-01

    CYP1B1 is a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily. It has been observed to be important in a variety of developmental processes including in utero development of ocular structures. Owing to its role in the developmental biology of eye, its dysfunction can lead to ocular developmental defects. This has been found to be true and CYP1B1 mutations have been observed in a majority of primary congenital glaucoma (PCG) patients from all over the globe. Primary congenital glaucoma is an irreversibly blinding childhood disorder (onset at birth or early infancy) typified by anomalous development of trabecular meshwork (TM). How CYP1B1 causes PCG is not known; however, some basic investigations have been reported. Understanding the CYP1B1 mediated etiopathomechanism of PCG is very important to identify targets for therapy and preventive management. In this perspective, we will make an effort to reconstruct the pathomechanism of PCG in the light of already reported information about the disease and the CYP1B1 gene. How to cite this article: Faiq MA, Dada R, Qadri R, Dada T. CYP1 B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract 2015;9(3):77-80.

  9. CYP1B1-mediated Pathobiology of Primary Congenital Glaucoma

    PubMed Central

    Faiq, Muneeb A; Dada, Rima; Qadri, Rizwana

    2015-01-01

    ABSTRACT CYP1B1 is a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily. It has been observed to be important in a variety of developmental processes including in utero development of ocular structures. Owing to its role in the developmental biology of eye, its dysfunction can lead to ocular developmental defects. This has been found to be true and CYP1B1 mutations have been observed in a majority of primary congenital glaucoma (PCG) patients from all over the globe. Primary congenital glaucoma is an irreversibly blinding childhood disorder (onset at birth or early infancy) typified by anomalous development of trabecular meshwork (TM). How CYP1B1 causes PCG is not known; however, some basic investigations have been reported. Understanding the CYP1B1 mediated etiopathomechanism of PCG is very important to identify targets for therapy and preventive management. In this perspective, we will make an effort to reconstruct the pathomechanism of PCG in the light of already reported information about the disease and the CYP1B1 gene. How to cite this article: Faiq MA, Dada R, Qadri R, Dada T. CYP1 B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract 2015;9(3):77-80. PMID:26997841

  10. Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3.

    PubMed

    Gozalpour, Elnaz; Greupink, Rick; Wortelboer, Heleen M; Bilos, Albert; Schreurs, Marieke; Russel, Frans G M; Koenderink, Jan B

    2014-06-02

    Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of β-estradiol 17-β-d-glucuronide (E217βG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 μM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 μM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12

  11. Hanford Site Hazardous waste determination report for transuranic debris waste streams NPFPDL1A, NPFPDL1B, NPFPDL1C and NPFPDL1D

    SciTech Connect

    WINTERHALDER, J.A.

    1999-09-29

    This Hazardous Waste Determination Report is intended to satisfy the terms of a Memorandum of Agreement (Agreement signed on June 16, 1999) between the U.S. Department of Energy and the New Mexico Environment Department. The Agreement pertains to the exchange of information before a final decision is made on the Waste Isolation Pilot Plant application for a permit under the ''New Mexico Hazardous Waste Act''. The Agreement will terminate upon the effective date of a final ''New Mexico Hazardous Waste Act'' permit for the Waste Isolation Pilot Plant. In keeping with the principles and terms of the Agreement, this report describes the waste stream data and information compilation process, and the physical and chemical analyses that the U.S. Department of Energy has performed on selected containers of transuranic debris waste to confirm that the waste is nonhazardous (non-mixed). This also summarizes the testing and analytical results that support the conclusion that the selected transuranic debris waste is not hazardous and thus, not subject to regulation under the ''Resource Conservation and Recovery Act'' or the ''New Mexico Hazardous Waste Act''. This report will be submitted to the New Mexico Environment Department no later than 45 days before the first shipment of waste from the Hanford Site to the Waste Isolation Pilot Plant, unless the parties mutually agree in writing to a shorter time. The 52 containers of transuranic debris waste addressed in this report were generated, packaged, and placed into storage between 1995 and 1997. Based on reviews of administrative documents, operating procedures, waste records, generator certifications, and personnel interviews, this transuranic debris waste was determined to be nonhazardous. This determination is supported by the data derived from nondestructive examination, confirmatory visual examination, and the results of container headspace gas sampling and analysis. Therefore, it is concluded that this transuranic debris waste, which consists of 52 containers from waste streams NPFPDLIA, NPFPDLIB, NPFPDLIC, and NPFPDLID, is not hazardous waste, and no hazardous waste numbers specified in Title 40 Code of Federal Regulations, Part 261, have been assigned. Accordingly, the 52 containers of transuranic debris waste addressed in this report meet the requirements for transuranic waste as defined by the Department of Energy Waste Acceptance Criteria for the Waste Isolation Pilot Plant. The 52 containers are acceptable for disposal at the Waste Isolation Pilot Plant as nonhazardous transuranic waste.

  12. The structure and conformational switching of Rap1B.

    PubMed

    Noguchi, Hiroki; Ikegami, Takahisa; Nagadoi, Aritaka; Kamatari, Yuji O; Park, Sam-Yong; Tame, Jeremy R H; Unzai, Satoru

    2015-06-19

    Rap1B is a small GTPase involved in the regulation of numerous cellular processes including synaptic plasticity, one of the bases of memory. Like other members of the Ras family, the active GTP-bound form of Rap1B can bind to a large number of effector proteins and so transmit signals to downstream components of the signaling pathways. The structure of Rap1B bound only to a nucleotide has yet to be solved, but might help reveal an inactive conformation that can be stabilized by a small molecule drug. Unlike other Ras family proteins such as H-Ras and Rap2A, Rap1B crystallizes in an intermediate state when bound to a non-hydrolyzable GTP analog. Comparison with H-Ras and Rap2A reveals conservative mutations relative to Rap1B, distant from the bound nucleotide, which control how readily the protein may adopt the fully activated form in the presence of GTP. High resolution crystallographic structures of mutant proteins show how these changes may influence the hydrogen bonding patterns of the key switch residues.

  13. Oncolytic Replication of E1b-Deleted Adenoviruses

    PubMed Central

    Cheng, Pei-Hsin; Wechman, Stephen L.; McMasters, Kelly M.; Zhou, Heshan Sam

    2015-01-01

    Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viral mRNA export, and cell cycle disruption. PMID:26561828

  14. In vitro enzymatic assays of protein tyrosine phosphatase 1B.

    PubMed

    Lubben, T; Clampit, J; Stashko, M; Trevillyan, J; Jirousek, M R

    2001-08-01

    Many hormone or growth factor receptors signal via the activation of protein-tyrosine kinases and phosphatases. Alteration of the phosphorylation state of tyrosine residues in certain proteins can directly regulate enzyme activity or cause formation of protein complexes necessary for transducing intracellular signals. Genetic and biochemical evidence also implicates protein-tyrosine phosphatases in several disease processes, including negative regulation of insulin receptor signaling at the level of the insulin receptor and perhaps in signaling at the IRS-1 level. The expression of protein tyrosine phosphatase-1B (PTP1B) is elevated in muscle and adipose tissue in insulin-resistant states both in man and rodents suggesting that PTP1B may play a role in the insulin-resistant state associated with diabetes and obesity. As described in this unit, PTP1B activity can be determined with the small molecule substrate, p-nitrophenyl phosphate (pNPP), in which the cleavage of the phosphate results in production of p-nitrophenol (pNP) and an increase in absorbance at 405 nm. Alternatively, PTP1B activity can be measured as described using model phosphotyrosyl-containing peptide substrates in which the release of free phosphate from the peptide is determined using a malachite green colorimetric assay.

  15. Brady 1D seismic velocity model ambient noise prelim

    SciTech Connect

    Mellors, Robert J.

    2013-10-25

    Preliminary 1D seismic velocity model derived from ambient noise correlation. 28 Green's functions filtered between 4-10 Hz for Vp, Vs, and Qs were calculated. 1D model estimated for each path. The final model is a median of the individual models. Resolution is best for the top 1 km. Poorly constrained with increasing depth.

  16. Dynamics of the reactions of O(1D) with HCl, DCl, and Cl2

    NASA Astrophysics Data System (ADS)

    Matsumi, Yutaka; Tonokura, Kenichi; Kawasaki, Masahiro; Tsuji, Kazuhide; Obi, Kinichi

    1993-05-01

    The reactions O(1D)+HCl→OH+Cl (1a) and OCl+H (1b), O(1D)+DCl→OD+Cl (2a) and OCl+D (2b), and O(1D)+Cl2→OCl+Cl (3) are studied at an average collision energy of 7.6, 7.7, and 8.8 kcal/mol for (1), (2), and (3), respectively. H, D, and Cl atoms are detected by the resonance-enhanced multiphoton ionization technique. The average kinetic energies released to the products are estimated from Doppler profile measurements of the product atoms. The relative yields [OCl+H]/[OH+Cl] and [OCl+D]/[OD+Cl] are directly measured, and a strong isotope effect (H/D) on the relative yields is found. The fine-structure branding ratios [Cl(2P1/2]/[Cl(2P3/2)] of the reaction products are also measured. The results suggest that nonadiabatic couplings take place at the exit channels of the reactions (1a) and (2a), while the reaction (3) is totally adiabatic.

  17. Potential energy surface intersections in the C(1D)H2 reactive system.

    PubMed

    Liu, Xiaojun; Bian, Wensheng; Zhao, Xian; Tao, Xutang

    2006-08-21

    Potential energy surface (PES) intersection seams of two or more electronic states from the 1 1A', 2 1A', 3 1A', 1 1A", and 2 1A" states in the C(1D)H2 reactive system are investigated using the internally contracted multireference configuration interaction method and the aug-cc-pVQZ basis set. Intersection seams with energies less than 20 kcal/mol relative to the C(1D) + H2 asymptote are searched systematically, and finally several seam lines (at the linear H-C-H, linear C-H-H, and C(2v), geometries, respectively) and a seam surface (at Cs geometries) are discovered and determined. The minimum energy crossing points on these seams are reported and the influences of the PES intersections, in particular, conical intersections, on the CH2 spectroscopy and the C(1D) + H2 reaction dynamics are discussed. In addition, geometries and energies of the 1 1A2 and 1 1B2 states of methylene biradical CH2 are reported in detail for the first time.

  18. A new release 06 of the GRACE Atmosphere and Ocean De-aliasing Level-1B (AOD1B) product

    NASA Astrophysics Data System (ADS)

    Fagiolini, E.; Dobslaw, H.; Flechtner, F.; Rudenko, S.

    2014-12-01

    We present a new release 06 of the GRACE AOD1B product, intended to serve as a background model for the removal of high-frequency non-tidal mass variations due to short-term (daily and sub-daily) mass transport in the atmosphere and oceans. AOD1B shall avoid aliasing of these high frequency signals into monthly gravity models derived from modern gravity missions (CHAMP, GRACE or GRACE-FO) and shall help to consistently reprocess altimetry and SLR satellites for later combination of gravimetric and geometric results. Therefore, AOD1B RL06 will be provided for an extended time-range (from 1976 till present). Some results on the use of the new and previous releases of the AOD1B product for precise orbit determination (POD) of these satellites are presented as well. For AOD1B RL06 the ocean part is the same as in RL05, while the atmospheric one includes an improved algorithm for the vertical integration of the atmospheric columns as well as a correction strategy for errors (jumps) present in the atmospheric input data. These errors are estimated by comparing the standard atmospheric coefficients based on the ECMWF operational analysis with independently generated coefficients based on the ECMWF ERA-Interim reanalysis. With this, we are able to correct the 6-hourly AOD1B data sets applied during GRACE POD. The derived gravity solutions, as well as the monthly averages 'GAA' (atmosphere only) and 'GAC' (atmosphere combined with ocean), are then free from errors present in the atmospheric input data. Furthermore, we are checking routinely processing changes at ECMWF, since they are strictly associated with the above mentioned errors, and will estimate new correction coefficients, if necessary.

  19. The phenotype Ae1B: a probable result of chimerism.

    PubMed Central

    Longster, G H; Robinson, E A; North, D I

    1978-01-01

    An apparently normal healthy adult with the blood group phenotype Ae1B is described. The unusual ABO group is apparently the result of chimerism, the proportion of the minor population of cells being so small as to be only detectable by absorption and elution techniques. PMID:739532

  20. Saturn 1B and Saturn 5 computer programs, software

    NASA Technical Reports Server (NTRS)

    1972-01-01

    Information on the progress and development of all Saturn 1B and Saturn 5 computer programs is presented. On-line, operating systems, test programs, and on-line display descriptions are given along with off-line programs. All programs are listed in tabular form.

  1. 7 CFR 1b.4 - Exclusion of agencies.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.4 Exclusion of agencies. (a... activities that have been found to have no individual or cumulative effect on the human environment. The USDA agencies and agency units listed in paragraph (b) of this section are excluded from the requirements...

  2. D1/D5 dopamine receptors modulate spatial memory formation.

    PubMed

    da Silva, Weber C N; Köhler, Cristiano C; Radiske, Andressa; Cammarota, Martín

    2012-02-01

    We investigated the effect of the intra-CA1 administration of the D1/D5 receptor antagonist SCH23390 and the D1/D5 receptor agonist SKF38393 on spatial memory in the water maze. When given immediately, but not 3h after training, SCH23390 hindered long-term spatial memory formation without affecting non-spatial memory or the normal functionality of the hippocampus. On the contrary, post-training infusion of SKF38393 enhanced retention and facilitated the spontaneous recovery of the original spatial preference after reversal learning. Our findings demonstrate that hippocampal D1/D5 receptors play an essential role in spatial memory processing.

  3. Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3.

    PubMed

    Suga, Takahiro; Yamaguchi, Hiroaki; Sato, Toshihiro; Maekawa, Masamitsu; Goto, Junichi; Mano, Nariyasu

    2017-01-01

    Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74-14.7 μM for OATP1B1 and 0.47-15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3.

  4. Cutting Edge: Resistance to Bacillus anthracis Infection Mediated by a Lethal Toxin Sensitive Allele of Nalp1b/Nlrp1b

    DTIC Science & Technology

    2010-01-01

    Nalp1b/Nlrp1b Lethal Toxin Sensitive Allele of Infection Mediated by aanthracis BacillusCutting Edge: Resistance to http://www.jimmunol.org/cgi/content...COVERED - 4. TITLE AND SUBTITLE Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin -sensitive allele of Nalp1b...Bacillus anthracis is associated with the production of lethal toxin (LT), which activates the murine Nalp1b/Nlrp1b inflammasome and induces caspase

  5. Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3

    PubMed Central

    Suga, Takahiro; Sato, Toshihiro; Maekawa, Masamitsu; Goto, Junichi; Mano, Nariyasu

    2017-01-01

    Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74–14.7 μM for OATP1B1 and 0.47–15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3. PMID:28060902

  6. Severe Hypertriglyceridemia in Glut1D on Ketogenic Diet.

    PubMed

    Klepper, Joerg; Leiendecker, Baerbel; Heussinger, Nicole; Lausch, Ekkehart; Bosch, Friedrich

    2016-04-01

    High-fat ketogenic diets are the only treatment available for Glut1 deficiency (Glut1D). Here, we describe an 8-year-old girl with classical Glut1D responsive to a 3:1 ketogenic diet and ethosuximide. After 3 years on the diet a gradual increase of blood lipids was followed by rapid, severe asymptomatic hypertriglyceridemia (1,910 mg/dL). Serum lipid apheresis was required to determine liver, renal, and pancreatic function. A combination of medium chain triglyceride-oil and a reduction of the ketogenic diet to 1:1 ratio normalized triglyceride levels within days but triggered severe myoclonic seizures requiring comedication with sultiam. Severe hypertriglyceridemia in children with Glut1D on ketogenic diets may be underdiagnosed and harmful. In contrast to congenital hypertriglyceridemias, children with Glut1D may be treated effectively by dietary adjustments alone.

  7. TBC1D24 genotype–phenotype correlation

    PubMed Central

    Balestrini, Simona; Milh, Mathieu; Castiglioni, Claudia; Lüthy, Kevin; Finelli, Mattea J.; Verstreken, Patrik; Cardon, Aaron; Stražišar, Barbara Gnidovec; Holder, J. Lloyd; Lesca, Gaetan; Mancardi, Maria M.; Poulat, Anne L.; Repetto, Gabriela M.; Banka, Siddharth; Bilo, Leonilda; Birkeland, Laura E.; Bosch, Friedrich; Brockmann, Knut; Cross, J. Helen; Doummar, Diane; Félix, Temis M.; Giuliano, Fabienne; Hori, Mutsuki; Hüning, Irina; Kayserili, Hulia; Kini, Usha; Lees, Melissa M.; Meenakshi, Girish; Mewasingh, Leena; Pagnamenta, Alistair T.; Peluso, Silvio; Mey, Antje; Rice, Gregory M.; Rosenfeld, Jill A.; Taylor, Jenny C.; Troester, Matthew M.; Stanley, Christine M.; Ville, Dorothee; Walkiewicz, Magdalena; Falace, Antonio; Fassio, Anna; Lemke, Johannes R.; Biskup, Saskia; Tardif, Jessica; Ajeawung, Norbert F.; Tolun, Aslihan; Corbett, Mark; Gecz, Jozef; Afawi, Zaid; Howell, Katherine B.; Oliver, Karen L.; Berkovic, Samuel F.; Scheffer, Ingrid E.; de Falco, Fabrizio A.; Oliver, Peter L.; Striano, Pasquale; Zara, Federico

    2016-01-01

    Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes. PMID:27281533

  8. Competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors, prenylated caged xanthones from Garcinia hanburyi and their inhibitory mechanism.

    PubMed

    Tan, Xue Fei; Uddin, Zia; Park, Chanin; Song, Yeong Hun; Son, Minky; Lee, Keun Woo; Park, Ki Hun

    2017-04-15

    Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70.25µM) and methylbutenyl 8 (IC50>200µM) showed less activity. The most potent inhibitor, gambogic acid 1 (IC50=0.47µM) showed 30-fold more potency than ursolic acid (IC50=15.5µM), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with Km, Vmax and Kik/Kiv ratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k5=0.0751µM(-)(1)S(-)(1), k6=0.0249µM(-)(1)S(-)(1) and Ki(app)=0.499µM. To develop a pharmacophore model, we explored the binding sites of compound 1 and 7 in PTP1B. These modeling results were in agreement with our findings, which revealed that the inhibitory activities are tightly related to caged motif and prenyl group in A ring.

  9. PTP1B: a new therapeutic target for Rett syndrome

    PubMed Central

    Tautz, Lutz

    2015-01-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is characterized by successive loss of acquired cognitive, social, and motor skills and development of autistic behavior. RTT affects approximately 1 in 10,000 live female births and is the second most common cause of severe mental retardation in females, after Down syndrome. Currently, there is no cure or effective therapy for RTT. Approved treatment regimens are presently limited to supportive management of specific physical and mental disabilities. In this issue, Krishnan and colleagues reveal that the protein tyrosine phosphatase PTP1B is upregulated in patients with RTT and in murine models and provide strong evidence that targeting PTP1B has potential as a viable therapeutic strategy for the treatment of RTT. PMID:26214520

  10. PTP1B: a new therapeutic target for Rett syndrome.

    PubMed

    Tautz, Lutz

    2015-08-03

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is characterized by successive loss of acquired cognitive, social, and motor skills and development of autistic behavior. RTT affects approximately 1 in 10,000 live female births and is the second most common cause of severe mental retardation in females, after Down syndrome. Currently, there is no cure or effective therapy for RTT. Approved treatment regimens are presently limited to supportive management of specific physical and mental disabilities. In this issue, Krishnan and colleagues reveal that the protein tyrosine phosphatase PTP1B is upregulated in patients with RTT and in murine models and provide strong evidence that targeting PTP1B has potential as a viable therapeutic strategy for the treatment of RTT.

  11. 1D and 2D NMR of nanocellulose in aqueous colloidal suspensions.

    PubMed

    Jiang, Feng; Dallas, Jerry L; Ahn, B Kollbe; Hsieh, You-Lo

    2014-09-22

    This is the first report on surface structural elucidation of individual nanocellulose as colloidal suspensions by 1D 1H, 2D heteronuclear single quantum coherence (HSQC) as well as 13C nuclear magnetic resonance (NMR). 1H NMR of rice straw CNCs (4.7 nm thick, 143 nm long, 0.04 sulfate per AG or 19.0% surface hydroxyl to sulfate conversion) resembled that of homogeneous cellulose solution. Conventional 2D HSQC NMR of CNC, CNF 1.5 (2-14 nm thick, several micrometers long, 0.10 COOH per AG) and CNF10 (2.0 nm thick, up to 1 μm long, 0.28 COOH per AG) gave H1:H2 ratios of 1.08:1, 0.97:1 and 0.94:1, respectively, all close to the theoretical 1:1 value for cellulose. The H1:H6 ratios determined from 2D HSQC NMR for CNCs, CNF1.5 and CNF10 were 1:1.47, 1:0.88 and 1:0.14, respectively, and corresponded to 26%, 56% and 93% C6 primary hydroxyl conversion to sulfate and carboxyl groups, consistent with, but more sensitive than those by conductometric titration and X-ray diffraction. Both 1H and 2D HSQC NMR data confirm that solution-state NMR detects nanocellulose surface carbons and protons primarily, validating this technique for direct surface characterization of nanocellulose in aqueous colloidal suspensions, presenting a sensitive and meaningful NMR tool for direct characterizing individual nanocellulose surfaces in never-dried state.

  12. Lithostratigraphy from downhole logs in Hole AND-1B, Antarctica

    USGS Publications Warehouse

    Williams, Trevor; Morin, Roger H.; Jarrard, Richard D.; Jackolski, Chris L.; Henrys, Stuart A.; Niessen, Frank; Magens, Diana; Kuhn, Gerhard; Monien, Donata; Powell, Ross D.

    2012-01-01

    The ANDRILL (Antarctic Drilling Project) McMurdo Ice Shelf (MIS) project drilled 1285 m of sediment in Hole AND–1B, representing the past 12 m.y. of glacial history. Downhole geophysical logs were acquired to a depth of 1018 mbsf (meters below seafloor), and are complementary to data acquired from the core. The natural gamma radiation (NGR) and magnetic susceptibility logs are particularly useful for understanding lithological and paleoenvironmental change at ANDRILL McMurdo Ice Shelf Hole AND–1B. NGR logs cover the entire interval from the seafloor to 1018 mbsf, and magnetic susceptibility and other logs covered the open hole intervals between 692 and 1018 and 237–342 mbsf. In the upper part of AND–1B, clear alternations between low and high NGR values distinguish between diatomite (lacking minerals containing naturally radioactive K, U, and Th) and diamictite (containing K-bearing clays, K-feldspar, mica, and heavy minerals). In the lower open hole logged section, NGR and magnetic susceptibility can also distinguish claystones (rich in K-bearing clay minerals, relatively low in magnetite) and diamictites (relatively high in magnetite). Sandstones can be distinguished by their high resistivity values in AND–1B. On the basis of these three downhole logs, diamictite, claystones, and sandstones can be predicted correctly for 74% of the 692–1018 mbsf interval. The logs were then used to predict facies for the 6% of this interval that was unrecovered by coring. Given the understanding of the physical property characteristics of different facies, it is also possible to identify subtle changes in lithology from the physical properties and help refine parts of the lithostratigraphy, for example, the varying terrigenous content of diatomites and the transitions from subice diamictite to open-water diatomite.

  13. NICMOS OBSERVATIONS OF THE TRANSITING HOT JUPITER XO-1b

    SciTech Connect

    Burke, Christopher J.; McCullough, P. R.; Bergeron, L. E.; Long, Douglas; Gilliland, Ronald L.; Nelan, Edmund P.; Valenti, Jeff A.; Johns-Krull, Christopher M.; Janes, Kenneth A.

    2010-08-20

    We refine the physical parameters of the transiting hot Jupiter planet XO-1b and its stellar host XO-1 using Hubble Space Telescope (HST) NICMOS observations. XO-1b has a radius R{sub p} = 1.21 {+-} 0.03 R{sub J} , and XO-1 has a radius R{sub *} = 0.94 {+-} 0.02 R{sub sun}, where the uncertainty in the mass of XO-1 dominates the uncertainty of R{sub p} and R{sub *}. There are no significant differences in the XO-1 system properties between these broadband NIR observations and previous determinations based upon ground-based optical observations. We measure two transit timings from these observations with 9 s and 15 s precision. As a residual to a linear ephemeris model, there is a 2.0{sigma} timing difference between the two HST visits that are separated by three transit events (11.8 days). These two transit timings and additional timings from the literature are sufficient to rule out the presence of an Earth mass planet orbiting in 2:1 mean motion resonance coplanar with XO-1b. We identify and correct for poorly understood 'gain-like' variations present in NICMOS time series data. This correction reduces the effective noise in time series photometry by a factor of 2 for the case of XO-1.

  14. Zinc ions modulate protein tyrosine phosphatase 1B activity.

    PubMed

    Bellomo, Elisa; Massarotti, Alberto; Hogstrand, Christer; Maret, Wolfgang

    2014-07-01

    Protein tyrosine phosphatases (PTPs) are key enzymes in cellular regulation. The 107 human PTPs are regulated by redox signalling, phosphorylation, dimerisation, and proteolysis. Recent findings of very strong inhibition of some PTPs by zinc ions at concentrations relevant in a cellular environment suggest yet another mechanism of regulation. One of the most extensively investigated PTPs is PTP1B (PTPN1). It regulates the insulin and leptin signalling pathway and is implicated in cancer and obesity/diabetes. The development of novel assay conditions to investigate zinc inhibition of PTP1B provides estimates of about 5.6 nM affinity for inhibitory zinc(II) ions. Analysis of three PTP1B 3D structures (PDB id: 2CM2, 3I80 and 1A5Y) identified putative zinc binding sites and supports the kinetic studies in suggesting an inhibitory zinc only in the closed and cysteinyl-phosphate intermediate forms of the enzyme. These observations gain significance with regard to recent findings of regulatory roles of zinc ions released from the endoplasmic reticulum.

  15. Polar discontinuities and 1D interfaces in monolayered materials

    NASA Astrophysics Data System (ADS)

    Martinez-Gordillo, Rafael; Pruneda, Miguel

    2015-12-01

    Interfaces are the birthplace of a multitude of fascinating discoveries in fundamental science, and have enabled modern electronic devices, from transistors, to lasers, capacitors or solar cells. These interfaces between bulk materials are always bi-dimensional (2D) 'surfaces'. However the advent of graphene and other 2D crystals opened up a world of possibilities, as in this case the interfaces become one-dimensional (1D) lines. Although the properties of 1D nanoribbons have been extensively discussed in the last few years, 1D interfaces within infinite 2D systems had remained mostly unexplored until very recently. These include grain boundaries in polycrystalline samples, or interfaces in hybrid 2D sheets composed by segregated domains of different materials (as for example graphene/BN hybrids, or chemically different transition metal dichalcogenides). As for their 2D counterparts, some of these 1D interfaces exhibit polar characteristics, and can give rise to fascinating new physical properties. Here, recent experimental discoveries and theoretical predictions on the polar discontinuities that arise at these 1D interfaces will be reviewed, and the perspectives of this new research topic, discussed.

  16. Ion-sensing properties of 1D vanadium pentoxide nanostructures

    PubMed Central

    2012-01-01

    The application of one-dimensional (1D) V2O5·nH2O nanostructures as pH sensing material was evaluated. 1D V2O5·nH2O nanostructures were obtained by a hydrothermal method with systematic control of morphology forming different nanostructures: nanoribbons, nanowires and nanorods. Deposited onto Au-covered substrates, 1D V2O5·nH2O nanostructures were employed as gate material in pH sensors based on separative extended gate FET as an alternative to provide FET isolation from the chemical environment. 1D V2O5·nH2O nanostructures showed pH sensitivity around the expected theoretical value. Due to high pH sensing properties, flexibility and low cost, further applications of 1D V2O5·nH2O nanostructures comprise enzyme FET-based biosensors using immobilized enzymes. PMID:22709724

  17. Cytochrome P1B1 (CYP1B1) polymorphisms and cancer risk: a meta-analysis of 52 studies.

    PubMed

    Li, Cuiping; Long, Bingshuang; Qin, Xianjing; Li, Weixiong; Zhou, Yang

    2015-01-02

    CYP1B1 plays a critical role in the oxidative metabolism of a variety of exogenous compounds, including carcinogenic compounds, which may be activated during metabolism. There are only a few studies that have examined the association between the two polymorphisms and cancer, and that these studies have been inconclusive. Hence, the aim of the present meta-analysis was to evaluate the relationship between polymorphisms in CYP1B1 G119T and A453G and cancer risk. We performed a detailed search using the PubMed and EMBASE libraries to obtain all relevant published reports on the relationship between the G119T and A453G polymorphisms in CYP1B1 and cancer risk. Combined odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by Stata version 11.2. We conducted stratified analyses based on cancer types, ethnicity, source of controls, and quality assessments. We also made assessments of heterogeneity tests, sensitivity analyses, and publication bias. There were a total of 25 articles with 15,376 cases and 18,382 controls concerning CYP1B1 G119T and 40 articles with 27,983 cases and 35,839 controls concerning A453G polymorphisms. Regarding G119T, the combined results indicate that the variant genotypes were significantly associated with a slightly increased cancer risk in comparison to the homozygote (TT versus GG: p=0.006, OR=1.231, 95% CI: 1.061-1.428), especially for breast cancer and prostate cancer. Moreover, significantly increased associations with cancer risk were demonstrated in Asians in all genetic models. The combined results indicated no association of A453G with cancer risk; however, an association was observed specifically for prostate cancer. This meta-analysis suggests that the CYP1B1 G119T polymorphism may confer to genetic susceptibility to cancer in Asians, especially to breast cancer and prostate cancer. The A453G polymorphism was found to modify the risk of prostate cancer.

  18. Cytochrome P1B1 (CYP1B1) polymorphisms and ovarian cancer risk: a meta-analysis.

    PubMed

    Gajjar, Ketan; Owens, Gemma; Sperrin, Matthew; Martin-Hirsch, Pierre L; Martin, Francis L

    2012-12-16

    CYP1B1 is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates and plays a key role in hormone-induced carcinogenesis. Risk factors for ovarian cancer are related to hormonal exposure and reproduction, and polymorphisms within genes involved in metabolism of oestrogen and certain xenobiotics may influence the risk of developing ovarian cancer. Current meta-analysis evaluated four CYP1B1 polymorphisms (Leu432Val, Arg48Gly, Ala119Ser and Asn453Ser) for their association with ovarian cancer risk. A search of the MEDLINE bibliographic database for the period up to April 2012 identified five relevant studies. With regards to Leu432Val polymorphism, all of the five studies were eligible (1199 cases and 2596 controls) for analysis, while for Arg48Gly (799 cases and 1169 controls), Ala119Ser (799 cases and 1172 controls) and Asn453Ser (361cases and 1577 controls) only two studies were eligible for analysis. Fixed-effect models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (95% CI) and chi-square based Q-test was used to test for heterogeneity. The pooled OR (95% CI) for CYP1B1_Leu432Val polymorphism were 1.1 (0.84-1.31) for heterozygous subjects and 0.82 (0.57-1.17) for homozygous Val subjects. In a recessive model, homozygous carriers of Leu432Val showed a weak trend towards reduced risk as compared to 'wild type' and heterozygous carriers (OR 0.8, 95% CI; 0.66-0.99); however, this association was of limited significance. Regarding Arg48Gly, the pooled OR (95% CI) were 1.06 (0.89-1.27) for heterozygous and 0.98 (1.72-1.33) for homozygous Gly subjects. With respect to Ala119Ser and Asn453Ser, the pooled OR were 1.06 (0.87-1.29) and 1.24 (0.94-1.63) for heterozygous and 1.1 (0.8-1.52) and 1.09 (0.5-2.34) for homozygous respectively. In conclusion, this meta-analysis suggests that CYP1B1 polymorphisms are not associated with ovarian cancer risk. Studies evaluating CYP1B1_Leu432Val polymorphism are required to

  19. Pitch-based pattern splitting for 1D layout

    NASA Astrophysics Data System (ADS)

    Nakayama, Ryo; Ishii, Hiroyuki; Mikami, Koji; Tsujita, Koichiro; Yaegashi, Hidetami; Oyama, Kenichi; Smayling, Michael C.; Axelrad, Valery

    2015-07-01

    The pattern splitting algorithm for 1D Gridded-Design-Rules layout (1D layout) for sub-10 nm node logic devices is shown. It is performed with integer linear programming (ILP) based on the conflict graph created from a grid map for each designated pitch. The relation between the number of times for patterning and the minimum pitch is shown systematically with a sample pattern of contact layer for each node. From the result, the number of times for patterning for 1D layout is fewer than that for conventional 2D layout. Moreover, an experimental result including SMO and total integrated process with hole repair technique is presented with the sample pattern of contact layer whose pattern density is relatively high among critical layers (fin, gate, local interconnect, contact, and metal).

  20. Flexible Photodetectors Based on 1D Inorganic Nanostructures

    PubMed Central

    Lou, Zheng

    2015-01-01

    Flexible photodetectors with excellent flexibility, high mechanical stability and good detectivity, have attracted great research interest in recent years. 1D inorganic nanostructures provide a number of opportunities and capabilities for use in flexible photodetectors as they have unique geometry, good transparency, outstanding mechanical flexibility, and excellent electronic/optoelectronic properties. This article offers a comprehensive review of several types of flexible photodetectors based on 1D nanostructures from the past ten years, including flexible ultraviolet, visible, and infrared photodetectors. High‐performance organic‐inorganic hybrid photodetectors, as well as devices with 1D nanowire (NW) arrays, are also reviewed. Finally, new concepts of flexible photodetectors including piezophototronic, stretchable and self‐powered photodetectors are examined to showcase the future research in this exciting field. PMID:27774404

  1. PC-1D installation manual and user's guide

    SciTech Connect

    Basore, P.A.

    1991-05-01

    PC-1D is a software package for personal computers that uses finite-element analysis to solve the fully-coupled two-carrier semiconductor transport equations in one dimension. This program is particularly useful for analyzing the performance of optoelectronic devices such as solar cells, but can be applied to any bipolar device whose carrier flows are primarily one-dimensional. This User's Guide provides the information necessary to install PC-1D, define a problem for solution, solve the problem, and examine the results. Example problems are presented which illustrate these steps. The physical models and numerical methods utilized are presented in detail. This document supports version 3.1 of PC-1D, which incorporates faster numerical algorithms with better convergence properties than previous versions of the program. 51 refs., 17 figs., 5 tabs.

  2. P27/CDKN1B Translational Regulators in Pituitary Tumorigenesis.

    PubMed

    Martins, C S; Camargo, R C; Saggioro, F P; Neder, L; Machado, H R; Moreira, A C; de Castro, M

    2016-12-01

    In pituitary tumors, P27(CDKN1B) is underexpressed. We aimed to clarify whether translational regulation underlies this phenomenon. This study evaluated the expression of P27/CDKN1B, its targets (CCNE1, CDK2) and translational regulators (DKC1, RPS13, miR221, miR222) and screened for DKC1 variants in sporadic pituitary adenomas. Samples were obtained during transsphenoidal surgery from 48 patients with pituitary adenomas: 10 ACTH-, 17 GH-secreting, and 21 nonfunctioning (NFPA). The control group comprised 7 normal pituitaries (NP) obtained during autopsies. Gene expression was assessed by RT-PCR and protein expression by immunohistochemistry. The 15 exons of DKC1 were sequenced. P27 protein underexpression was observed in all adenomas subtypes (p=0.001). CCNE1 mRNA (p=0.01) overexpression, but not protein, was observed in NFPA. No differential gene expression among groups was observed in CDKN1B regulators RPS13 (p=0.23) and DKC1 (p=0.34). The expression of miR221 and miR222 was similar among tumors and NP. Frequent DKC1 variants (SNPs) were found in exon 14 and in the 3'-UTR in similar frequency to NCBI-dsSNP databases. We also observed rare DKC1 variants in 11% of the studied tumor samples, indicating a high prevalence in pituitary adenomas, however, in silico studies failed to indicate deleterious effects. The high frequency of DKC1 variants may influence, in some extent, pituitary tumors development, without clear role in its tumorigenesis. Our data reinforce the P27 underexpression in pituitary adenomas and provide further evidence of the post-translational machinery involvement, although this phenomenon cannot be explained either by mis-expression of P27 translational regulators - DKC1, RPS13, miR221, miR222 - or directly by DKC1 mutations.

  3. GIS-BASED 1-D DIFFUSIVE WAVE OVERLAND FLOW MODEL

    SciTech Connect

    KALYANAPU, ALFRED; MCPHERSON, TIMOTHY N.; BURIAN, STEVEN J.

    2007-01-17

    This paper presents a GIS-based 1-d distributed overland flow model and summarizes an application to simulate a flood event. The model estimates infiltration using the Green-Ampt approach and routes excess rainfall using the 1-d diffusive wave approximation. The model was designed to use readily available topographic, soils, and land use/land cover data and rainfall predictions from a meteorological model. An assessment of model performance was performed for a small catchment and a large watershed, both in urban environments. Simulated runoff hydrographs were compared to observations for a selected set of validation events. Results confirmed the model provides reasonable predictions in a short period of time.

  4. Organic Anion–Transporting Polypeptide 1b2 (Oatp1b2) Is Important for the Hepatic Uptake of Unconjugated Bile Acids: Studies in Oatp1b2-Null Mice

    PubMed Central

    Csanaky, Iván L.; Lu, Hong; Zhang, Youcai; Ogura, Kenichiro; Choudhuri, Supratim; Klaassen, Curtis D.

    2011-01-01

    The organic anion–transporting polypeptide 1b family (Oatp1b2 in rodents and OATP1B1/1B3 in humans) is liver-specific and transports various chemicals into the liver. However, the role of the Oatp1b family in the hepatic uptake of bile acids (BAs) into the liver is unknown. Therefore, in Oatp1b2-null mice, the concentrations of BAs in plasma, liver, and bile were compared with wild-type (WT) mice. It was first determined that livers of the Oatp1b2-null mice were not compensated by altered expression of other hepatic transporters. However, the messenger RNA of Cyp7a1 was 70% lower in the Oatp1b2-null mice. Increased expression of fibroblast growth factor 15 in intestines of Oatp1b2-null mice might be responsible for decreased hepatic expression of Cyp7a1 in Oatp1b2-null mice. The hepatic concentration and biliary excretion of conjugated and unconjugated BAs were essentially the same in Oatp1b2-null and WT mice. The serum concentration of taurine-conjugated BAs was essentially the same in the two genotypes. In contrast, the serum concentrations of unconjugated BAs were 3–45 times higher in Oatp1b2-null than WT mice. After intravenous administration of cholate to Oatp1b2-null mice, its clearance was 50% lower than in WT mice, but the clearance of taurocholate was similar in the two genotypes. Conclusion This study indicates that Oatp1b2 has a major role in the hepatic uptake of unconjugated BAs. PMID:20949553

  5. Berberine inhibits PTP1B activity and mimics insulin action.

    PubMed

    Chen, Chunhua; Zhang, Yuebo; Huang, Cheng

    2010-07-02

    Type 2 diabetes patients show defects in insulin signal transduction that include lack of insulin receptor, decrease in insulin stimulated receptor tyrosine kinase activity and receptor-mediated phosphorylation of insulin receptor substrates (IRSs). A small molecule that could target insulin signaling would be of significant advantage in the treatment of diabetes. Berberine (BBR) has recently been shown to lower blood glucose levels and to improve insulin resistance in db/db mice partly through the activation of AMP-activated protein kinase (AMPK) signaling and induction of phosphorylation of insulin receptor (IR). However, the underlying mechanism remains largely unknown. Here we report that BBR mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes and L6 myocytes in an insulin-independent manner, inhibiting phosphatase activity of protein tyrosine phosphatase 1B (PTP1B), and increasing phosphorylation of IR, IRS1 and Akt in 3T3-L1 adipocytes. In diabetic mice, BBR lowers hyperglycemia and improves impaired glucose tolerance, but does not increase insulin release and synthesis. The results suggest that BBR represents a different class of anti-hyperglycemic agents.

  6. RELATIVE PHOTOMETRY OF HAT-P-1b OCCULTATIONS

    SciTech Connect

    Beky, Bence; Holman, Matthew J.; Noyes, Robert W.; Sasselov, Dimitar D.; Gilliland, Ronald L.; Bakos, Gaspar A.; Winn, Joshua N.

    2013-06-01

    We present Hubble Space Telescope (HST) Space Telescope Imaging Spectrograph observations of two occultations of the transiting exoplanet HAT-P-1b. By measuring the planet to star flux ratio near opposition, we constrain the geometric albedo of the planet, which is strongly linked to its atmospheric temperature gradient. An advantage of HAT-P-1 as a target is its binary companion ADS 16402 A, which provides an excellent photometric reference, simplifying the usual steps in removing instrumental artifacts from HST time-series photometry. We find that without this reference star, we would need to detrend the lightcurve with the time of the exposures as well as the first three powers of HST orbital phase, and this would introduce a strong bias in the results for the albedo. However, with this reference star, we only need to detrend the data with the time of the exposures to achieve the same per-point scatter, therefore we can avoid most of the bias associated with detrending. Our final result is a 2{sigma} upper limit of 0.64 for the geometric albedo of HAT-P-1b between 577 and 947 nm.

  7. Non-cooperative Brownian donkeys: A solvable 1D model

    NASA Astrophysics Data System (ADS)

    Jiménez de Cisneros, B.; Reimann, P.; Parrondo, J. M. R.

    2003-12-01

    A paradigmatic 1D model for Brownian motion in a spatially symmetric, periodic system is tackled analytically. Upon application of an external static force F the system's response is an average current which is positive for F < 0 and negative for F > 0 (absolute negative mobility). Under suitable conditions, the system approaches 100% efficiency when working against the external force F.

  8. Down-regulated expression of the protein-tyrosine phosphatase 1B (PTP1B) is associated with aggressive clinicopathologic features and poor prognosis in hepatocellular carcinoma

    SciTech Connect

    Zheng, Long-Yi; Zhou, Dong-Xun; Lu, Jin; Zhang, Wen-Jun; Zou, Da-Jin

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer PTP1B protein showed decreased expression in 67.79% of the HCC patients. Black-Right-Pointing-Pointer Low PTP1B expression predicts poor prognosis of HCC. Black-Right-Pointing-Pointer Low PTP1B expression is correlated with expansion of OV6{sup +} tumor-initiating cells. Black-Right-Pointing-Pointer Down-regulation of PTP1B is associated with activation of Wnt/{beta}-Catenin signaling. -- Abstract: The protein-tyrosine phosphatase 1B (PTP1B) is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and can exert both tumor suppressing and tumor promoting effects in different cancers depending on the substrate involved and the cellular context. However, the expression level and function of PTP1B in hepatocellular carcinoma (HCC) remain unclear. In this study, PTP1B expression was detected by immunohistochemistry in normal liver tissue (n = 16) and hepatocellular carcinoma (n = 169). The correlations between PTP1B expression level and clinicopathologic features and patient survival were also analyzed. One hundred and eleven of 169 HCC patients (65.7%) had negative or low PTP1B expression in tumorous tissues, whereas normal tissues always expressed strong PTP1B. Decreased PTP1B expression was significantly associated with aggressive clinicopathologic features and poor prognosis. Immunohistochemistry also showed that low PTP1B expression level was correlated with high percentage of OV6{sup +} tumor-initiating cells (T-ICs) and high frequency of nuclear {beta}-Catenin expression in HCC specimens. Our findings demonstrate for the first time that the loss of inhibitory effect of PTP1B may contribute to progression and invasion of HCC through activation of Wnt/{beta}-Catenin signaling and expansion of liver T-ICs. PTP1B may serve as a valuable prognostic biomarker and potential therapeutic target in HCC.

  9. Respective roles of neurofilaments, microtubules, MAP1B, and tau in neurite outgrowth and stabilization.

    PubMed Central

    Shea, T B; Beermann, M L

    1994-01-01

    The respective roles of neurofilaments (NFs), microtubules (MTs), and the microtubule-associated proteins (MAPs) MAP 1B and tau on neurite outgrowth and stabilization were probed by the intracellular delivery of specific antisera into transiently permeabilized NB2a/d1 cells during treatment with dbcAMP. Intracellular delivery of antisera specific for the low (NF-L), middle (NF-M), or extensively phosphorylated high (NF-H) molecular weight subunits did not prevent initial neurite elaboration, nor did it induce retraction of existing neurites elaborated by cells that had been previously treated for 1 d with dbcAMP. By contrast, intracellular delivery of antisera directed against tubulin reduced the percentage of cells with neurites at both these time points. Intracellular delivery of anti-NF-L and anti-NF-M antisera did not induce retraction in cells treated with dbcAMP for 3 d. However, intracellular delivery of antisera directed against extensively phosphorylated NF-H, MAP1B, tau, or tubulin induced similar levels of neurite retraction at this time. Intracellular delivery of monoclonal antibodies (RT97 or SMI-31) directed against phosphorylated NF-H induced neurite retraction in cell treated with dbcAMP for 3 d; a monoclonal antibody (SMI-32) directed against nonphosphorylated NF-H did not induce neurite retraction at this time. By contrast, none of the above antisera induced retraction of neurites in cells treated with dbcAMP for 7 d. Neurites develop resistance to retraction by colchicine, first detectable in some neurites after 3 d and in the majority of neurites after 7 d of dbcAMP treatment. We therefore examined whether or not colchicine resistance was compromised by intracellular delivery of the above antisera. Colchicine treatment resulted in rapid neurite retraction after intracellular delivery of antisera directed against extensively phosphorylated NF-H, MAP1B, or tau into cells that had previously been treated with dbcAMP for 7 d. By contrast, colchicine

  10. The Response of Marine Biota to OAE 1b

    NASA Astrophysics Data System (ADS)

    Herrle, J. O.

    2006-12-01

    The latest Aptian to earliest Albian is characterized by the first appearance of a distinctly modern phytoplankton community accompanied by a cold episode during a generally extreme greenhouse climate. Massive burial of organic matter caused the formation of the black shale `Niveaus' Jacob, Kilian, Paquier and Leenhardt in the Vocontian Basin (SE France). This interval is reported as the Oceanic Anoxic Event 1b (OAE1b) following the definition of Leckie et al. (2002). Lasting about four million years, OAE1b facilitates analysis of rapid climate change in a greenhouse world, and crucial for understanding climate change. During latest Aptian angiosperms and diatoms became abundant in the terrestrial and marine environments (Gersonde & Haywood 1990; Heimhofer et al. 2005). Planktic foraminifera experienced their greatest turnover rates since their first appearance, accompanied by a decrease in test size and changes of the ultrastructures of their shells (Leckie et al. 2002). Calcareous nannoplankton show a major change characterized by the influx of the boreal cool water indicator Repagulum parvidentatum into the Tethyan Realm (Herrle & Mutterlose 2003). Moreover, ammonite faunas became more cosmopolitan at the expense of Tethyan taxa during this period. Both the influx of boreal nannoplankton taxa and the trend to more cosmopolitian ammonite assemblages in the Tethyan Realm was probably favored by a long-term sea level rise accompanied by a global cooling during the late Aptian to early Albian interval. Most dramatic changes of the marine carbonate system are reflected by the stepwise decrease of nannoconids and carbonate platform drowning accompanied by a positive carbon isotope excursion which is similar to the biocalcification crisis associated with the early Aptian OAE1a (Erba 1994, Weissert et al., 1998). The massive change in the global carbon cycle is probably linked to a major change in global marine productivity from a calcareous system (nannoconids

  11. 77 FR 53912 - Agency Information Collection Activities; Submission for OMB Review; Comment Request; H-1B...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-04

    ...; H-1B Technical Skills Training Grants and H-1B Jobs and Innovation Accelerator Challenge Grants... Administration (ETA) sponsored information collection request (ICR) proposal titled, ``H-1B Technical Skills Training Grants and H-1B Jobs and Innovation Accelerator Challenge Grants,'' to the Office of...

  12. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 13 2013-07-01 2012-07-01 true Add-on Control Systems Compliance Options 1B Table 1B to Subpart DDDD of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Products Pt. 63, Subpt. DDDD, Table 1B Table 1B to Subpart DDDD of Part 63—Add-on Control...

  13. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 13 2014-07-01 2014-07-01 false Add-on Control Systems Compliance Options 1B Table 1B to Subpart DDDD of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Products Pt. 63, Subpt. DDDD, Table 1B Table 1B to Subpart DDDD of Part 63—Add-on Control...

  14. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 13 2012-07-01 2012-07-01 false Add-on Control Systems Compliance Options 1B Table 1B to Subpart DDDD of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Products Pt. 63, Subpt. DDDD, Table 1B Table 1B to Subpart DDDD of Part 63—Add-on Control...

  15. 50 CFR Table 1b to Part 679 - Discard and Disposition Codes

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 9 2010-10-01 2010-10-01 false Discard and Disposition Codes 1b Table 1b... ALASKA Pt. 679, Table 1b Table 1b to Part 679—Discard and Disposition Codes Description Code Confiscation... bait. 95 Whole fish/sold, for human consumption. 60 NOTE: When using whole fish codes, record...

  16. Level1B Performance Evaluation On CryoSat Products

    NASA Astrophysics Data System (ADS)

    Scagliola, Michele; Fornari, Marco; Tagliani, Nicolas

    2013-12-01

    A performance assessment of the CryoSat products for SAR/SARin modes is here presented. The effective across-track IRF has been compared with the expected one, according to the system requirements, and exploiting the calibration products. Then, starting from the along-track processing for Delay/Doppler Radar altimeters, the theoretical model of the along-track IRF for CryoSat has been derived. Moreover the effects of the azimuth windowing on the along-track resolution and on the clutter suppression have been investigated. In particular, the clutter has been evaluated on the Level1b products for both sea ice and ocean scenario, revealing that the azimuth window allows to improve the signal to clutter ratio also in case of ocean waveforms.

  17. Plasmonic Excitations of 1D Metal-Dielectric Interfaces in 2D Systems: 1D Surface Plasmon Polaritons

    NASA Astrophysics Data System (ADS)

    Mason, Daniel R.; Menabde, Sergey G.; Yu, Sunkyu; Park, Namkyoo

    2014-04-01

    Surface plasmon-polariton (SPP) excitations of metal-dielectric interfaces are a fundamental light-matter interaction which has attracted interest as a route to spatial confinement of light far beyond that offered by conventional dielectric optical devices. Conventionally, SPPs have been studied in noble-metal structures, where the SPPs are intrinsically bound to a 2D metal-dielectric interface. Meanwhile, recent advances in the growth of hybrid 2D crystals, which comprise laterally connected domains of distinct atomically thin materials, provide the first realistic platform on which a 2D metal-dielectric system with a truly 1D metal-dielectric interface can be achieved. Here we show for the first time that 1D metal-dielectric interfaces support a fundamental 1D plasmonic mode (1DSPP) which exhibits cutoff behavior that provides dramatically improved light confinement in 2D systems. The 1DSPP constitutes a new basic category of plasmon as the missing 1D member of the plasmon family: 3D bulk plasmon, 2DSPP, 1DSPP, and 0D localized SP.

  18. Proteasomal degradation of human CYP1B1: effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression.

    PubMed

    Bandiera, Silvio; Weidlich, Simone; Harth, Volker; Broede, Peter; Ko, Yun; Friedberg, Thomas

    2005-02-01

    Allelic variations in CYP1B1 are reported to modulate the incidence of several types of cancer. To provide a mechanistic basis for this association, we investigated the impact of nonsilent allelic changes on the intracellular levels and post-translational regulation of CYP1B1 protein. When transiently expressed in COS-1 cells, either in the presence or absence of recombinant cytochrome P450 reductase, the cellular level of the CYP1B1.4 allelic variant (containing a Ser at the amino acid position 453; Ser453) was 2-fold lower compared with the other four allelic CYP1B1 proteins (containing Asn453), as analyzed by both immunoblotting and ethoxyresorufin O-deethylase activity. This difference was caused by post-translational regulation; as in the presence of cycloheximide, the rate of degradation of immunodetectable and enzymatically active CYP1B1.4 was distinctly faster than that of CYP1B1.1. Pulse-chase analysis revealed that the half-life of CYP1B1.4 was a mere 1.6 h compared with 4.8 h for CYP1B1.1. The presence of the proteasome inhibitor MG132 [N-benzoyloxycarbonyl (Z)-Leu-Leuleucinal] increased the stability not only of immunodetectable CYP1B1, but also--unexpectedly given the size of the proteasome access channel--increased the stability of enzymatically active CYP1B1. The data presented herein also demonstrate that CYP1B1 is targeted for its polymorphism-dependent degradation by polyubiquitination but not phosphorylation. Our results importantly provide a mechanism to explain the recently reported lower incidence of endometrial cancer in individuals carrying the CYP1B1*4 compared with the CYP1B1*1 haplo-type. In addition, the mechanistic paradigms revealed herein may explain the strong overexpression of CYP1B1 in tumors compared with nondiseased tissues.

  19. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms

    PubMed Central

    Hartkoorn, Ruben C; San Kwan, Wai; Shallcross, Victoria; Chaikan, Ammara; Liptrott, Neill; Egan, Deirdre; Enrique Salcedo Sora, J; James, Chloe E; Gibbons, Sara; Bray, Pat G; Back, David J; Khoo, Saye H; Owen, Andrew

    2016-01-01

    OATP1B1 and OATP1B3 are major hepatic drug transporters whilst OATP1A2 is mainly located in the brain but is also located in liver and several other organs. These transporters affect the distribution and clearance of many endo- and xenobiotics and have been reported to have functional SNPs. We have assessed the substrate specificites of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir. SLCO1A2, SLCO1B1 and SLCO1B3 were cloned, verified and used to generate cRNA for use in the Xenopus laevis oocyte transport system. Using the oocyte system, antiretrovirals were tested for their substrate specificities. Plasma samples (n=349) from the Liverpool therapeutic drug monitoring registry were genotyped for SNPs in SLCO1A2, SLCO1B1 and SLCO1B3 and associations between SNPs and lopinavir plasma concentrations were analysed. Antiretroviral protease inhibitors, but not non-nucleoside reverse transcriptase inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3. Furthermore, ritonavir was not an inhibitor of OATP1B1. The 521T>C polymorphism in SLCO1B1 was significantly associated with higher lopinavir plasma concentrations. No associations were observed with functional variants of SLCO1A2 and SLCO1B3. These data add to our understanding of the factors that contribute to variability in plasma concentrations of protease inhibitors. Further studies are now required to confirm the association of SLCO1B1 521T>C with lopinavir plasma concentrations and to assess the influence of other polymorphisms in the SLCO family. PMID:20051929

  20. 1D Josephson quantum interference grids: diffraction patterns and dynamics

    NASA Astrophysics Data System (ADS)

    Lucci, M.; Badoni, D.; Corato, V.; Merlo, V.; Ottaviani, I.; Salina, G.; Cirillo, M.; Ustinov, A. V.; Winkler, D.

    2016-02-01

    We investigate the magnetic response of transmission lines with embedded Josephson junctions and thus generating a 1D underdamped array. The measured multi-junction interference patterns are compared with the theoretical predictions for Josephson supercurrent modulations when an external magnetic field couples both to the inter-junction loops and to the junctions themselves. The results provide a striking example of the analogy between Josephson phase modulation and 1D optical diffraction grid. The Fiske resonances in the current-voltage characteristics with voltage spacing {Φ0}≤ft(\\frac{{\\bar{c}}}{2L}\\right) , where L is the total physical length of the array, {Φ0} the magnetic flux quantum and \\bar{c} the speed of light in the transmission line, demonstrate that the discrete line supports stable dynamic patterns generated by the ac Josephson effect interacting with the cavity modes of the line.

  1. 1-D Numerical Analysis of ABCC Engine Performance

    NASA Technical Reports Server (NTRS)

    Holden, Richard

    1999-01-01

    ABCC engine combines air breathing and rocket engine into a single engine to increase the specific impulse over an entire flight trajectory. Except for the heat source, the basic operation of the ABCC is similar to the basic operation of the RBCC engine. The ABCC is intended to have a higher specific impulse than the RBCC for single stage Earth to orbit vehicle. Computational fluid dynamics (CFD) is a useful tool for the analysis of complex transport processes in various components in ABCC propulsion system. The objective of the present research was to develop a transient 1-D numerical model using conservation of mass, linear momentum, and energy equations that could be used to predict flow behavior throughout a generic ABCC engine following a flight path. At specific points during the development of the 1-D numerical model a myriad of tests were performed to prove the program produced consistent, realistic numbers that follow compressible flow theory for various inlet conditions.

  2. Ultrahigh-Q nanocavity with 1D photonic gap.

    PubMed

    Notomi, M; Kuramochi, E; Taniyama, H

    2008-07-21

    Recently, various wavelength-sized cavities with theoretical Q values of approximately 10(8) have been reported, however, they all employ 2D or 3D photonic band gaps to realize strong light confinement. Here we numerically demonstrate that ultrahigh-Q (2.0x10(8)) and wavelength-sized (V(eff) approximately 1.4(lambda/n)3) cavities can be achieved by employing only 1D periodicity.

  3. Nonreciprocity of edge modes in 1D magnonic crystal

    NASA Astrophysics Data System (ADS)

    Lisenkov, I.; Kalyabin, D.; Osokin, S.; Klos, J. W.; Krawczyk, M.; Nikitov, S.

    2015-03-01

    Spin waves propagation in 1D magnonic crystals is investigated theoretically. Mathematical model based on plane wave expansion method is applied to different types of magnonic crystals, namely bi-component magnonic crystal with symmetric/asymmetric boundaries and ferromagnetic film with periodically corrugated top surface. It is shown that edge modes in magnonic crystals may exhibit nonreciprocal behaviour at much lower frequencies than in homogeneous films.

  4. 5-HT1B receptor-mediated contractions in human temporal artery: evidence from selective antagonists and 5-HT receptor mRNA expression

    PubMed Central

    Verheggen, R; Hundeshagen, A G; Brown, A M; Schindler, M; Kaumann, A J

    1998-01-01

    In the human temporal artery both 5-HT1-like and 5-HT2A receptors mediate the contractile effects of 5-hydroxytryptamine (5-HT) and we have suggested that the 5-HT1-like receptors resemble more closely recombinant 5-HT1B than 5-HT1D receptors. To investigate further which subtype is involved, we investigated the blockade of 5-HT-induced contractions by the 5-HT1B-selective antagonist SB-224289 (2,3,6,7-tetrahydro-1′-methyl-5-{2-methyl-4′[(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] carbonyl} furo[2,3-f]indole-3-spiro-4′-piperidine oxalate) and the 5-HT1D-selective antagonist BRL-15572 (1-phenyl-3[4-3-chlorophenyl piperazin-1-yl] phenylpropan-2-ol). We also used RT-PCR to search for the mRNA of 5-HT1B, 5-HT1D and other 5-HT receptors.The contractile effects of 5-HT in temporal artery rings were partially antagonized by SB-224289 (20, 200 nM) (apparent KB=1 nM) and ketanserin (1 μM) but not by BRL-15572 (500 nM).Sumatriptan evoked contractions (EC50, 170 nM) that were resistant to blockade by BRL-15572 (500 nM) but antagonized by SB-224289 (20, 200 nM).The potency of 5-HT (EC50) was estimated to be 94 nM for the ketanserin-sensitive receptor and 34 nM for the SB-224289-sensitive receptor. The fraction of maximal 5-HT response mediated through SB-224289-sensitive receptors was 0.20–0.67, the remainder being mediated through ketanserin-sensitive receptors.We detected arterial receptor mRNA for the following receptors (incidence): 5-HT1B (8/8), 5-HT1D (2/8), 5-HT1F (0/4), 5-HT2A (0/8), 5-HT2B (0/8), 5-HT2C (0/8), 5-HT4 (4/8) and 5-HT7 (4/8).We conclude that the ketanserin-resistant fraction of the 5-HT effects and the effects of sumatriptan are mediated by 5-HT1B receptors. The lack of antagonism by BRL-15572 rules out 5-HT1D receptors as mediators of the contractile effects of 5-HT and sumatriptan. PMID:9723944

  5. Protein tyrosine phosphatase 1B (PTP1B)-inhibiting constituents from the leaves of Syzygium polyanthum.

    PubMed

    Saifudin, Azis; Tanaka, Ken; Kadota, Shigetoshi; Tezuka, Yasuhiro

    2012-08-01

    A methanol extract of the leaves of Syzygium polyanthum (Wight) Walp. afforded four new acylbenzene derivatives (1-4) together with seven known compounds (5-11). The structures of 1-11 were elucidated by extensive spectroscopic methods and comparison with the literature data. The new compounds 1-3 and a known compound, campest-4-en-3-one (10), exhibited a significant protein tyrosine phosphatase 1B inhibitory activity with IC₅₀ values of 13.1 ± 0.1, 5.77 ± 0.15, 4.01 ± 0.26, and 10.4 ± 0.5 µM, respectively. The inhibitory potency of the new compounds 2 and 3 was comparable to that of a positive control RK-682 (IC₅₀, 5.51 ± 0.04 µM).

  6. The stability of 1-D soliton in transverse direction

    NASA Astrophysics Data System (ADS)

    Verma, Deepa; Bera, Ratan Kumar; Das, Amita; Kaw, Predhiman

    2016-12-01

    The complete characterization of the exact 1-D solitary wave solutions (both stationary and propagating) for light plasma coupled system have been studied extensively in the parameter space of light frequency and the group speed [Poornakala et al., Phys. Plasmas 9(5), 1820 (2002)]. It has been shown in 1-D that solutions with single light wave peak and paired structures are stable and hence long lived. However, solutions having multiple peaks of light wave are unstable due to Raman scattering instability [Saxena et al., Phys. Plasmas 14, 072307 (2007)]. Here, we have shown with the help of 2-D fluid simulation that single peak and paired solutions too get destabilized by the transverse filamentation instability. The numerical growth rates obtained from simulations is seen to compare well with the analytical values. It is also shown that multiple peaks solitons first undergo the regular 1-D forward Raman scattering instability. Subsequently, they undergo a distinct second phase of destabilization through transverse filamentation instability. This is evident from the structure as well as the plot of the perturbed energy which shows a second phase of growth after saturating initially. The growth rate of the filamentation instability being comparatively slower than the forward Raman instability this phase comes quite late and is clearly distinguishable.

  7. Examining Prebiotic Chemistry Using O(^1D) Insertion Reactions

    NASA Astrophysics Data System (ADS)

    Hays, Brian M.; Laas, Jacob C.; Weaver, Susanna L. Widicus

    2013-06-01

    Aminomethanol, methanediol, and methoxymethanol are all prebiotic molecules expected to form via photo-driven grain surface chemistry in the interstellar medium (ISM). These molecules are expected to be precursors for larger, biologically-relevant molecules in the ISM such as sugars and amino acids. These three molecules have not yet been detected in the ISM because of the lack of available rotational spectra. A high resolution (sub)millimeter spectrometer coupled to a molecular source is being used to study these molecules using O(^1D) insertion reactions. The O(^1D) chemistry is initiated using an excimer laser, and the products of the insertion reactions are adiabatically cooled using a supersonic expansion. Experimental parameters are being optimized by examination of methanol formed from O(^1D) insertion into methane. Theoretical studies of the structure and reaction energies for aminomethanol, methanediol, and methoxymethanol have been conducted to guide the laboratory studies once the methanol experiment has been optimized. The results of the calculations and initial experimental results will be presented.

  8. Development of 1D Liner Compression Code for IDL

    NASA Astrophysics Data System (ADS)

    Shimazu, Akihisa; Slough, John; Pancotti, Anthony

    2015-11-01

    A 1D liner compression code is developed to model liner implosion dynamics in the Inductively Driven Liner Experiment (IDL) where FRC plasmoid is compressed via inductively-driven metal liners. The driver circuit, magnetic field, joule heating, and liner dynamics calculations are performed at each time step in sequence to couple these effects in the code. To obtain more realistic magnetic field results for a given drive coil geometry, 2D and 3D effects are incorporated into the 1D field calculation through use of correction factor table lookup approach. Commercial low-frequency electromagnetic fields solver, ANSYS Maxwell 3D, is used to solve the magnetic field profile for static liner condition at various liner radius in order to derive correction factors for the 1D field calculation in the code. The liner dynamics results from the code is verified to be in good agreement with the results from commercial explicit dynamics solver, ANSYS Explicit Dynamics, and previous liner experiment. The developed code is used to optimize the capacitor bank and driver coil design for better energy transfer and coupling. FRC gain calculations are also performed using the liner compression data from the code for the conceptual design of the reactor sized system for fusion energy gains.

  9. Enhancing Solar Cell Efficiencies through 1-D Nanostructures

    PubMed Central

    2009-01-01

    The current global energy problem can be attributed to insufficient fossil fuel supplies and excessive greenhouse gas emissions resulting from increasing fossil fuel consumption. The huge demand for clean energy potentially can be met by solar-to-electricity conversions. The large-scale use of solar energy is not occurring due to the high cost and inadequate efficiencies of existing solar cells. Nanostructured materials have offered new opportunities to design more efficient solar cells, particularly one-dimensional (1-D) nanomaterials for enhancing solar cell efficiencies. These 1-D nanostructures, including nanotubes, nanowires, and nanorods, offer significant opportunities to improve efficiencies of solar cells by facilitating photon absorption, electron transport, and electron collection; however, tremendous challenges must be conquered before the large-scale commercialization of such cells. This review specifically focuses on the use of 1-D nanostructures for enhancing solar cell efficiencies. Other nanostructured solar cells or solar cells based on bulk materials are not covered in this review. Major topics addressed include dye-sensitized solar cells, quantum-dot-sensitized solar cells, and p-n junction solar cells.

  10. Distribution and evolution of the mobile vma-1b intein.

    PubMed

    Swithers, Kristen S; Soucy, Shannon M; Lasek-Nesselquist, Erica; Lapierre, Pascal; Gogarten, Johann Peter

    2013-12-01

    Inteins are self-splicing parasitic genetic elements found in all domains of life. These genetic elements are found in highly conserved positions in conserved proteins. One protein family that has been invaded by inteins is the vacuolar and archaeal catalytic ATPase subunits (vma-1). There are two intein insertion sites in this protein, "a" and "b." The b site was previously thought to be only invaded in archaeal lineages. Here we survey the distribution and evolutionary histories of the b site inteins and show that the intein is present in more lineages than previously annotated, including a bacterial lineage, Mahella australiensis 50-1 BON. We present evidence, through ancestral character state reconstruction and substitution ratios between host genes and inteins, for several transfers of this intein between divergent species, including an interdomain transfer between the archaea and bacteria. Although inteins may persist within a single population or species for long periods of time, transfer of the vma-1b intein between divergent species contributed to the distribution of this intein.

  11. A Photometric Survey of Ori OB1b

    NASA Astrophysics Data System (ADS)

    Merritt, Allison T.; Sherry, W.

    2011-01-01

    Several mechanisms have been suggested to describe the formation of sub-stellar mass objects (SSMOs), specifically brown dwarfs. Each proposed mechanism predicts a unique spatial distribution of the brown dwarfs relative to the O and B stars of the association. We have 9 square degrees of optical (VRI) data and 7 square degrees of NIR (JHK) data of Orion OB1b. The purpose of the survey is to obtain the photometric data that will allow us to determine the spatial distribution of brown dwarfs in this region and constrain the various formation theories. We present an overview of the survey, with an emphasis on the NIR data, as well as color-magnitude diagrams. This research was supported by the NOAO/KPNO Research Experiences for Undergraduates (REU) Program which is funded by the National Science Foundation Research Experiences for Undergraduates Program and the Department of Defense ASSURE program through Scientific Program Order No. 13 (AST-0754223) of the Cooperative Agreement No. AST-0132798 between the Association of Universities for Research in Astronomy (AURA) and the NSF.

  12. Genetic variants in MTNR1B affecting insulin secretion.

    PubMed

    Müssig, Karsten; Staiger, Harald; Machicao, Fausto; Häring, Hans-Ulrich; Fritsche, Andreas

    2010-09-01

    The incidence of type 2 diabetes mellitus has markedly increased worldwide over the past decades. Pancreatic beta-cell dysfunction as well as central and peripheral insulin resistance appears to be elementary features in the pathophysiology of type 2 diabetes mellitus. Major environmental conditions predisposing to the development of type 2 diabetes are excessive food intake and sedentary life-style on the background of a genetic predisposition. Recent genome-wide association studies identified several novel type 2 diabetes risk genes, with impaired pancreatic beta-cell function as the underlying mechanism of increased diabetes risk in the majority of genes. Many of the novel type 2 diabetes risk genes, including MTNR1B which encodes one of the two known human melatonin receptors, were unexpected at first glance. However, previous animal as well as human studies already pointed to a significant impact of the melatonin system on the regulation of glucose homeostasis, in addition to its well known role in modulation of sleep and circadian rhythms. This brief review aims to give an overview of how alterations in the melatonin system could contribute to an increased diabetes risk, paying special attention to the role of melatonin receptors in pancreatic beta-cell function.

  13. Growth factor independence 1b (gfi1b) is important for the maturation of erythroid cells and the regulation of embryonic globin expression.

    PubMed

    Vassen, Lothar; Beauchemin, Hugues; Lemsaddek, Wafaa; Krongold, Joseph; Trudel, Marie; Möröy, Tarik

    2014-01-01

    Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis. Gfi1b-null embryos die at midgestation very likely due to defects in erythro- and megakaryopoiesis. To analyze the full functionality of Gfi1b, we used conditionally deficient mice that harbor floxed Gfi1b alleles and inducible (Mx-Cre, Cre-ERT) or erythroid specific (EpoR-Cre) Cre expressing transgenes. In contrast to the germline knockout, EpoR-Cre mediated erythroid specific ablation of Gfi1b allows full gestation, but causes perinatal lethality with very few mice surviving to adulthood. Both the embryonic deletion of Gfi1b by EpoR-Cre and the deletion in adult mice by Mx-Cre or Cre-ERT leads to reduced numbers of erythroid precursors, perturbed and delayed erythroid maturation, anemia and extramedullary erythropoiesis. Global expression analyses showed that the Hba-x, Hbb-bh1 and Hbb-y embryonic globin genes were upregulated in Gfi1b deficient TER119+ fetal liver cells over the gestation period from day 12.5-17.5 p.c. and an increased level of Hbb-bh1 and Hbb-y embryonic globin gene expression was even maintained in adult Gfi1b deficient mice. While the expression of Bcl11a, a regulator of embryonic globin expression was not affected by Gfi1b deficiency, the expression of Gata1 was reduced and the expression of Sox6, also involved in globin switch, was almost entirely lost when Gfi1b was absent. These findings establish Gfi1b as a regulator of embryonic globin expression and embryonic and adult erythroid maturation.

  14. Extended-Range Ultrarefractive 1D Photonic Crystal Prisms

    NASA Technical Reports Server (NTRS)

    Ting, David Z.

    2007-01-01

    A proposal has been made to exploit the special wavelength-dispersive characteristics of devices of the type described in One-Dimensional Photonic Crystal Superprisms (NPO-30232) NASA Tech Briefs, Vol. 29, No. 4 (April 2005), page 10a. A photonic crystal is an optical component that has a periodic structure comprising two dielectric materials with high dielectric contrast (e.g., a semiconductor and air), with geometrical feature sizes comparable to or smaller than light wavelengths of interest. Experimental superprisms have been realized as photonic crystals having three-dimensional (3D) structures comprising regions of amorphous Si alternating with regions of SiO2, fabricated in a complex process that included sputtering. A photonic crystal of the type to be exploited according to the present proposal is said to be one-dimensional (1D) because its contrasting dielectric materials would be stacked in parallel planar layers; in other words, there would be spatial periodicity in one dimension only. The processes of designing and fabricating 1D photonic crystal superprisms would be simpler and, hence, would cost less than do those for 3D photonic crystal superprisms. As in 3D structures, 1D photonic crystals may be used in applications such as wavelength-division multiplexing. In the extended-range configuration, it is also suitable for spectrometry applications. As an engineered structure or artificially engineered material, a photonic crystal can exhibit optical properties not commonly found in natural substances. Prior research had revealed several classes of photonic crystal structures for which the propagation of electromagnetic radiation is forbidden in certain frequency ranges, denoted photonic bandgaps. It had also been found that in narrow frequency bands just outside the photonic bandgaps, the angular wavelength dispersion of electromagnetic waves propagating in photonic crystal superprisms is much stronger than is the angular wavelength dispersion obtained

  15. ESO science data product standard for 1D spectral products

    NASA Astrophysics Data System (ADS)

    Micol, Alberto; Arnaboldi, Magda; Delmotte, Nausicaa A. R.; Mascetti, Laura; Retzlaff, Joerg

    2016-07-01

    The ESO Phase 3 process allows the upload, validation, storage, and publication of reduced data through the ESO Science Archive Facility. Since its introduction, 2 million data products have been archived and published; 80% of them are one-dimensional extracted and calibrated spectra. Central to Phase3 is the ESO science data product standard that defines metadata and data format of any product. This contribution describes the ESO data standard for 1d-spectra, its adoption by the reduction pipelines of selected instrument modes for in-house generation of reduced spectra, the enhanced archive legacy value. Archive usage statistics are provided.

  16. Deconvolution/identification techniques for 1-D transient signals

    SciTech Connect

    Goodman, D.M.

    1990-10-01

    This paper discusses a variety of nonparametric deconvolution and identification techniques that we have developed for application to 1-D transient signal problems. These methods are time-domain techniques that use direct methods for matrix inversion. Therefore, they are not appropriate for large data'' problems. These techniques involve various regularization methods and permit the use of certain kinds of a priori information in estimating the unknown. These techniques have been implemented in a package using standard FORTRAN that should make the package readily transportable to most computers. This paper is also meant to be an instruction manual for the package. 25 refs., 17 figs., 1 tab.

  17. Breakdown of 1D water wires inside charged carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Pant, Shashank

    2016-11-01

    Using molecular dynamics approach we investigated the structure and dynamics of water confined inside pristine and charged 6,6 carbon nanotubes (CNTs). This study reports the breakdown of 1D water wires and the emergence of triangular faced water on incorporating charges in 6,6 CNTs. Incorporation of charges results in high potential barriers to flipping of water molecules due to the formation of large number of hydrogen bonds. The PMF analyses show the presence of ∼2 kcal/mol barrier for the movement of water inside pristine CNT and almost negligible barrier in charged CNTs.

  18. Spatial coherence of polaritons in a 1D channel

    SciTech Connect

    Savenko, I. G.; Iorsh, I. V.; Kaliteevski, M. A.; Shelykh, I. A.

    2013-01-15

    We analyze time evolution of spatial coherence of a polariton ensemble in a quantum wire (1D channel) under constant uniform resonant pumping. Using the theoretical approach based on the Lindblad equation for a one-particle density matrix, which takes into account the polariton-phonon and excitonexciton interactions, we study the behavior of the first-order coherence function g{sup 1} for various pump intensities and temperatures in the range of 1-20 K. Bistability and hysteresis in the dependence of the first-order coherence function on the pump intensity is demonstrated.

  19. Nonlocal order parameters for the 1D Hubbard model.

    PubMed

    Montorsi, Arianna; Roncaglia, Marco

    2012-12-07

    We characterize the Mott-insulator and Luther-Emery phases of the 1D Hubbard model through correlators that measure the parity of spin and charge strings along the chain. These nonlocal quantities order in the corresponding gapped phases and vanish at the critical point U(c)=0, thus configuring as hidden order parameters. The Mott insulator consists of bound doublon-holon pairs, which in the Luther-Emery phase turn into electron pairs with opposite spins, both unbinding at U(c). The behavior of the parity correlators is captured by an effective free spinless fermion model.

  20. Nonlocal Order Parameters for the 1D Hubbard Model

    NASA Astrophysics Data System (ADS)

    Montorsi, Arianna; Roncaglia, Marco

    2012-12-01

    We characterize the Mott-insulator and Luther-Emery phases of the 1D Hubbard model through correlators that measure the parity of spin and charge strings along the chain. These nonlocal quantities order in the corresponding gapped phases and vanish at the critical point Uc=0, thus configuring as hidden order parameters. The Mott insulator consists of bound doublon-holon pairs, which in the Luther-Emery phase turn into electron pairs with opposite spins, both unbinding at Uc. The behavior of the parity correlators is captured by an effective free spinless fermion model.

  1. Nanofluidic sustainable energy conversion using a 1D nanofluidic network.

    PubMed

    Kim, Sang Hui; Kwak, Seungmin; Han, Sung Il; Chun, Dong Won; Lee, Kyu Hyoung; Kim, Jinseok; Lee, Jeong Hoon

    2014-05-01

    We propose a 1-dimensional (1D) nanofluidic energy conversion device by implementing a surface-patterned Nafion membrane for the direct energy conversion of the pressure to electrical power. By implementing a -200-nm-thick nano-bridge with a 5-nm pore size between two microfluidic channels, we acquired an effective streaming potential of 307 mV and output power of 94 pW with 0.1 mM KCI under pressure difference of 45 MPa. The experimental results show both the effects of applied pressure differences and buffer concentrations on the effective streaming potential, and are consistent with the analytical prediction.

  2. 1-D blood flow modelling in a running human body.

    PubMed

    Szabó, Viktor; Halász, Gábor

    2017-04-10

    In this paper an attempt was made to simulate blood flow in a mobile human arterial network, specifically, in a running human subject. In order to simulate the effect of motion, a previously published immobile 1-D model was modified by including an inertial force term into the momentum equation. To calculate inertial force, gait analysis was performed at different levels of speed. Our results show that motion has a significant effect on the amplitudes of the blood pressure and flow rate but the average values are not effected significantly.

  3. Oligouridylate Binding Protein 1b Plays an Integral Role in Plant Heat Stress Tolerance

    PubMed Central

    Nguyen, Cam Chau; Nakaminami, Kentaro; Matsui, Akihiro; Kobayashi, Shuhei; Kurihara, Yukio; Toyooka, Kiminori; Tanaka, Maho; Seki, Motoaki

    2016-01-01

    Stress granules (SGs), which are formed in the plant cytoplasm under stress conditions, are transient dynamic sites (particles) for mRNA storage. SGs are actively involved in protecting mRNAs from degradation. Oligouridylate binding protein 1b (UBP1b) is a component of SGs. The formation of microscopically visible cytoplasmic foci, referred to as UBP1b SG, was induced by heat treatment in UBP1b-overexpressing Arabidopsis plants (UBP1b-ox). A detailed understanding of the function of UBP1b, however, is still not clear. UBP1b-ox plants displayed increased heat tolerance, relative to control plants, while ubp1b mutants were more sensitive to heat stress than control plants. Microarray analysis identified 117 genes whose expression was heat-inducible and higher in the UBP1b-ox plants. RNA decay analysis was performed using cordycepin, a transcriptional inhibitor. In order to determine if those genes serve as targets of UBP1b, the rate of RNA degradation of a DnaJ heat shock protein and a stress-associated protein (AtSAP3) in UBP1b-ox plants was slower than in control plants; indicating that the mRNAs of these genes were protected within the UBP1b SG granule. Collectively, these data demonstrate that UBP1b plays an integral role in heat stress tolerance in plants. PMID:27379136

  4. Cyp1b1 Mediates Periostin Regulation of Trabecular Meshwork Development by Suppression of Oxidative Stress

    PubMed Central

    Zhao, Yun; Wang, Shoujian; Sorenson, Christine M.; Teixeira, Leandro; Dubielzig, Richard R.; Peters, Donna M.; Conway, Simon J.; Jefcoate, Colin R.

    2013-01-01

    Mutation in CYP1B1 has been reported for patients with congenital glaucoma. However, the underlying mechanisms remain unknown. Here we show increased diurnal intraocular pressure (IOP) in Cyp1b1-deficient (Cyp1b1−/−) mice. Cyp1b1−/− mice presented ultrastructural irregular collagen distribution in their trabecular meshwork (TM) tissue along with increased oxidative stress and decreased levels of periostin (Postn). Increased levels of oxidative stress and decreased levels of Postn were also detected in human glaucomatous TM tissues. Furthermore, Postn-deficient mice exhibited TM tissue ultrastructural abnormalities similar to those of Cyp1b1−/− mice. Administration of the antioxidant N-acetylcysteine (NAC) restored structural abnormality of TM tissue in Cyp1b1−/− mice. In addition, TM cells prepared from Cyp1b1−/− mice exhibited increased oxidative stress, altered adhesion, and decreased levels of Postn. These aberrant cellular responses were reversed in the presence of NAC or by restoration of Cyp1b1 expression. Cyp1b1 knockdown or inhibition of CYP1B1 activity in Cyp1b1+/+ TM cells resulted in a Cyp1b1−/− phenotype. Thus, metabolic activity of CYP1B1 contributes to oxidative homeostasis and ultrastructural organization and function of TM tissue through modulation of Postn expression. PMID:23979599

  5. EOS MLS Level 1B Data Processing Software. Version 3

    NASA Technical Reports Server (NTRS)

    Perun, Vincent S.; Jarnot, Robert F.; Wagner, Paul A.; Cofield, Richard E., IV; Nguyen, Honghanh T.; Vuu, Christina

    2011-01-01

    This software is an improvement on Version 2, which was described in EOS MLS Level 1B Data Processing, Version 2.2, NASA Tech Briefs, Vol. 33, No. 5 (May 2009), p. 34. It accepts the EOS MLS Level 0 science/engineering data, and the EOS Aura spacecraft ephemeris/attitude data, and produces calibrated instrument radiances and associated engineering and diagnostic data. This version makes the code more robust, improves calibration, provides more diagnostics outputs, defines the Galactic core more finely, and fixes the equator crossing. The Level 1 processing software manages several different tasks. It qualifies each data quantity using instrument configuration and checksum data, as well as data transmission quality flags. Statistical tests are applied for data quality and reasonableness. The instrument engineering data (e.g., voltages, currents, temperatures, and encoder angles) is calibrated by the software, and the filter channel space reference measurements are interpolated onto the times of each limb measurement with the interpolates being differenced from the measurements. Filter channel calibration target measurements are interpolated onto the times of each limb measurement, and are used to compute radiometric gain. The total signal power is determined and analyzed by each digital autocorrelator spectrometer (DACS) during each data integration. The software converts each DACS data integration from an autocorrelation measurement in the time domain into a spectral measurement in the frequency domain, and estimates separately the spectrally, smoothly varying and spectrally averaged components of the limb port signal arising from antenna emission and scattering effects. Limb radiances are also calibrated.

  6. Insulin-mimetic selaginellins from Selaginella tamariscina with protein tyrosine phosphatase 1B (PTP1B) inhibitory activity.

    PubMed

    Nguyen, Phi-Hung; Zhao, Bing-Tian; Ali, Md Yousof; Choi, Jae-Sue; Rhyu, Dong-Young; Min, Byung-Sun; Woo, Mi-Hee

    2015-01-23

    As part of an ongoing search for new antidiabetic agents from medicinal plants, three new (2, 4, and 5) and two known selaginellin derivatives (1 and 3) were isolated from a methanol extract of Selaginella tamariscina. The structures of the new compounds were determined by spectroscopic data analysis. All isolates showed strong glucose uptake stimulatory effects in 3T3-L1 adipocyte cells at a concentration of 5 μM. Furthermore, these compounds were found to possess inhibitory effects on PTP1B enzyme activity with IC50 values ranging from 4.6 ± 0.1 to 21.6 ± 1.5 μM. Compound 2 showed the greatest potency, with an IC50 value of 4.6 ± 0.1 μM, when compared with the positive control (ursolic acid, IC50 = 3.5 ± 0.1 μM). Therefore, these selaginellin derivatives may have value as new lead compounds for the development of agents against type 2 diabetes.

  7. Lack of XAGE-1b and NY-ESO-1 in metastatic lymph nodes may predict the potential survival of stage III melanoma patients.

    PubMed

    Mori, Mariko; Funakoshi, Takeru; Kameyama, Kaori; Kawakami, Yutaka; Sato, Eiichi; Nakayama, Eiichi; Amagai, Masayuki; Tanese, Keiji

    2017-01-20

    The cancer-testis antigens (CTA) are a large family of tumor-associated antigens expressed by a variety of cancer cells and primitive germ cells of the adult testis and placenta. These tumor-restricted expressing patterns suggest that CTA would be ideal targets for tumor-specific immunotherapy. XAGE-1 is a CTA that was originally identified by computer-based screening, and four transcription variants, XAGE-1a, -1b, -1c and -1d, have been characterized to date. Although the presence of XAGE-1 transcripts has been reported in various cancers, the expression of XAGE-1b in melanoma has not been fully characterized. In this study, we performed immunohistochemical staining of XAGE-1b together with NY-ESO-1, a well-known CTA, in 113 melanoma samples obtained from 84 patients and evaluated their expression in tumor cells. The effects of expression on tumor progression and patient prognosis were analyzed. Both XAGE-1b and NY-ESO-1 were expressed at high levels in lymph node metastasis and skin metastasis samples compared with the primary site (P < 0.01 in XAGE-1b and P < 0.05 in NY-ESO-1). In a subgroup analysis of 22 patients with stage III lymph node metastasis, overall survival was significantly higher in the XAGE-1b and NY-ESO-1 double-negative group than in the other groups (P < 0.05). These results suggest that lack of XAGE-1b and NY-ESO-1 expression could have a positive influence on clinical outcome in patients with melanoma.

  8. The N-terminal region of organic anion transporting polypeptide 1B3 (OATP1B3) plays an essential role in regulating its plasma membrane trafficking.

    PubMed

    Chun, Se-Eun; Thakkar, Nilay; Oh, Yunseok; Park, Ji Eun; Han, Songhee; Ryoo, Gongmi; Hahn, Hyunggu; Maeng, Sang Hyun; Lim, Young-Ran; Han, Byung Woo; Lee, Wooin

    2017-05-01

    Organic anion transporting polypeptide 1B3 (OATP1B3) is a major influx transporter mediating the hepatic uptake of various endogenous substrates as well as clinically important drugs such as statins and anticancer drugs. However, molecular mechanisms controlling the membrane trafficking of OATP1B3 have been largely unknown. Several reports recently indicated the presence of a distinct, cancer-type OATP1B3 variant lacking the N-terminal 28 amino acids compared to OATP1B3 expressed in non-malignant hepatocytes. Interestingly, the cancer-type OATP1B3 variant is located predominantly in the cytoplasm, implicating the involvement of the N-terminal region of OATP1B3 in its membrane trafficking. In the current study, we set out to experimentally validate the importance of the N-terminal region of OATP1B3 and to identify responsible sequence motif(s) in that region. A number of truncation or point mutants of OATP1B3 were transiently expressed in HEK293T, HCT-8 or MDCK II cells and their expression in cytoplasmic and surface membrane fractions were analyzed by immunoblotting. Our results indicated that the N-terminal sequence of OATP1B3, in particular, at the amino acid positions between 12 and 28, may be indispensable in its membrane trafficking. Moreover, our results using a fusion construct indicated that the first 50 amino acids of OATP1B3 are sufficient for its membrane localization. The importance of the N-terminal region in membranous localization was shared among the other OATP1B subfamily members, OATP1B1 and rat Oatp1b2. Our efforts to identify the responsible amino acid(s) or structure motif(s) in the N-terminal region did not pinpoint individual amino acids or motifs with putative secondary structures. Our current findings however demonstrate that the N-terminal region is important for the membrane localization of the OATP1B subfamily members and should facilitate future investigations of the mechanisms involved in the regulation and membrane trafficking of

  9. Blood flow quantification using 1D CFD parameter identification

    NASA Astrophysics Data System (ADS)

    Brosig, Richard; Kowarschik, Markus; Maday, Peter; Katouzian, Amin; Demirci, Stefanie; Navab, Nassir

    2014-03-01

    Patient-specific measurements of cerebral blood flow provide valuable diagnostic information concerning cerebrovascular diseases rather than visually driven qualitative evaluation. In this paper, we present a quantitative method to estimate blood flow parameters with high temporal resolution from digital subtraction angiography (DSA) image sequences. Using a 3D DSA dataset and a 2D+t DSA sequence, the proposed algorithm employs a 1D Computational Fluid Dynamics (CFD) model for estimation of time-dependent flow values along a cerebral vessel, combined with an additional Advection Diffusion Equation (ADE) for contrast agent propagation. The CFD system, followed by the ADE, is solved with a finite volume approximation, which ensures the conservation of mass. Instead of defining a new imaging protocol to obtain relevant data, our cost function optimizes the bolus arrival time (BAT) of the contrast agent in 2D+t DSA sequences. The visual determination of BAT is common clinical practice and can be easily derived from and be compared to values, generated by a 1D-CFD simulation. Using this strategy, we ensure that our proposed method fits best to clinical practice and does not require any changes to the medical work flow. Synthetic experiments show that the recovered flow estimates match the ground truth values with less than 12% error in the mean flow rates.

  10. Tunability and Sensing Properties of Plasmonic/1D Photonic Crystal

    NASA Astrophysics Data System (ADS)

    Shaban, Mohamed; Ahmed, Ashour M.; Abdel-Rahman, Ehab; Hamdy, Hany

    2017-02-01

    Gold/one-dimensional photonic crystal (Au/1D-PC) is fabricated and applied for sensitive sensing of glucose and different chemical molecules of various refractive indices. The Au layer thickness is optimized to produce surface plasmon resonance (SPR) at the right edge of the photonic band gap (PBG). As the Au deposition time increased to 60 sec, the PBG width is increased from 46 to 86 nm in correlation with the behavior of the SPR. The selectivity of the optimized Au/1D-PC sensor is tested upon the increase of the environmental refractive index of the detected molecules. The resonance wavelength and the PBG edges increased linearly and the transmitted intensity increased nonlinearly as the environment refractive index increased. The SPR splits to two modes during the detection of chloroform molecules based on the localized capacitive coupling of Au particles. Also, this structure shows high sensitivity at different glucose concentrations. The PBG and SPR are shifted to longer wavelengths, and PBG width is decreased linearly with a rate of 16.04 Å/(μg/mm3) as the glucose concentration increased. The proposed structure merits; operation at room temperature, compact size, and easy fabrication; suggest that the proposed structure can be efficiently used for the biomedical and chemical application.

  11. Tunability and Sensing Properties of Plasmonic/1D Photonic Crystal

    PubMed Central

    Shaban, Mohamed; Ahmed, Ashour M.; Abdel-Rahman, Ehab; Hamdy, Hany

    2017-01-01

    Gold/one-dimensional photonic crystal (Au/1D-PC) is fabricated and applied for sensitive sensing of glucose and different chemical molecules of various refractive indices. The Au layer thickness is optimized to produce surface plasmon resonance (SPR) at the right edge of the photonic band gap (PBG). As the Au deposition time increased to 60 sec, the PBG width is increased from 46 to 86 nm in correlation with the behavior of the SPR. The selectivity of the optimized Au/1D-PC sensor is tested upon the increase of the environmental refractive index of the detected molecules. The resonance wavelength and the PBG edges increased linearly and the transmitted intensity increased nonlinearly as the environment refractive index increased. The SPR splits to two modes during the detection of chloroform molecules based on the localized capacitive coupling of Au particles. Also, this structure shows high sensitivity at different glucose concentrations. The PBG and SPR are shifted to longer wavelengths, and PBG width is decreased linearly with a rate of 16.04 Å/(μg/mm3) as the glucose concentration increased. The proposed structure merits; operation at room temperature, compact size, and easy fabrication; suggest that the proposed structure can be efficiently used for the biomedical and chemical application. PMID:28176799

  12. Engineered atom-light interactions in 1D photonic crystals

    NASA Astrophysics Data System (ADS)

    Martin, Michael J.; Hung, Chen-Lung; Yu, Su-Peng; Goban, Akihisa; Muniz, Juan A.; Hood, Jonathan D.; Norte, Richard; McClung, Andrew C.; Meenehan, Sean M.; Cohen, Justin D.; Lee, Jae Hoon; Peng, Lucas; Painter, Oskar; Kimble, H. Jeff

    2014-05-01

    Nano- and microscale optical systems offer efficient and scalable quantum interfaces through enhanced atom-field coupling in both resonators and continuous waveguides. Beyond these conventional topologies, new opportunities emerge from the integration of ultracold atomic systems with nanoscale photonic crystals. One-dimensional photonic crystal waveguides can be engineered for both stable trapping configurations and strong atom-photon interactions, enabling novel cavity QED and quantum many-body systems, as well as distributed quantum networks. We present the experimental realization of such a nanophotonic quantum interface based on a nanoscale photonic crystal waveguide, demonstrating a fractional waveguide coupling of Γ1 D /Γ' of 0 . 32 +/- 0 . 08 , where Γ1 D (Γ') is the atomic emission rate into the guided (all other) mode(s). We also discuss progress towards intra-waveguide trapping of ultracold Cs. This work was supported by the IQIM, an NSF Physics Frontiers Center with support from the Moore Foundation, the DARPA ORCHID program, the AFOSR QuMPASS MURI, the DoD NSSEFF program, NSF, and the Kavli Nanoscience Institute (KNI) at Caltech.

  13. Constitutive modeling and control of 1D smart composite structures

    NASA Astrophysics Data System (ADS)

    Briggs, Jonathan P.; Ostrowski, James P.; Ponte-Castaneda, Pedro

    1998-07-01

    Homogenization techniques for determining effective properties of composite materials may provide advantages for control of stiffness and strain in systems using hysteretic smart actuators embedded in a soft matrix. In this paper, a homogenized model of a 1D composite structure comprised of shape memory alloys and a rubber-like matrix is presented. With proportional and proportional/integral feedback, using current as the input state and global strain as an error state, implementation scenarios include the use of tractions on the boundaries and a nonlinear constitutive law for the matrix. The result is a simple model which captures the nonlinear behavior of the smart composite material system and is amenable to experiments with various control paradigms. The success of this approach in the context of the 1D model suggests that the homogenization method may prove useful in investigating control of more general smart structures. Applications of such materials could include active rehabilitation aids, e.g. wrist braces, as well as swimming/undulating robots, or adaptive molds for manufacturing processes.

  14. Tunability and Sensing Properties of Plasmonic/1D Photonic Crystal.

    PubMed

    Shaban, Mohamed; Ahmed, Ashour M; Abdel-Rahman, Ehab; Hamdy, Hany

    2017-02-08

    Gold/one-dimensional photonic crystal (Au/1D-PC) is fabricated and applied for sensitive sensing of glucose and different chemical molecules of various refractive indices. The Au layer thickness is optimized to produce surface plasmon resonance (SPR) at the right edge of the photonic band gap (PBG). As the Au deposition time increased to 60 sec, the PBG width is increased from 46 to 86 nm in correlation with the behavior of the SPR. The selectivity of the optimized Au/1D-PC sensor is tested upon the increase of the environmental refractive index of the detected molecules. The resonance wavelength and the PBG edges increased linearly and the transmitted intensity increased nonlinearly as the environment refractive index increased. The SPR splits to two modes during the detection of chloroform molecules based on the localized capacitive coupling of Au particles. Also, this structure shows high sensitivity at different glucose concentrations. The PBG and SPR are shifted to longer wavelengths, and PBG width is decreased linearly with a rate of 16.04 Å/(μg/mm(3)) as the glucose concentration increased. The proposed structure merits; operation at room temperature, compact size, and easy fabrication; suggest that the proposed structure can be efficiently used for the biomedical and chemical application.

  15. Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx.

    PubMed

    Sissung, Tristan M; Ley, Ariel M; Strope, Jonathan D; McCrea, Edel M; Beedie, Shaunna L; Peer, Cody J; Shukla, Suneet; van Velkinburgh, Jennifer C; Reece, Kelie; Troutman, Sarah; Campbell, Tessa; Fernandez, Elena; Huang, Phoebe; Smith, Jordan; Thakkar, Nilay; Venzon, David; Brenner, Steffan; Lee, Wooin; Merino, Maria J; Luo, Ji; Jager, Walter; Chau, Cindy H; Price, Douglas K; Figg, William D

    2017-04-07

    Castration resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. The present study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (KM=23.2µM; VMAX=321.6pmol/mg/min), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50nM; 1.6-fold, P=0.0027). When compared to Slco1b2 (-/-) mice, Slco1b2 (-/-)/hSLCO1B3 knockins had greater hepatic uptake (15% greater AUC, P=0.0040) and lower plasma exposure to 3H-testosterone (17% lower AUC, P=0.0030). Of 82 transporters genes, SLCO1B3 is the second-most differentially-expressed transporter in CRPC cell lines (116-fold vs androgen sensitive cells), with a differentially-spliced cancer-type ct-SLCO1B3 making up the majority of SLCO1B3 expression. Overexpression of SLCO1B3 in androgen responsive cells results in 1.5- to 2-fold greater testosterone uptake whereas siRNA knockdown of SLCO1B3 in CRPC cells did not change intracellular testosterone concentration. Primary human prostate tumors express SLCO1B3 to a greater extent than ct-SLCO1B3 (26% of total SLCO1B3 expression vs 0.08%), suggesting that androgen uptake in these tumor cells also is greater. Non-liver tumors do not differentially express SLCO1B3.

  16. Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration

    PubMed Central

    Xu, Jin; Cui, Jiaxi; Del Campo, Aranzazu; Shin, Chong Hyun

    2016-01-01

    The liver and pancreas originate from overlapping embryonic regions, and single-cell lineage tracing in zebrafish has shown that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining the fate of bipotential hepatopancreatic progenitors towards the liver or pancreas. Despite its pivotal role, the gene regulatory networks functioning downstream of Bmp2b signaling in this process are poorly understood. We have identified four and a half LIM domains 1b (fhl1b), which is primarily expressed in the prospective liver anlage, as a novel target of Bmp2b signaling. fhl1b depletion compromised liver specification and enhanced induction of pancreatic cells from endodermal progenitors. Conversely, overexpression of fhl1b favored liver specification and inhibited induction of pancreatic cells. By single-cell lineage tracing, we showed that fhl1b depletion led lateral endodermal cells, destined to become liver cells, to become pancreatic cells. Reversely, when fhl1b was overexpressed, medially located endodermal cells, fated to differentiate into pancreatic and intestinal cells, contributed to the liver by directly or indirectly modulating the discrete levels of pdx1 expression in endodermal progenitors. Moreover, loss of fhl1b increased the regenerative capacity of β-cells by increasing pdx1 and neurod expression in the hepatopancreatic ductal system. Altogether, these data reveal novel and critical functions of Fhl1b in the hepatic versus pancreatic fate decision and in β-cell regeneration. PMID:26845333

  17. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... obtained from an DHS district or area office. (3) If DHS approves the H-1B classification, the nonimmigrant... nurses. Therefore, the references in this part to “H-1B nonimmigrant” apply to any Mexican citizen nonimmigrant who is classified by DHS as “TN.” In the case of a registered nurse, the following...

  18. 20 CFR 655.705 - What Federal agencies are involved in the H-1B and H-1B1 programs, and what are the...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and... whether the individual is a fashion model of distinguished merit and ability, and whether the... § 655.700(d)(4). Each employer seeking an H-1B nonimmigrant in a specialty occupation or as a...

  19. Involvement of α1B-adrenoceptors in the anti-immobility effect of imipramine in the tail suspension test.

    PubMed

    Ribeiro, Carlos Alberto S; Pupo, André S

    2015-03-05

    Imipramine is a tricyclic antidepressant inhibitor of norepinephrine and serotonin neuronal reuptake. The roles of specific α1-adrenoceptor subtypes that might be targeted by the increased synaptic levels of noradrenaline induced by imipramine are not well understood. This study investigates the α1-adrenoceptor subtypes involved in the anti-immobility effect of imipramine in the mouse tail suspension test. The anti-immobility effect of imipramine (32mg/kg, i.p.) was significantly antagonised by the non-subtype-selective α1-adrenoceptor antagonist prazosin (0.5 and 1.0mg/kg, i.p.). Neither the selective α1A-adrenoceptor antagonist 5-methyl-3-[3-[3-[4-[2-(2,2,2,-trifluroethoxy)phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione (RS-100329, 0.5 and 1.0mg/kg) nor the selective α1D-adrenoceptor antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride, (BMY-7378, up to 1.0mg/kg, i.p.) affected the anti-immobility effect of imipramine. However, the anti-immobility effect of imipramine was significantly antagonised by the selective α1B-adrenoceptor antagonist (2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylate (L-765,314). In addition, mice treated only with RS-100329 or BMY-7378, but not with L-765,314, showed reduced immobility times in comparison to mice treated with vehicle. These results indicate that the selective antagonism of α1A- and α1D-adrenoceptors results in antidepressant-like effects and that the α1B-subtype is the main target for the increased levels of noradrenaline caused by imipramine.

  20. 18 CFR 1b.15 - Non-compliance with compulsory processes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Non-compliance with compulsory processes. 1b.15 Section 1b.15 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.15 Non-compliance...

  1. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Appearance and practice before the Commission. 1b.17 Section 1b.17 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.17...

  2. 18 CFR 1b.15 - Non-compliance with compulsory processes.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Non-compliance with compulsory processes. 1b.15 Section 1b.15 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.15 Non-compliance...

  3. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Appearance and practice before the Commission. 1b.17 Section 1b.17 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.17...

  4. 39 CFR 3010.28 - Maximum size of Type 1-B rate adjustments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 39 Postal Service 1 2014-07-01 2014-07-01 false Maximum size of Type 1-B rate adjustments. 3010.28... DOMINANT PRODUCTS Rules for Determining the Maximum Rate Adjustment § 3010.28 Maximum size of Type 1-B rate... used to make a Type 1-B rate adjustment for any class in any 12-month period may not exceed...

  5. 18 CFR 1b.15 - Non-compliance with compulsory processes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Non-compliance with compulsory processes. 1b.15 Section 1b.15 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.15 Non-compliance...

  6. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Appearance and practice before the Commission. 1b.17 Section 1b.17 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.17...

  7. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Appearance and practice before the Commission. 1b.17 Section 1b.17 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.17...

  8. 18 CFR 1b.17 - Appearance and practice before the Commission.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Appearance and practice before the Commission. 1b.17 Section 1b.17 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.17...

  9. 18 CFR 1b.15 - Non-compliance with compulsory processes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Non-compliance with compulsory processes. 1b.15 Section 1b.15 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.15 Non-compliance...

  10. 18 CFR 1b.15 - Non-compliance with compulsory processes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Non-compliance with compulsory processes. 1b.15 Section 1b.15 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.15 Non-compliance...

  11. Development of an In Vitro Model to Screen CYP1B1-Targeted Anticancer Prodrugs.

    PubMed

    Wang, Zhiying; Chen, Yao; Drbohlav, Laura M; Wu, Judy Qiju; Wang, Michael Zhuo

    2016-12-01

    Cytochrome P450 1B1 (CYP1B1) is an anticancer therapeutic target due to its overexpression in a number of steroid hormone-related cancers. One anticancer drug discovery strategy is to develop prodrugs specifically activated by CYP1B1 in malignant tissues to cytotoxic metabolites. Here, we aimed to develop an in vitro screening model for CYP1B1-targeted anticancer prodrugs using the KLE human endometrial carcinoma cell line. KLE cells demonstrated superior stability of CYP1B1 expression relative to transiently transfected cells and did not express any appreciable amount of cognate CYP1A1 or CYP1A2, which would have compromised the specificity of the screening assay. The effect of two CYP1B1-targeted probe prodrugs on KLE cells was evaluated in the absence and presence of a CYP1B1 inhibitor to chemically "knock out" CYP1B1 activity (CYP1B1 inhibited). Both probe prodrugs were more toxic to KLE cells than to CYP1B1-inhibited KLE cells and significantly induced G0/G1 arrest and decreased the S phase in KLE cells. They also exhibited pro-apoptotic effects in KLE cells, which were attenuated in CYP1B1-inhibited KLE cells. In summary, a KLE cell-based model has been characterized to be suitable for identifying CYP1B1-targeted anticancer prodrugs and should be further developed and employed for screening chemical libraries.

  12. Deregulation of FoxM1b leads to tumour metastasis

    PubMed Central

    Park, Hyun Jung; Gusarova, Galina; Wang, Zebin; Carr, Janai R; Li, Jing; Kim, Ki-Hyun; Qiu, Jin; Park, Yoon-Dong; Williamson, Peter R; Hay, Nissim; Tyner, Angela L; Lau, Lester F; Costa, Robert H; Raychaudhuri, Pradip

    2011-01-01

    The forkhead box M1b (FoxM1b) transcription factor is over-expressed in human cancers, and its expression often correlates with poor prognosis. Previously, using conditional knockout strains, we showed that FoxM1b is essential for hepatocellular carcinoma (HCC) development. However, over-expression of FoxM1b had only marginal effects on HCC progression. Here we investigated the effect of FoxM1b expression in the absence of its inhibitor Arf. We show that transgenic expression of FoxM1b in an Arf-null background drives hepatic fibrosis and metastasis of HCC. We identify novel mechanisms of FoxM1b that are involved in epithelial–mesenchymal transition, cell motility, invasion and a pre-metastatic niche formation. FoxM1b activates the Akt-Snail1 pathway and stimulates expression of Stathmin, lysyl oxidase, lysyl oxidase like-2 and several other genes involved in metastasis. Furthermore, we show that an Arf-derived peptide, which inhibits FoxM1b, impedes metastasis of the FoxM1b-expressing HCC cells. The observations indicate that FoxM1b is a potent activator of tumour metastasis and that the Arf-mediated inhibition of FoxM1b is a critical mechanism for suppression of tumour metastasis. PMID:21204266

  13. Changes in the expression of α1B-adrenoceptor in peripheral mononuclear cells correlates with blood pressure and plasmatic homocysteine.

    PubMed

    Oliver, Eduardo; Montó, Fermí; Rovira, Eduardo; Valldecabres, Carmen; Muedra, Vicente; D'Ocon, Pilar

    2017-04-01

    Human peripheral mononuclear cells (HPMC) have been suggested as a practical surrogate for myocardial or vascular cells. Present work analyses if changes in the expression of α1-adrenoceptors (ARs) in HPMC are related to the hypertensive state and its clinical consequences. Quantitative RT-PCR was employed to evaluate the mRNA levels of the three α1-ARs (α1A, α1B, α1D) in HPMC isolated from normotensive and hypertensive patients, and also in tissues from two animal models of hypertension: spontaneously hypertensive rats (SHR) and hypertension induced by chronic treatment with L-NAME. In patients, 24-h ambulatory blood pressure and serum biochemical profile were also recorded. We found that α1B-AR expression was higher in HPMC from hypertensive patients and correlated with blood pressure and plasmatic homocysteine. A rise in the α1B-AR expression in kidneys, but not in heart from hypertensive animal models was also found. α1D-AR did not change in HPMC, not in rat heart or kidney, but a significant correlation with plasmatic aldosterone was found. In conclusion, we have proved that α1-ARs mRNA expression in HPMC correlates with clinical variables and could be used as a potential biomarker in hypertensive patients.

  14. The effect of organic anion-transporting polypeptides 1B1, 1B3 and 2B1 on the antitumor activity of flavopiridol in breast cancer cells.

    PubMed

    Brenner, Stefan; Riha, Juliane; Giessrigl, Benedikt; Thalhammer, Theresia; Grusch, Michael; Krupitza, Georg; Stieger, Bruno; Jäger, Walter

    2015-01-01

    The contribution of organic anion transporting polypeptides (OATPs) to the cellular uptake of flavopiridol was investigated in OATP1B1-, OATP1B3- and OATP2B1-expressing Chinese hamster ovary (CHO) cells. Uptake of flavopiridol into these cells showed typical Michaelis-Menten kinetics with much higher transport capacity for OATP1B3 compared to OATP1B1 and OATP2B1 (Vmax/Km, 33.9 vs. 8.84 and 2.41 µl/mg/min, respectively). The predominant role of OATPs was further supported by a dramatic inhibition of flavopiridol uptake in the presence of the OATP substrate rifampicin. Uptake of flavopiridol by OATPs also seems to be an important determinant in breast cancer cells. The much higher mRNA level for OATP1B1 found in wild-type compared to ZR-75-1 OATP1B1 knockdown cells correlated with higher flavopiridol initial uptake leading to 4.6-fold decreased IC50 values in the cytotoxicity assay (IC50, 1.45 vs. 6.64 µM). Cell cycle profile also showed a clear incidence for a stronger cell cycle arrest in the G2/M phase for ZR-75-1 wild-type cells compared to OATP1B1 knockdown cells, further indicating an active uptake via OATP1B1. In conclusion, our results revealed OATP1B1, OATP1B3 and OATP2B1 as uptake transporters for flavopiridol in cancer cells, which may also apply in patients during cancer therapy.

  15. The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3.

    PubMed

    Seithel, Annick; Eberl, Sonja; Singer, Katrin; Auge, Daniel; Heinkele, Georg; Wolf, Nadine B; Dörje, Frank; Fromm, Martin F; König, Jörg

    2007-05-01

    Macrolides may cause severe drug interactions due to the inhibition of metabolizing enzymes. Transporter-mediated uptake of drugs into cells [e.g., by members of the human organic anion transporting polypeptide (OATP) family] is a determinant of drug disposition and a prerequisite for subsequent metabolism. However whether macrolides are also inhibitors of uptake transporters, thereby providing an additional mechanism of drug interactions, has not been systematically studied. The human OATP family members OATP1B1 and OATP1B3 mediate the uptake of endogenous substances and drugs such as antibiotics and HMG-CoA reductase inhibitors (statins) into hepatocytes. In this study we investigated the potential role of these uptake transporters on macrolide-induced drug interactions. By using sulfobromophthalein (BSP) and the HMG-CoA reductase inhibitor pravastatin as substrates, the effects of the macrolides azithromycin, clarithromycin, erythromycin, and roxithromycin and of the ketolide telithromycin on the OATP1B1- and OATP1B3-mediated uptake were analyzed. These experiments demonstrated that the OATP1B1- and OATP1B3-mediated uptake of BSP and pravastatin can be inhibited by increasing concentrations of all macrolides except azithromycin. The IC50 values for the inhibition of OATP1B3-mediated BSP uptake were 11 microM for telithromycin, 32 microM for clarithromycin, 34 microM for erythromycin, and 37 microM for roxithromycin. These IC50 values were lower than the IC50 values for inhibition of OATP1B1-mediated BSP uptake (96-217 microM). These macrolides also inhibited in a concentration-dependent manner the OATP1B1- and OATP1B3-mediated uptake of pravastatin. In summary, these results indicate that alterations of uptake transporter function by certain macrolides/ketolides have to be considered as a potential additional mechanism underlying drug-drug interactions.

  16. Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen*

    PubMed Central

    Sayegh, Joyce; Cao, Jian; Zou, Mike Ran; Morales, Alfonso; Blair, Lauren P.; Norcia, Michael; Hoyer, Denton; Tackett, Alan J.; Merkel, Jane S.; Yan, Qin

    2013-01-01

    JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character. Therefore, JARID1B represents an attractive target for cancer therapy. Here we characterized JARID1B using a homogeneous luminescence-based demethylase assay. We then conducted a high throughput screen of over 15,000 small molecules to identify inhibitors of JARID1B. From this screen, we identified several known JmjC histone demethylase inhibitors, including 2,4-pyridinedicarboxylic acid and catechols. More importantly, we identified several novel inhibitors, including 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), which inhibits JARID1B with an IC50 of about 3 μm in vitro. Consistent with this, PBIT treatment inhibited removal of H3K4me3 by JARID1B in cells. Furthermore, this compound inhibited proliferation of cells expressing higher levels of JARID1B. These results suggest that this novel small molecule inhibitor is a lead compound that can be further optimized for cancer therapy. PMID:23408432

  17. Cyp1b1 exerts opposing effects on intestinal tumorigenesis via exogenous and endogenous substrates

    PubMed Central

    Halberg, Richard B.; Larsen, Michele Campaigne; Elmergreen, Tammy L.; Ko, Alex Y.; Irving, Amy A.; Clipson, Linda; Jefcoate, Colin R.

    2008-01-01

    Cytochrome P450 1B1 (Cyp1b1) metabolism contributes to physiological functions during embryogenesis, but also to carcinogenic activation of polycyclic aromatic hydrocarbons (PAH). We generated Cyp1b1-deficient mice carrying the Min allele of the Adenomatous polyposis coli gene. These Cyp1b1-deficient Min mice developed twice as many tumors as Min controls, which, however, remained similar in size and histology. Tumors from older (130 day) Cyp1b1-deficient Min mice exhibited focal areas of nuclear atypia associated with less organized epithelia. The metabolism of endogenous substrates by Cyp1b1, therefore, suppresses tumor initiation, but also affects progression. Treatment of Min mice with 7,12-dimethylbenzanthracene (DMBA) doubled both tumor multiplicity and size within 20 days, but not when mice lacked Cyp1b1. This was paralleled by an abnormal staining of crypts with β catenin, phospho-IKK, and ReIA, which may represent an early stage of tumorigenesis similar to aberrant crypt formation. Cyp1b1 deletion did not affect circulating DMBA and metabolites. Cyp1b1 expression was higher in the tumors compared to normal small intestines. Increased tumorigenesis may, therefore, arise from generation of DMBA metabolites by Cyp1b1 in the developing tumors. Benzo(a)pyrene (BP), which is similarly activated by Cyp1b1 in vitro, did not affect tumorigenesis in Min mice. By contrast, BP and DMBA each suppressed tumor multiplicity in absence of Cyp1b1. Cyp1b1 metabolism of DMBA and endogenous oxygenation products may each impact a tumor promoting NF-κB. activation, whereas Ah receptor activation by PAH effects suppression. Tumorigenesis may, therefore, depend on activation of PAH by Cyp1b1, and on off-setting suppression by Cyp1b1 of endogenous tumor-enhancing substrates. PMID:18794127

  18. Axion string dynamics I: 2+1D

    NASA Astrophysics Data System (ADS)

    Fleury, Leesa M.; Moore, Guy D.

    2016-05-01

    If the axion exists and if the initial axion field value is uncorrelated at causally disconnected points, then it should be possible to predict the efficiency of cosmological axion production, relating the axionic dark matter density to the axion mass. The main obstacle to making this prediction is correctly treating the axion string cores. We develop a new algorithm for treating the axionic string cores correctly in 2+1 dimensions. When the axionic string cores are given their full physical string tension, axion production is about twice as efficient as in previous simulations. We argue that the string network in 2+1 dimensions should behave very differently than in 3+1 dimensions, so this result cannot be simply carried over to the physical case. We outline how to extend our method to 3+1D axion string dynamics.

  19. 1-D ELECTRO-OPTIC BEAM STEERING DEVICE.

    PubMed

    Wang, Wei-Chih; Tsui, Chi Leung

    2011-06-05

    In this paper, we present the design and fabrication of a 1D beam steering device based on planar electro-optic thermal-plastic prisms and a collimator lens array. With the elimination of moving parts, the proposed device is able to overcome the mechanical limitations of present scanning devices, such as fatigue and low operating frequency, while maintaining a small system footprint (~0.5mm×0.5mm). From experimental data, our prototype device is able to achieve a maximum deflection angle of 5.6° for a single stage prism design and 29.2° for a cascaded three prisms stage design. The lens array shows a 4µm collimated beam diameter.

  20. Combinatorial approach to exactly solve the 1D Ising model

    NASA Astrophysics Data System (ADS)

    Seth, Swarnadeep

    2017-01-01

    The Ising model is a well known statistical model which can be solved exactly by various methods. The most familiar one is the transfer matrix method. Sometimes it can be difficult to approach the open boundary case rather than periodic boundary ones in higher dimensions. But physically it is more intuitive to study the open boundary case, as it gives a closer view of the real system. We have introduced a new method called the pairing method to determine the exact partition function for the simplest case, a 1D Ising lattice. This method simplifies the problem's complexities and reduces it to a pure combinatorial problem. The study also reveals that it is possible to apply this pairing method in the case of a 2D square lattice. The obtained results agree perfectly with the values in the literature and this new approach provides an algorithmic insight to deal with such problems.

  1. Statistical analysis of 1D HRR target features

    NASA Astrophysics Data System (ADS)

    Gross, David C.; Schmitz, James L.; Williams, Robert L.

    2000-08-01

    Automatic target recognition (ATR) and feature-aided tracking (FAT) algorithms that use one-dimensional (1-D) high range resolution (HRR) profiles require unique or distinguishable target features. This paper explores the use of statistical measures to quantify the separability and stability of ground target features found in HRR profiles. Measures of stability, such as the mean and variance, can be used to determine the stability of a target feature as a function of the target aspect and elevation angle. Statistical measures of feature predictability and separability, such as the Fisher and Bhattacharyya measures, demonstrate the capability to adequately predict the desired target feature over a specified aspect angular region. These statistical measures for separability and stability are explained in detail and their usefulness is demonstrated with measured HRR data.

  2. Axion string dynamics I: 2+1D

    SciTech Connect

    Fleury, Leesa M.; Moore, Guy D.

    2016-05-03

    If the axion exists and if the initial axion field value is uncorrelated at causally disconnected points, then it should be possible to predict the efficiency of cosmological axion production, relating the axionic dark matter density to the axion mass. The main obstacle to making this prediction is correctly treating the axion string cores. We develop a new algorithm for treating the axionic string cores correctly in 2+1 dimensions. When the axionic string cores are given their full physical string tension, axion production is about twice as efficient as in previous simulations. We argue that the string network in 2+1 dimensions should behave very differently than in 3+1 dimensions, so this result cannot be simply carried over to the physical case. We outline how to extend our method to 3+1D axion string dynamics.

  3. Effective theory of black holes in the 1/D expansion

    NASA Astrophysics Data System (ADS)

    Emparan, Roberto; Shiromizu, Tetsuya; Suzuki, Ryotaku; Tanabe, Kentaro; Tanaka, Takahiro

    2015-06-01

    The gravitational field of a black hole is strongly localized near its horizon when the number of dimensions D is very large. In this limit, we can effectively replace the black hole with a surface in a background geometry (e.g. Minkowski or Anti-deSitter space). The Einstein equations determine the effective equations that this `black hole surface' (or membrane) must satisfy. We obtain them up to next-to-leading order in 1/ D for static black holes of the Einstein-(A)dS theory. To leading order, and also to next order in Minkowski backgrounds, the equations of the effective theory are the same as soap-film equations, possibly up to a redshift factor. In particular, the Schwarzschild black hole is recovered as a spherical soap bubble. Less trivially, we find solutions for `black droplets', i.e. black holes localized at the boundary of AdS, and for non-uniform black strings.

  4. Uniform Propagation of Chaos for Kac's 1D Particle System

    NASA Astrophysics Data System (ADS)

    Cortez, Roberto

    2016-12-01

    In this paper we study Kac's 1D particle system, consisting of the velocities of N particles colliding at constant rate and randomly exchanging energies. We prove uniform (in time) propagation of chaos in Wasserstein distance with explicit polynomial rates in N, for both the squared (i.e., the energy) and non-squared particle system. These rates are of order N^{-1/3} (almost, in the non-squared case), assuming that the initial distribution of the limit nonlinear equation has finite moments of sufficiently high order (4+ɛ is enough when using the 2-Wasserstein distance). The proof relies on a convenient parametrization of the collision recently introduced by Hauray, as well as on a coupling technique developed by Cortez and Fontbona.

  5. 1-D ELECTRO-OPTIC BEAM STEERING DEVICE

    PubMed Central

    Wang, Wei-Chih; Tsui, Chi Leung

    2011-01-01

    In this paper, we present the design and fabrication of a 1D beam steering device based on planar electro-optic thermal-plastic prisms and a collimator lens array. With the elimination of moving parts, the proposed device is able to overcome the mechanical limitations of present scanning devices, such as fatigue and low operating frequency, while maintaining a small system footprint (~0.5mm×0.5mm). From experimental data, our prototype device is able to achieve a maximum deflection angle of 5.6° for a single stage prism design and 29.2° for a cascaded three prisms stage design. The lens array shows a 4µm collimated beam diameter. PMID:22199458

  6. The Wheat GT Factor TaGT2L1D Negatively Regulates Drought Tolerance and Plant Development

    PubMed Central

    Zheng, Xin; Liu, Haipei; Ji, Hongtao; Wang, Youning; Dong, Baodi; Qiao, Yunzhou; Liu, Mengyu; Li, Xia

    2016-01-01

    GT factors are trihelix transcription factors that specifically regulate plant development and stress responses. Recently, several GT factors have been characterized in different plant species; however, little is known about the role of GT factors in wheat. Here, we show that TaGT2L1A, TaGT2L1B, and TaGT2L1D are highly homologous in hexaploid wheat, and are localized to wheat chromosomes 2A, 2B, and 2D, respectively. These TaGT2L1 genes encode proteins containing two SANT domains and one central helix. All three homologs were ubiquitously expressed during wheat development and were responsive to osmotic stress. Functional analyses demonstrated that TaGT2L1D acts as a transcriptional repressor; it was able to suppress the expression of AtSDD1 in Arabidopsis by binding directly to the GT3 box in its promoter that negatively regulates drought tolerance. TaGT2L1D overexpression markedly increased the number of stomata and reduced drought tolerance in gtl1-3 plants. Notably, ectopic expression of TaGT2L1D also affected floral organ development and overall plant growth. These results demonstrate that TaGT2L1 is an ortholog of AtGTL1, and that it plays an evolutionarily conserved role in drought resistance by fine tuning stomatal density in wheat. Our data also highlight the role of TaGT2L1 in plant growth and development. PMID:27245096

  7. Lanczos diagonalizations of the 1-D Peierls-Hubbard model

    SciTech Connect

    Loh, E.Y.; Campbell, D.K.; Gammel, J.T.

    1989-01-01

    In studies of interacting electrons in reduced dimensions'' one is trapped between the Scylla of exponential growth of the number of states in any exact many-body basis and the Charybdis of the failure of mean-field theories to capture adequately the effects of interactions. In the present article we focus on one technique -- the Lanczos method -- which, at least in the case of the 1-D Peierls-Hubbard model, appears to allow us to sail the narrow channel between these two hazards. In contrast to Quantum Monte Carlo methods, which circumvent the exponential growth of states by statistical techniques and importance sampling, the Lanczos approach attacks this problem head-on by diagonalizing the full Hamiltonian. Given the restrictions of present computers, this approach is thus limited to studying finite clusters of roughly 12--14 sites. Fortunately, in one dimension, such clusters are usually sufficient for extracting many of the properties of the infinite system provided that one makes full use of the ability to vary the boundary conditions. In this article we shall apply the Lanczos methodology and novel phase randomization'' techniques to study the 1-D Peierls-Hubbard model, with particular emphasis on the optical absorption properties, including the spectrum of absorptions as a function of photon energy. Despite the discreteness of the eigenstates in our finite clusters, we are able to obtain optical spectra that, in cases where independent tests can be made, agree well with the known exact results for the infinite system. Thus we feel that this combination of techniques represents an important and viable means of studying many interesting novel materials involving strongly correlated electrons. 26 refs., 6 figs.

  8. Evaluating 1d Seismic Models of the Lunar Interior

    NASA Astrophysics Data System (ADS)

    Yao, Y.; Thorne, M. S.; Weber, R. C.; Schmerr, N. C.

    2012-12-01

    A four station seismic network was established on the Moon from 1969 to 1977 as part of the Apollo Lunar Surface Experiment Package (ALSEP). A total of nine 1D seismic velocity models were generated using a variety of different techniques. In spite of the fact that these models were generated from the same data set, significant differences exist between them. We evaluate these models by comparing predicted travel-times to published catalogs of lunar events. We generate synthetic waveform predictions for 1D lunar models using a modified version of the Green's Function of the Earth by Minor Integration (GEMINI) technique. Our results demonstrate that the mean square errors between predicted and measured P-wave travel times are smaller than those for S-wave travel times in all cases. Moreover, models fit travel times for artificial and meteoroid impacts better than for shallow and deep moonquakes. Overall, models presented by Nakamura [Nakamura, 1983] and Garcia et al. [Garcia et al., 2011] predicted the observed travel times better than all other models and were comparable in their explanation of travel-times. Nevertheless, significant waveform differences exist between these models. In particular, the seismic velocity structure of the lunar crust and regolith strongly affect the waveform characteristics predicted by these models. Further complexity is added by possible mantle discontinuity structure that exists in a subset of these models. We show synthetic waveform predictions for these models demonstrating the role that crustal structure has in generating long duration seismic coda inherent in the lunar waveforms.

  9. CYP1B1 expression, a potential risk factor for breast cancer

    SciTech Connect

    Goth-Goldstein, Regine; Erdmann, Christine A.; Russell, Marion

    2001-05-31

    CYP1B1 expression in non-tumor breast tissue from breast cancer patients and cancer-free individuals was determined to test the hypothesis that high CYP1B1 expression is a risk factor for breast cancer. Large interindividual variations in CYP1B1 expression were found with CYP1B1 levels notably higher in breast cancer patients than cancer-free individuals. The results indicate that CYP1B1 might play a role in breast cancer either through increased PAH activation or through metabolism of endogenous estrogen to a carcinogenic derivative.

  10. Role of CYP1B1 in PAH-DNA Adduct Formation and Breast Cancer Risk

    DTIC Science & Technology

    2006-03-01

    xenobiotic metabolism, CYP1B1 , gene expression, genetic polymorphism , DNA adducts 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18...Task 2: Characterize the breast tissue samples in respect to CYP1B1 expression and CYP1B1 polymorphism – in progress a. Isolate DNA and RNA from...19.78) 0.06 – 73.7 d. Perform CYP1B1 genotype analysis The CYP1B1 genotype at two polymorphic sites located in the catalytic side of the enzyme

  11. Yif1B Is Involved in the Anterograde Traffic Pathway and the Golgi Architecture.

    PubMed

    Alterio, Jeanine; Masson, Justine; Diaz, Jorge; Chachlaki, Konstantina; Salman, Haysam; Areias, Julie; Al Awabdh, Sana; Emerit, Michel Boris; Darmon, Michèle

    2015-09-01

    Yif1B is an intracellular membrane-bound protein belonging to the Yip family, shown previously to control serotonin 5-HT1A receptor targeting to dendrites. Because some Yip proteins are involved in the intracellular traffic between the ER and the Golgi, here we investigated the precise localization of Yif1B in HeLa cells. We found that Yif1B is not resident into the Golgi, but rather belongs to the IC compartment. After analyzing the role of Yif1B in protein transport, we showed that the traffic of the VSVG protein marker was accelerated in Yif1B depleted HeLa cells, as well as in hippocampal neurons from Yif1B KO mice. Conversely, Yif1B depletion in HeLa cells did not change the retrograde traffic of ShTx. Interestingly, in long term depletion of Yif1B as in Yif1B KO mice, we observed a disorganized Golgi architecture in CA1 pyramidal hippocampal neurons, which was confirmed by electron microscopy. However, because short term depletion of Yif1B did not change Golgi structure, it is likely that the implication of Yif1B in anterograde traffic does not rely on its role in structural organization of the Golgi apparatus, but rather on its shuttling between the ER, the IC and the Golgi compartments.

  12. CYP1B1 is polymorphic in cynomolgus and rhesus macaques.

    PubMed

    Uno, Yasuhiro; Matsushita, Akinori; Yamazaki, Hiroshi

    2011-09-01

    Cytochrome P450 (CYP) 1B1 is involved in the metabolic activation of various procarcinogens, and some CYP1B1 genetic variants alter CYP1B1-dependent procarcinogen metabolism. Cynomolgus and rhesus macaques are frequently used in toxicity tests due to their evolutionary closeness to humans. In this study, we attempted to identify CYP1B1 genetic variants in 13 cynomolgus and 4 rhesus macaques. A total of 17 genetic variants were identified, including 8 non-synonymous genetic variants, indicating that, similar to humans, CYP1B1 is polymorphic in macaques. These CYP1B1 genetic variants could be the basis for understanding potential inter-animal differences in macaque CYP1B1-dependent metabolism of promutagens.

  13. Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity.

    PubMed

    Maples, Jill M; Brault, Jeffrey J; Witczak, Carol A; Park, Sanghee; Hubal, Monica J; Weber, Todd M; Houmard, Joseph A; Shewchuk, Brian M

    2015-08-15

    The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity.

  14. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.

    PubMed

    Tichomirowa, Maria A; Lee, Misu; Barlier, Anne; Daly, Adrian F; Marinoni, Ilaria; Jaffrain-Rea, Marie-Lise; Naves, Luciana A; Rodien, Patrice; Rohmer, Vincent; Faucz, Fabio Rueda; Caron, Philippe; Estour, Bruno; Lecomte, Pierre; Borson-Chazot, Françoise; Penfornis, Alfred; Yaneva, Maria; Guitelman, Mirtha; Castermans, Emily; Verhaege, Catherine; Wémeau, Jean-Louis; Tabarin, Antoine; Fajardo Montañana, Carmen; Delemer, Brigitte; Kerlan, Veronique; Sadoul, Jean-Louis; Cortet Rudelli, Christine; Archambeaud, Françoise; Zacharieva, Sabine; Theodoropoulou, Marily; Brue, Thierry; Enjalbert, Alain; Bours, Vincent; Pellegata, Natalia S; Beckers, Albert

    2012-06-01

    Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

  15. Analysis of in vitro interactions of protein tyrosine phosphatase 1B with insulin receptors.

    PubMed

    Wang, X Y; Bergdahl, K; Heijbel, A; Liljebris, C; Bleasdale, J E

    2001-02-28

    One strategy to treat the insulin resistance that is central to type II diabetes mellitus may be to maintain insulin receptors (IR) in the active (tyrosine phosphorylated) form. Because protein tyrosine phosphatase 1B (PTP1B) binds and subsequently dephosphorylates IR, inhibitors of PTP1B-IR binding are potential insulin 'sensitizers.' A Scintillation Proximity Assay (SPA) was developed to characterize and quantitate PTP1B-IR binding. Human IR were solubilized and captured on wheat germ agglutinin (WGA)-coated SPA beads. Subsequent binding of human, catalytically inactive [35S] PTP1B Cys(215)/Ser (PTP1B(C215S)) to the lectin-anchored IR results in scintillation from the SPA beads that can be quantitated. Binding of PTP1B to IR was pH- and divalent cation-sensitive. Ca(2+) and Mn(2+), but not Mg(2+), dramatically attenuated the loss of PTP1B-IR binding observed when pH was raised from 6.2 to 7.8. PTP1B binding to IR from insulin-stimulated cells was much greater than to IR from unstimulated cells and was inhibited by either an antiphosphotyrosine antibody or treatment of IR with alkaline phosphatase, suggesting that tyrosine phosphorylation of IR is required for PTP1B binding. Phosphopeptides modeled after various IR phosphotyrosine domains each only partially inhibited PTP1B-IR binding, indicating that multiple domains of IR are likely involved in binding PTP1B. However, competitive displacement of [35S]PTP1B(C215S) by PTP1B(C215S) fitted best to a single binding site with a K(d) in the range 100-1000 nM, depending upon pH and divalent cations. PNU-200898, a potent and selective inhibitor of PTP1B whose orientation in the active site of PTP1B has been solved, competitively inhibited catalysis and PTP1B-IR binding with equal potency. The results of this novel assay for PTP1B-IR binding suggest that PTP1B binds preferentially to tyrosine phosphorylated IR through its active site and that binding may be susceptible to therapeutic disruption by small molecules.

  16. CYP1B1 mRNA inducibility due to benzo(a)pyrene is modified by the CYP1B1 L432V gene polymorphism.

    PubMed

    Helmig, Simone; Wenzel, Sibylle; Maxeiner, Hagen; Schneider, Joachim

    2014-07-01

    Benzo(a)pyrene (BaP), a primary component of tobacco smoke, is activated by cytochrome P450 1B1 (CYP1B1). Smokers homozygous for the C-allele (*1/*1) at the CYP1B1 Leu432Val polymorphism have shown increased CYP1B1 expression, compared to smokers homozygous for the G-allele *3/*3. Since no difference has been shown in CYP1B1 expression between both genotypes in non-smokers, we assumed that the genetic impact is produced in combination with an exogenous induction (e.g. BaP). To confirm this theory and to quantify the effect, we induced human leucocytes with increasing BaP concentrations and determined CYP1B1 mRNA expression with real-time polymerase chain reaction (PCR). We incubated human leucocytes from 27 healthy donors with BaP concentrations ranging from 2.5 to 250 µM. We identified the CYP1B1 genotypes by melting curve analysis and assessed relative CYP1B1 mRNA expression using real-time PCR. Expression was related to β-2-microglobulin with the 2(-ΔΔCT) method. Inducibility of CYP1B1 mRNA by BaP was higher in leucocytes carrying the CYP1B1*1/*1 genotype than in leucocytes carrying the CYP1B1*3/*3 genotype (P = 0.012). We revealed significant differences, with BaP concentrations of 2.5 µM (P = 0.0094), 5 µM (P = 0.027), 10 µM (P = 0.0006), 25 µM (P = 0.0007) and 50 µM (P = 0.017). Homozygous carriers of the C-allele (*1/*1) at the CYP1B1 Leu432Val polymorphism show a higher response to environmental factors, such as carcinogenic BaP, than homozygous carriers of the G-allele *3/*3.

  17. Oxo Complexes of Tungstenocene via Oxidation of (W(Eta(5)-C5H5)2(OCH3) (CH3)) and Related Reactions: Synthesis, Structural Characterization, and Photodisproportionation of the Spin Paired d(1)-d(1) Oxo Bridged Dimer ((W(Eta(5)-C5H5)2(CH3))2(Mu-O))2(+) and Synthesis and Charaterization of the d(0) Terminal Oxo Complex (W(Eta(5)-C5H5)2(O)(CH3))(+)

    DTIC Science & Technology

    1993-02-15

    work was supported in part by the Office of Na\\ al Research We thank Dr . Steven Geib and Professor Bruce Foxman for helpful discusions of the X-ra...techniques or a Vacuum Atmospheres dr % box under an atmosphere of prepunfied nitrogen unless otherise noted Glass%%are wvas flame dncd under vacuum or...of Naval Research (2)" Dr . Richard W. Drisko (1) Chemistry Division, Code 1113 Naval Civil Engineering 800 North Quincy Street Laboratory Arlington

  18. Consequence of the tumor-associated conversion to cyclin D1b

    PubMed Central

    Augello, Michael A; Berman-Booty, Lisa D; Carr, Richard; Yoshida, Akihiro; Dean, Jeffry L; Schiewer, Matthew J; Feng, Felix Y; Tomlins, Scott A; Gao, Erhe; Koch, Walter J; Benovic, Jeffrey L; Diehl, John Alan; Knudsen, Karen E

    2015-01-01

    Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre-clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant. PMID:25787974

  19. Alcohol dehydrogenase 1B genotype and fetal alcohol syndrome: a HuGE minireview.

    PubMed

    Green, Ridgely Fisk; Stoler, Joan Marilyn

    2007-07-01

    Fetal alcohol syndrome (FAS), 1 of the most common developmental disabilities in the United States, occurs at a rate of 0.5-2.0:1000 live births. Animal model, family, and twin studies suggest a genetic component to FAS susceptibility. Alcohol dehydrogenases (ADHs) catalyze the rate-limiting step in alcohol metabolism. Studies of genetic associations with FAS have focused on the alcohol dehydrogenase 1B (ADH1B) gene, comparing mothers and children with the alleles ADH1B*2 or ADH1B*3, associated with faster ethanol metabolism, with those homozygous for ADH1B*1. While most studies have found a protective effect for genotypes containing ADH1B*2 or ADH1B*3, results have been conflicting, and further investigation into the association between the ADH1B genotype and FAS is needed. Whether increased alcohol intake accounts for the elevated risk reported for the ADH1B*1/ADH1B*1 genotype should be addressed, and future studies would benefit from consistent case definitions, enhanced exposure measurements, larger sample sizes, and careful study design.

  20. Knockdown of poc1b causes abnormal photoreceptor sensory cilium and vision impairment in zebrafish.

    PubMed

    Zhang, Conghui; Zhang, Qi; Wang, Fang; Liu, Qin

    2015-10-02

    Proteomic analysis of the mouse photoreceptor sensory cilium identified a set of cilia proteins, including Poc1 centriolar protein b (Poc1b). Previous functional studies in human cells and zebrafish embryos implicated that Poc1b plays important roles in centriole duplication and length control, as well as ciliogenesis. To study the function of Poc1b in photoreceptor sensory cilia and other primary cilia, we expressed a tagged recombinant Poc1b protein in cultured renal epithelial cells and rat retina. Poc1b was localized to the centrioles and spindle bundles during cell cycle progression, and to the basal body of photoreceptor sensory cilia. A morpholino knockdown and complementation assay of poc1b in zebrafish showed that loss of poc1b led to a range of morphological anomalies of cilia commonly associated with human ciliopathies. In the retina, the development of retinal laminae was significantly delayed and the length of photoreceptor outer segments was shortened. Visual behavior studies revealed impaired visual function in the poc1b morphants. In addition, ciliopathy-associated developmental defects, such as small eyes, curved body axis, heart defects, and shortened cilia in Kupffer's vesicle, were observed as well. These data suggest that poc1b is required for normal development and ciliogenesis of retinal photoreceptor sensory cilia and other cilia. Furthermore, this conclusion is supported by recent findings that mutations in POC1B gene have been identified in patients with inherited retinal dystrophy and syndromic retinal ciliopathy.

  1. LMX1B is Essential for the Maintenance of Differentiated Podocytes in Adult Kidneys

    PubMed Central

    Burghardt, Tillmann; Kastner, Jürgen; Suleiman, Hani; Rivera-Milla, Eric; Stepanova, Natalya; Lottaz, Claudio; Kubitza, Marion; Böger, Carsten A.; Schmidt, Sarah; Gorski, Mathias; de Vries, Uwe; Schmidt, Helga; Hertting, Irmgard; Kopp, Jeffrey; Rascle, Anne; Moser, Markus; Heid, Iris M.; Warth, Richard; Spang, Rainer; Wegener, Joachim; Mierke, Claudia T.; Englert, Christoph

    2013-01-01

    Mutations of the LMX1B gene cause nail–patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes. PMID:23990680

  2. Arabidopsis HEAT SHOCK TRANSCRIPTION FACTORA1b overexpression enhances water productivity, resistance to drought, and infection

    PubMed Central

    Richard, François; Bowden, Laura; Morison, James I.L.; Mullineaux, Philip M.

    2013-01-01

    Heat-stressed crops suffer dehydration, depressed growth, and a consequent decline in water productivity, which is the yield of harvestable product as a function of lifetime water consumption and is a trait associated with plant growth and development. Heat shock transcription factor (HSF) genes have been implicated not only in thermotolerance but also in plant growth and development, and therefore could influence water productivity. Here it is demonstrated that Arabidopsis thaliana plants with increased HSFA1b expression showed increased water productivity and harvest index under water-replete and water-limiting conditions. In non-stressed HSFA1b-overexpressing (HSFA1bOx) plants, 509 genes showed altered expression, and these genes were not over-represented for development-associated genes but were for response to biotic stress. This confirmed an additional role for HSFA1b in maintaining basal disease resistance, which was stress hormone independent but involved H2O2 signalling. Fifty-five of the 509 genes harbour a variant of the heat shock element (HSE) in their promoters, here named HSE1b. Chromatin immunoprecipitation-PCR confirmed binding of HSFA1b to HSE1b in vivo, including in seven transcription factor genes. One of these is MULTIPROTEIN BRIDGING FACTOR1c (MBF1c). Plants overexpressing MBF1c showed enhanced basal resistance but not water productivity, thus partially phenocopying HSFA1bOx plants. A comparison of genes responsive to HSFA1b and MBF1c overexpression revealed a common group, none of which harbours a HSE1b motif. From this example, it is suggested that HSFA1b directly regulates 55 HSE1b-containing genes, which control the remaining 454 genes, collectively accounting for the stress defence and developmental phenotypes of HSFA1bOx. PMID:23828547

  3. 5-HT1B autoreceptor regulation of serotonin transporter activity in synaptosomes

    PubMed Central

    Hagan, Catherine E.; McDevitt, Ross A.; Liu, Yusha; Furay, Amy R.; Neumaier, John F.

    2012-01-01

    Serotonin-1B (5-HT1B) autoreceptors are located in serotonin (5-HT) terminals along with serotonin transporters (SERT), and play a critical role in autoregulation of serotonergic neurotransmission, and are implicated in disorders of serotonergic function, particularly emotional regulation. SERT modulates serotonergic neurotransmission by high-affinity reuptake of 5-HT. Alterations in SERT activity are associated with increased risk for depression and anxiety. Several neurotransmitter receptors are known to regulate SERT Km and Vmax, and previous work suggests that 5-HT1B autoreceptors may regulate 5-HT reuptake, in addition to modulating 5-HT release and synthesis. We used rotating disk electrode voltammetry to investigate 5-HT1B autoreceptor regulation of SERT-mediated 5-HT uptake into synaptosomes. The selective 5-HT1B antagonist SB224289 decreased SERT activity in synaptosomes prepared from wild-type but not 5-HT1B knockout mice, whereas SERT uptake was enhanced after pre-treatment with the selective 5-HT1B agonist CP94253. Furthermore, SERT activity varies as a function of 5-HT1B receptor expression—specifically, genetic deletion of 5-HT1B decreased SERT function, while viral-mediated overexpression of 5-HT1B autoreceptors in rat raphe neurons increased SERT activity in rat hippocampal synaptosomes. Considered collectively, these results provide evidence that 5-HT1B autoreceptors regulate SERT activity. Since SERT clearance rate varies as a function of 5-HT1B autoreceptor expression levels and is modulated by both activation and inhibition of 5-HT1B autoreceptors, this dynamic interaction may be an important mechanism of serotonin autoregulation with therapeutic implications. PMID:22961814

  4. Impact of Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) products on precise orbits of altimetry satellites and altimetry results

    NASA Astrophysics Data System (ADS)

    Rudenko, Sergei; Dettmering, Denise; Esselborn, Saskia; Fagiolini, Elisa; Schöne, Tilo

    2016-03-01

    We have extended backwards from 2001 to 1979 the current release 05 (RL05) of the Gravity Recovery and Climate Experiment (GRACE) Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) product and studied the impact of this and a previous release 04 (RL04) of the AOD1B product on precise orbits of five altimetry satellites (ERS-1, ERS-2, TOPEX/Poseidon, Envisat and Jason-1) for the time span 1991-2012, as compared to the case when no AOD1B product is used. We have found that using AOD1B RL05 product reduces root mean square (RMS) fits of satellite laser ranging (SLR) observations by about 1.0-6.4 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by about 1.3-12.0, 0.3-10.0 and 2.0-10.0 per cent, respectively, for various satellites tested, as compared to the case without AOD1B product. Using AOD1B RL05 product instead of RL04 one reduces SLR RMS fits by 0.1-0.7 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by 0.1-0.6, 0.1-1.3 and 0.2-1.2 per cent, respectively, for the satellite orbits tested. The multi-mission crossover analysis shows that the application of an AOD1B product reduces the scatter of radial errors by 0.4-2.8 per cent for the satellite missions studied. At the regions with the most pronounced changes the use of the AOD1B products improves the consistency between the sea level as measured by the TOPEX and ERS-2 missions and by the Jason-1 and Envisat missions by 5 to 10 per cent (globally by about 2 per cent). The results of our study show that extended AOD1B RL05 product performs better than the AOD1B RL04 and improves orbits of altimetry satellites and consistency of sea level products.

  5. Dynamic decoupling in the presence of 1D random walk

    NASA Astrophysics Data System (ADS)

    Chakrabarti, Arnab; Chakraborty, Ipsita; Bhattacharyya, Rangeet

    2016-05-01

    In the recent past, many dynamic decoupling sequences have been proposed for the suppression of decoherence of spins connected to thermal baths of various natures. Dynamic decoupling schemes for suppressing decoherence due to Gaussian diffusion have also been developed. In this work, we study the relative performances of dynamic decoupling schemes in the presence of a non-stationary Gaussian noise such as a 1D random walk. Frequency domain analysis is not suitable to determine the performances of various dynamic decoupling schemes in suppressing decoherence due to such a process. Thus, in this work, we follow a time domain calculation to arrive at the following conclusions: in the presence of such a noise, we show that (i) the traditional Carr-Purcell-Meiboom-Gill (CPMG) sequence outperforms Uhrig’s dynamic decoupling scheme, (ii) CPMG remains the optimal sequence for suppression of decoherence due to random walk in the presence of an external field gradient. Later, the theoretical predictions are experimentally verified by using nuclear magnetic resonance spectroscopy on spin 1/2 particles diffusing in a liquid medium.

  6. 1-D Modeling of Massive Particle Injection (MPI) in Tokamaks

    NASA Astrophysics Data System (ADS)

    Wu, W.; Parks, P. B.; Izzo, V. A.

    2008-11-01

    A 1-D Fast Current Quench (FCQ) model is developed to study current evolution and runaway electron suppression under massive density increase. The model consists of coupled toroidal electric field and energy equations, and it is solved numerically for DIII-D and ITER operating conditions. Simulation results suggest that fast shutdown by D2 liquid jet/pellet injection is in principle achievable for the desired plasma cooling time (˜15 ms for DIII-D and ˜50 ms for ITER) under ˜150x or higher densification. The current density and pressure profile are practically unaltered during the initial phase of jet propagation when dilution cooling dominates. With subsequent radiation cooling, the densified discharge enters the strongly collisional regime where Pfirsch-Schluter thermal diffusion can inhibit current contraction on the magnetic axis. Often the 1/1 kink instability, addressed by Kadomtsev's magnetic reconnection model, can be prevented. Our results are compared with NIMROD simulations in which the plasma is suddenly densified by ˜100x and experiences instantaneous dilution cooling, allowing for use of actual (lower) Lundquist numbers.

  7. Energy eigenfunctions of the 1D Gross-Pitaevskii equation

    NASA Astrophysics Data System (ADS)

    Marojević, Želimir; Göklü, Ertan; Lämmerzahl, Claus

    2013-08-01

    We developed a new and powerful algorithm by which numerical solutions for excited states in a gravito-optical surface trap have been obtained. They represent solutions in the regime of strong nonlinearities of the Gross-Pitaevskii equation. In this context we also briefly review several approaches which allow, in principle, for calculating excited state solutions. It turns out that without modifications these are not applicable to strongly nonlinear Gross-Pitaevskii equations. The importance of studying excited states of Bose-Einstein condensates is also underlined by a recent experiment of Bücker et al. in which vibrational state inversion of a Bose-Einstein condensate has been achieved by transferring the entire population of the condensate to the first excited state. Here we focus on demonstrating the applicability of our algorithm for three different potentials by means of numerical results for the energy eigenstates and eigenvalues of the 1D Gross-Pitaevskii-equation. We compare the numerically found solutions and find out that they completely agree with the case of known analytical solutions.

  8. 1-D Numerical Analysis of RBCC Engine Performance

    NASA Technical Reports Server (NTRS)

    Han, Samuel S.

    1998-01-01

    An RBCC engine combines air breathing and rocket engines into a single engine to increase the specific impulse over an entire flight trajectory. Considerable research pertaining to RBCC propulsion was performed during the 1960's and these engines were revisited recently as a candidate propulsion system for either a single-stage-to-orbit (SSTO) or two-stage-to-orbit (TSTO) launch vehicle. There are a variety of RBCC configurations that had been evaluated and new designs are currently under development. However, the basic configuration of all RBCC systems is built around the ejector scramjet engine originally developed for the hypersonic airplane. In this configuration, a rocket engine plays as an ejector in the air-augmented initial acceleration mode, as a fuel injector in scramjet mode and the rocket in all rocket mode for orbital insertion. Computational fluid dynamics (CFD) is a useful tool for the analysis of complex transport processes in various components in RBCC propulsion systems. The objective of the present research was to develop a transient 1-D numerical model that could be used to predict flow behavior throughout a generic RBCC engine following a flight path.

  9. Control and imaging of O(1D2) precession.

    PubMed

    Wu, Shiou-Min; Radenovic, Dragana Č; van der Zande, Wim J; Groenenboom, Gerrit C; Parker, David H; Vallance, Claire; Zare, Richard N

    2011-01-01

    Larmor precession of a quantum mechanical angular momentum vector about an applied magnetic field forms the basis for a range of magnetic resonance techniques, including nuclear magnetic resonance spectroscopy and magnetic resonance imaging. We have used a polarized laser pump-probe scheme with velocity-map imaging detection to visualize, for the first time, the precessional motion of a quantum mechanical angular momentum vector. Photodissociation of O(2) at 157 nm provides a clean source of fast-moving O((1)D(2)) atoms, with their electronic angular momentum vector strongly aligned perpendicular to the recoil direction. In the presence of an external magnetic field, the distribution of atomic angular momenta precesses about the field direction, and polarization-sensitive images of the atomic scattering distribution recorded as a function of field strength yield 'time-lapse-photography' style movies of the precessional motion. We present movies recorded in various experimental geometries, and discuss potential consequences and applications in atmospheric chemistry and reaction dynamics.

  10. Cavitation Influence in 1D Part-load Vortex Models

    NASA Astrophysics Data System (ADS)

    Dörfler, P. K.

    2016-11-01

    Residual swirl in the draft tube of Francis turbines may cause annoying low- frequency pulsation of pressure and power output, in particular during part-load operation. A 1D analytical model for these dynamic phenomena would enable simulation by some conventional method for computing hydraulic transients. The proper structure of such a model has implications for the prediction of prototype behaviour based on laboratory tests. The source of excitation as well as the dynamic transmission behaviour of the draft tube flow may both be described either by lumped or distributed parameters. The distributed version contains more information and, due to limited possibilities of identification, some data must be estimated. The distributed cavitation compliance is an example for this dilemma. In recent publications, the customary assumption of a constant wave speed has produced dubious results. The paper presents a more realistic model for distributed compressibility. The measured influence of the Thoma number is applied with the local cavitation factor. This concept is less sensitive to modelling errors and explains both the Thoma and Froude number influence. The possible effect of the normally unknown non-condensable gas content in the vortex cavity is shortly commented. Its measurement in future tests is recommended. It is also recommended to check the available analytical vortex models for possible dispersion effects.

  11. Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis

    PubMed Central

    Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

    2016-01-01

    Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39–45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing. PMID:27217144

  12. Contractile 5-HT1 receptors in human isolated pial arterioles: correlation with 5-HT1D binding sites.

    PubMed Central

    Hamel, E.; Bouchard, D.

    1991-01-01

    1. The 5-hydroxytryptamine (5-HT) receptor responsible for inducing vasoconstriction in human isolated pial arterioles has been pharmacologically characterized. 2. Of several 5-HT agonists tested, 5-carboxamidotryptamine (5-CT) was the most potent and the rank order of agonist potency can be summarized as: 5-CT greater than 5-HT greater than RU 24969 = alpha-methyl-5-HT = methysergide much greater than MDL 72832 = 2-methyl-5-HT much greater than 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydro-naphthalene (8-OH-DPAT). With few exceptions, the maximal contractile responses of these agonists were comparable to that induced by 5-HT. 3. A correlation analysis performed between the agonists vascular potency (pD2 values) and their affinities (pKD values) published at various subtypes of 5-HT binding sites showed a positive significant correlation with rat cortical 5-HT1B (r = 0.86; P less than 0.01) and human caudate 5-HT1D (r = 0.98; P less than 0.005) subtypes. 4. Selective antagonists at 5-HT2 (ketanserin, mianserin, MDL 11939) and 5-HT3 (MDL 72222) sites were totally devoid of inhibitory activity on the 5-HT-induced contraction, an observation which agreed with the agonist data and further excluded activation of these receptors. In contrast, the 5-HT1-like/5-HT2 antagonist methiothepin and the non-selective 5-HT1D compound metergoline inhibited with high affinity the contraction induced by 5-HT with respective pA2 values of 8.55 +/- 0.16 and 6.88 +/- 0.05. This contractile response was, however, insensitive to 5-HT1B (propranolol) and 5-HT1C (mesulergine, mianserin) antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2043924

  13. T cell receptor recognition of CD1b presenting a mycobacterial glycolipid

    PubMed Central

    Gras, Stephanie; Van Rhijn, Ildiko; Shahine, Adam; Cheng, Tan-Yun; Bhati, Mugdha; Tan, Li Lynn; Halim, Hanim; Tuttle, Kathryn D.; Gapin, Laurent; Le Nours, Jérôme; Moody, D. Branch; Rossjohn, Jamie

    2016-01-01

    CD1 proteins present microbial lipids to T cells. Germline-encoded mycolyl lipid-reactive (GEM) T cells with conserved αβ T cell receptors (TCRs) recognize CD1b presenting mycobacterial mycolates. As the molecular basis underpinning TCR recognition of CD1b remains unknown, here we determine the structure of a GEM TCR bound to CD1b presenting glucose-6-O-monomycolate (GMM). The GEM TCR docks centrally above CD1b, whereby the conserved TCR α-chain extensively contacts CD1b and GMM. Through mutagenesis and study of T cells from tuberculosis patients, we identify a consensus CD1b footprint of TCRs present among GEM T cells. Using both the TCR α- and β-chains as tweezers to surround and grip the glucose moiety of GMM, GEM TCRs create a highly specific mechanism for recognizing this mycobacterial glycolipid. PMID:27807341

  14. Src regulates membrane trafficking of the Kv3.1b channel.

    PubMed

    Bae, Seong Han; Kim, Dong Hyun; Shin, Seok Kyo; Choi, Jin Sung; Park, Kang-Sik

    2014-01-03

    The Kv3.1 channel plays a crucial role in regulating the high-frequency firing properties of neurons. Here, we determined whether Src regulates the subcellular distributions of the Kv3.1b channel. Co-expression of active Src induced a dramatic redistribution of Kv3.1b to the endoplasmic reticulum. Furthermore, co-expression of the Kv3.1b channel with active Src induced a remarkable decrease in the pool of Kv3.1b at the cell surface. Moreover, the co-expression of active Src results in a significant decrease in the peak current densities of the Kv3.1b channel, and a substantial alteration in the voltage dependence of its steady-state inactivation. Taken together, these results indicate that Src kinase may play an important role in regulating membrane trafficking of Kv3.1b channels.

  15. PASylation technology improves recombinant interferon-β1b solubility, stability, and biological activity.

    PubMed

    Zvonova, Elizaveta A; Ershov, Alexander V; Ershova, Olga A; Sudomoina, Marina A; Degterev, Maksim B; Poroshin, Grigoriy N; Eremeev, Artem V; Karpov, Andrey P; Vishnevsky, Alexander Yu; Goldenkova-Pavlova, Irina V; Petrov, Andrei V; Ruchko, Sergey V; Shuster, Alexander M

    2017-03-01

    Recombinant interferon-β1b (IFN-β1b) is an effective remedy against multiple sclerosis and other diseases. However, use of small polypeptide (molecular weight is around 18.5 kDa) is limited due to poor solubility, stability, and short half-life in systemic circulation. To solve this problem, we constructed two variants of PASylated IFN-β1b, with PAS sequence at C- or N-terminus of IFN-β1b. The PAS-modified proteins demonstrated 4-fold increase in hydrodynamic volume of the molecule combined with 2-fold increase of in vitro biological activity, as well as advanced stability and solubility of the protein in solution as opposed to unmodified IFN-β1b. Our results demonstrate that PASylation has a positive impact on stability, solubility, and functional activity of IFN-β1b and potentially might improve pharmacokinetic properties of the molecule as a therapeutic agent.

  16. Catch-bond behaviour facilitates membrane tubulation by non-processive myosin 1b

    NASA Astrophysics Data System (ADS)

    Yamada, Ayako; Mamane, Alexandre; Lee-Tin-Wah, Jonathan; di Cicco, Aurélie; Prévost, Coline; Lévy, Daniel; Joanny, Jean-François; Coudrier, Evelyne; Bassereau, Patricia

    2014-04-01

    Myosin 1b is a single-headed membrane-associated motor that binds to actin filaments with a catch-bond behaviour in response to load. In vivo, myosin 1b is required to form membrane tubules at both endosomes and the trans-Golgi network. To establish the link between these two fundamental properties, here we investigate the capacity of myosin 1b to extract membrane tubes along bundled actin filaments in a minimal reconstituted system. We show that single-headed non-processive myosin 1b can extract membrane tubes at a biologically relevant low density. In contrast to kinesins we do not observe motor accumulation at the tip, suggesting that the underlying mechanism for tube formation is different. In our theoretical model, myosin 1b catch-bond properties facilitate tube extraction under conditions of increasing membrane tension by reducing the density of myo1b required to pull tubes.

  17. Cyp1B1 mRNA expression in correlation to cotinine levels with respect to the Cyp1B1 L432V gene polymorphism.

    PubMed

    Helmig, Simone; Seelinger, Jens Udo; Philipp-Gehlhaar, Monika; Döhrel, Juliane; Schneider, Joachim

    2010-12-01

    Cytochrome P450 1B1 (CYP1B1) is involved in the activation of a broad spectrum of procarcinogens. An association of the Cyp1B1 Leu432Val polymorphism with cancer as well as an impact on the enzyme activity has been described. To study gene-environmental interactions we investigated the quantitative Cyp1B1 mRNA expression in smokers (N = 102) and non-smokers (N = 192) with regards to the Cyp1B1 L432V gene polymorphism. Tobacco smoke exposure was assessed by serum cotinine levels. Genotypes were analysed by melting curve analysis and quantification of Cyp1B1 mRNA by real-time PCR. In comparing Cyp1B1 expression, significant differences between the two homozygote genotypes *1/*1 and *3/*3 (0.105 ± 0.019; n = 26 vs. 0.051 ± 0.017; n = 14; P = 0.039) and between the heterozygote genotype *1/*3 and *3/*3 (0.121 ± 0.029; n = 55 vs. 0.051 ± 0.017; n = 14; P = 0.039) of smokers were revealed. According to the serum cotinine levels, three subgroups (low; medium; high) were build. The group "high" (0.248 ± 0.089; n = 32) showed proportionally high Cyp1B1 mRNA expression compared to "medium" (0.101 ± 0.024; n = 33), "low" (0.086 ± 0.015; n = 32) and non-smokers (0.084 ± 0.007; n = 176). This result was reflected in the homozygote *1/*1 and the heterozygote *1/*3 genotypes. In contrast the homozygote *3/*3 genotype was missing the high Cyp1B1 mRNA expression in the cotinine subgroup "high". Our results suggest that genotypes carrying the C-allele (*1/*1 and *1/*3) at Cyp1B1 Leu432Val polymorphism show a higher response to environmental factors, such as tobacco smoke than homozygote *3/*3 genotypes.

  18. CYP1B1 Polymorphism as a Risk Factor for Race-Related Prostate Cancer

    DTIC Science & Technology

    2008-06-01

    AD_________________ Award Number: W81XWH-04-1-0579 TITLE: CYP1B1 Polymorphism as a Risk Factor...TITLE AND SUBTITLE CYP1B1 Polymorphism as a Risk Factor for Race-Related Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-04-1-0579...collected; as well as further experimentation with aim #1to be performed. 15. SUBJECT TERMS CYP1B1 , Polymorphism , Prostate cancer, Race-related

  19. Role of CYP1B1 in PAH-DNA Adduct Formation and Breast Cancer Risk

    DTIC Science & Technology

    2004-09-01

    The cytochrome P450 enzyme CYP1B1 is a major enzyme involved in metabolizing polycyclic aromatic hydrocarbons (PAHs) to reactive intermediates. Given...that certain exposure to PAHs may be a breast cancer risk factor, we have set out to examine CYP1B1 gene expression in breast tissue. After...hired Research Coordinators and interviewers have been trained and recruitment of participants has begun. The method to measure CYP1B1 expression has

  20. CYP1B1 Polymorphism as a Risk Factor for Race-Related Prostate Cancer

    DTIC Science & Technology

    2006-06-01

    AD_________________ Award Number: W81XWH-04-1-0579 TITLE: CYP1B1 Polymorphism as a Risk Factor...TITLE AND SUBTITLE CYP1B1 Polymorphism as a Risk Factor for Race-Related Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-04-1-0579...hypothesis, single nucleotide polymorphisms (SNPs) at three codons (119, 432, and 453) of CYP1B1 have been evaluated to determine if they are risk factors

  1. Spatio-temporal stability of 1D Kerr cavity solitons

    NASA Astrophysics Data System (ADS)

    Gelens, L.; Parra-Rivas, P.; Leo, F.; Gomila, D.; Matias, Manuel A.; Coen, S.

    2014-05-01

    The Lugiato-Lefever equation (LLE) has been extensively studied since its derivation in 1987, when this meanfield model was introduced to describe nonlinear optical cavities. The LLE was originally derived to describe a ring cavity or a Fabry-Perot resonator with a transverse spatial extension and partially filled with a nonlinear medium but it has also been shown to be applicable to other types of cavities, such as fiber resonators and microresonators. Depending on the parameters used, the LLE can present a monostable or bistable input-output response curve. A large number of theoretical studies have been done in the monostable regime, but the bistable regime has remained widely unexplored. One of the reasons for this was that previous experimental setups were not able to works in such regimes of the parameter space. Nowadays the possibility of reaching such parameter regimes experimentally has renewed the interest in the LLE. In this contribution, we present an in-depth theoretical study of the different dynamical regimes that can appear in parameter space, focusing on the dynamics of localized solutions, also known as cavity solitons (CSs). We show that time-periodic oscillations of a 1D CS appear naturally in a broad region of parameter space. More than this oscillatory regime, which has been recently demonstrated experimentally,1 we theoretically report on several kinds of chaotic dynamics. We show that the existence of CSs and their dynamics is related with the spatial dynamics of the system and with the presence of a codimension-2 point known as a Fold-Hopf bifurcation point. These dynamical regimes can become accessible by using devices such as microresonators, for instance widely used for creating optical frequency combs.

  2. Nonlinear electrical conductivity in a 1D granular medium

    NASA Astrophysics Data System (ADS)

    Falcon, E.; Castaing, B.; Creyssels, M.

    2004-04-01

    We report on observations of the electrical transport within a chain of metallic beads (slightly oxidized) under an applied stress. A transition from an insulating to a conductive state is observed as the applied current is increased. The voltage-current ( U- I) characteristics are nonlinear and hysteretic, and saturate to a low voltage per contact (0.4 V). Our 1D experiment allows us to understand phenomena (such as the “Branly effect”) related to this conduction transition by focusing on the nature of the contacts instead of the structure of the granular network. We show that this transition comes from an electro-thermal coupling in the vicinity of the microcontacts between each bead - the current flowing through these contact points generates their local heating which leads to an increase of their contact areas, and thus enhances their conduction. This current-induced temperature rise (up to 1050 ^{circ}C) results in the microsoldering of the contact points (even for voltages as low as 0.4 V). Based on this self-regulated temperature mechanism, an analytical expression for the nonlinear U- I back trajectory is derived, and is found to be in very good agreement with the experiments. In addition, we can determine the microcontact temperature with no adjustable parameters. Finally, the stress dependence of the resistance is found to be strongly non-hertzian due to the presence of the surface films. This dependence cannot be usually distinguished from the one due to the disorder of the granular contact network in 2D or 3D experiments.

  3. Restrained dark U (1 )d at low energies

    NASA Astrophysics Data System (ADS)

    Correia, Fagner C.; Fajfer, Svjetlana

    2016-12-01

    We investigate a spontaneously broken U (1 )d gauge symmetry with a muon-specific dark Higgs. Our first goal is to verify how the presence of a new dark Higgs, ϕ , and a dark gauge boson, V , can simultaneously face the anomalies from the muon magnetic moment and the proton charge radius. Second, by assuming that V must decay to an electron-positron pair, we explore the corresponding parameter space determined with the low-energy constraints coming from K →μ X , electron (g -2 )e, K →μ νμe+e-, K →μ νμμ+μ-, and τ →ντμ νμe+e-. We focus on the scenario where the V mass is below ˜2 mμ and the ϕ mass runs from few MeV to 250 MeV, with V -photon mixing of the order ˜O (10-3). Among weak process at low energies, we check the influence of the new light vector on kaon decays as well as on the scattering e+e-→μ+μ-e+e- and discuss the impact of the dark Higgs on e+e-→μ+μ-μ+μ-. Finally, we consider contributions of the V -photon mixing in the decays π0→γ e+e-, η →γ e+e-, ρ →π e+e-, K*→K e+e-, and ϕ (1020 )→η e+e-.

  4. A new general 1-D vadose zone flow solution method

    NASA Astrophysics Data System (ADS)

    Ogden, Fred L.; Lai, Wencong; Steinke, Robert C.; Zhu, Jianting; Talbot, Cary A.; Wilson, John L.

    2015-06-01

    We have developed an alternative to the one-dimensional partial differential equation (PDE) attributed to Richards (1931) that describes unsaturated porous media flow in homogeneous soil layers. Our solution is a set of three ordinary differential equations (ODEs) derived from unsaturated flux and mass conservation principles. We used a hodograph transformation, the Method of Lines, and a finite water-content discretization to produce ODEs that accurately simulate infiltration, falling slugs, and groundwater table dynamic effects on vadose zone fluxes. This formulation, which we refer to as "finite water-content", simulates sharp fronts and is guaranteed to conserve mass using a finite-volume solution. Our ODE solution method is explicitly integrable, does not require iterations and therefore has no convergence limits and is computationally efficient. The method accepts boundary fluxes including arbitrary precipitation, bare soil evaporation, and evapotranspiration. The method can simulate heterogeneous soils using layers. Results are presented in terms of fluxes and water content profiles. Comparing our method against analytical solutions, laboratory data, and the Hydrus-1D solver, we find that predictive performance of our finite water-content ODE method is comparable to or in some cases exceeds that of the solution of Richards' equation, with or without a shallow water table. The presented ODE method is transformative in that it offers accuracy comparable to the Richards (1931) PDE numerical solution, without the numerical complexity, in a form that is robust, continuous, and suitable for use in large watershed and land-atmosphere simulation models, including regional-scale models of coupled climate and hydrology.

  5. Modeling shear band interaction in 1D torsion

    NASA Astrophysics Data System (ADS)

    Partom, Yehuda; Hanina, Erez

    2017-01-01

    When two shear bands are being formed at close distance from each other they interact, and further development of one of them may be quenched down. As a result there should be a minimum distance between shear bands. In the literature there are at least three analytical models for this minimum distance. Predictions of these models do not generally agree with each other and with test results. Recently we developed a 1D numerical scheme to predict the formation of shear bands in a torsion test of a thin walled pipe. We validated our code by reproducing results of the pioneering experiments of Marchand and Duffy, and then used it to investigate the mechanics of shear localization and shear band formation. We describe our shear band code in a separate publication, and here we use it only as a tool to investigate the interaction between two neighboring shear bands during the process of their formation. We trigger the formation of shear bands by specifying two perturbations of the initial strength. We vary the perturbations in terms of their amplitude and/or their width. Usually, the stronger perturbation triggers a faster developing shear band, which then prevails and quenches the development of the other shear band. We change the distance between the two shear bands and find, that up to a certain distance one of the shear bands becomes fully developed, and the other stays only partially developed. Beyond this distance the two shear bands are both fully developed. Finally, we check the influence of certain material and loading parameters on the interaction between the two shear bands, and compare the results to predictions of the analytical models from the literature.

  6. The ING1b tumor suppressor facilitates nucleotide excision repair by promoting chromatin accessibility to XPA

    SciTech Connect

    Kuo, Wei-Hung W.; Wang Yemin; Wong, Ronald P.C.; Campos, Eric I.; Li Gang . E-mail: gangli@interchange.ubc.ca

    2007-05-01

    ING1b is the most studied ING family protein and perhaps the most ubiquitously and abundantly expressed. This protein is involved in the regulation of various biological functions ranging from senescence, cell cycle arrest, apoptosis, to DNA repair. ING1b is upregulated by UV irradiation and enhances the removal of bulky nucleic acid photoproducts. In this study, we provide evidence that ING1b mediates nucleotide excision repair by facilitating the access to damaged nucleosomal DNA. We demonstrate that ING1b is not recruited to UV-induced DNA lesions but enhances nucleotide excision repair only in XPC-proficient cells, implying an essential role in early steps of the 'access, repair, restore' model. We also find that ING1b alters histone acetylation dynamics upon exposure to UV radiation and induces chromatin relaxation in microccocal nuclease digestion assay, revealing that ING1b may allow better access to nucleotide excision repair machinery. More importantly, ING1b associates with chromatin in a UV-inducible manner and facilitates DNA access to nucleotide excision repair factor XPA. Furthermore, depletion of the endogenous ING1b results to the sensitization of cells at S-phase to UV irradiation. Taken together, these observations establish a role of ING1b acting as a chromatin accessibility factor for DNA damage recognition proteins upon genotoxic injury.

  7. Smyd1b is required for skeletal and cardiac muscle function in zebrafish

    PubMed Central

    Li, Huiqing; Zhong, Yongwang; Wang, Zengfeng; Gao, Jie; Xu, Jin; Chu, Wuying; Zhang, Jianshe; Fang, Shenyun; Du, Shao Jun

    2013-01-01

    Smyd1b is a member of the Smyd family that is specifically expressed in skeletal and cardiac muscles. Smyd1b plays a key role in thick filament assembly during myofibrillogenesis in skeletal muscles of zebrafish embryos. To better characterize Smyd1b function and its mechanism of action in myofibrillogenesis, we analyzed the effects of smyd1b knockdown on myofibrillogenesis in skeletal and cardiac muscles of zebrafish embryos. The results show that knockdown of smyd1b causes significant disruption of myofibril organization in both skeletal and cardiac muscles of zebrafish embryos. Microarray and quantitative reverse transcription-PCR analyses show that knockdown of smyd1b up-regulates heat shock protein 90 (hsp90) and unc45b gene expression. Biochemical analysis reveals that Smyd1b can be coimmunoprecipitated with heat shock protein 90 α-1 and Unc45b, two myosin chaperones expressed in muscle cells. Consistent with its potential function in myosin folding and assembly, knockdown of smyd1b significantly reduces myosin protein accumulation without affecting mRNA expression. This likely results from increased myosin degradation involving unc45b overexpression. Together these data support the idea that Smyd1b may work together with myosin chaperones to control myosin folding, degradation, and assembly into sarcomeres during myofibrillogenesis. PMID:24068325

  8. Kv3.1b is a novel component of CNS nodes.

    PubMed

    Devaux, Jérôme; Alcaraz, Gisèle; Grinspan, Judith; Bennett, Vann; Joho, Rolf; Crest, Marcel; Scherer, Steven S

    2003-06-01

    We herein demonstrate that Kv3.1b subunits are present at nodes of Ranvier in the CNS of both rats and mice. Kv3.1b colocalizes with voltage-gated Na+ channels in a subset of nodes in the spinal cord, particularly those of large myelinated axons. Kv3.1b is abundantly expressed in the gray matter of the spinal cord, but does not colocalize with Na+ channels in initial segments. In the PNS, few nodes are Kv3.1b-positive. During the development of the CNS, Kv3.1b clustering at nodes occurs later than that of Na+ channels, but precedes the juxtaparanodal clustering of Kv1.2. Moreover, in myelin-deficient rats, which have severe CNS dysmyelination, node-like clusters of Kv3.1b and Na+ channels are observed even in regions devoid of oligodendrocytes. Ankyrin G coimmunoprecipitates Kv3.1b in vivo, indicating that these two proteins may interact in the CNS at nodes. 4-Aminopyridine, a K+ channel blocker, broadened the compound action potential recorded from adult rat optic nerve and spinal cord, but not from the sciatic nerve. These effects were also observed in Kv3.1-deficient mice. In conclusion, Kv3.1b is the first K+ channel subunit to be identified in CNS nodes; but Kv3.1b does not account for the effects of 4-aminopyridine on central myelinated tracts.

  9. Yersinia pestis Requires Host Rab1b for Survival in Macrophages

    PubMed Central

    Connor, Michael G.; Pulsifer, Amanda R.; Price, Christopher T.; Abu Kwaik, Yousef; Lawrenz, Matthew B.

    2015-01-01

    Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. During infection of macrophages Y. pestis actively evades the normal phagosomal maturation pathway to establish a replicative niche within the cell. However, the mechanisms used by Y. pestis to subvert killing by the macrophage are unknown. Host Rab GTPases are central mediators of vesicular trafficking and are commonly targeted by bacterial pathogens to alter phagosome maturation and killing by macrophages. Here we demonstrate for the first time that host Rab1b is required for Y. pestis to effectively evade killing by macrophages. We also show that Rab1b is specifically recruited to the Yersinia containing vacuole (YCV) and that Y. pestis is unable to subvert YCV acidification when Rab1b expression is knocked down in macrophages. Furthermore, Rab1b knockdown also altered the frequency of association between the YCV with the lysosomal marker Lamp1, suggesting that Rab1b recruitment to the YCV directly inhibits phagosome maturation. Finally, we show that Rab1b knockdown also impacts the pH of the Legionella pneumophila containing vacuole, another pathogen that recruits Rab1b to its vacuole. Together these data identify a novel role for Rab1b in the subversion of phagosome maturation by intracellular pathogens and suggest that recruitment of Rab1b to the pathogen containing vacuole may be a conserved mechanism to control vacuole pH. PMID:26495854

  10. [Design, synthesis and evaluation of malonic acid-based PTP1B inhibitors].

    PubMed

    Du, Xin; Zhang, Shu-En; Liu, Jun-Zheng; Nie, Fei-Lin; Ye, Fei; Tian, Jin-Ying; Xiao, Zhi-Yan

    2012-03-01

    Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. Phosphotyrosine (pTyr) is the substrate for PTP1B dephosphorylation. Malonic acid moiety was used herein as a mimic of the phosphate group in pTyr, and novel malonic acid derivatives 1-7 were designed, synthesized and evaluated as PTP1B inhibitors. Results from enzymatic assays indicated that compounds 3 and 4 exhibited potent inhibition against human recombinant PTP1B with IC50 values of 7.66 and 1.88 micromol x L(-1), respectively.

  11. The Mechanism of Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

    PubMed Central

    Lu, Shaoyong; Huang, Wenkang; Geng, Lv; Shen, Qiancheng; Zhang, Jian

    2014-01-01

    As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors. PMID:24831294

  12. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

    PubMed

    Schubert, Julian; Siekierska, Aleksandra; Langlois, Mélanie; May, Patrick; Huneau, Clément; Becker, Felicitas; Muhle, Hiltrud; Suls, Arvid; Lemke, Johannes R; de Kovel, Carolien G F; Thiele, Holger; Konrad, Kathryn; Kawalia, Amit; Toliat, Mohammad R; Sander, Thomas; Rüschendorf, Franz; Caliebe, Almuth; Nagel, Inga; Kohl, Bernard; Kecskés, Angela; Jacmin, Maxime; Hardies, Katia; Weckhuysen, Sarah; Riesch, Erik; Dorn, Thomas; Brilstra, Eva H; Baulac, Stephanie; Møller, Rikke S; Hjalgrim, Helle; Koeleman, Bobby P C; Jurkat-Rott, Karin; Lehman-Horn, Frank; Roach, Jared C; Glusman, Gustavo; Hood, Leroy; Galas, David J; Martin, Benoit; de Witte, Peter A M; Biskup, Saskia; De Jonghe, Peter; Helbig, Ingo; Balling, Rudi; Nürnberg, Peter; Crawford, Alexander D; Esguerra, Camila V; Weber, Yvonne G; Lerche, Holger

    2014-12-01

    Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

  13. Resolution-optimized NMR measurement of (1)D(CH), (1)D(CC) and (2)D(CH) residual dipolar couplings in nucleic acid bases.

    PubMed

    Boisbouvier, Jérôme; Bryce, David L; O'neil-Cabello, Erin; Nikonowicz, Edward P; Bax, Ad

    2004-11-01

    New methods are described for accurate measurement of multiple residual dipolar couplings in nucleic acid bases. The methods use TROSY-type pulse sequences for optimizing resolution and sensitivity, and rely on the E.COSY principle to measure the relatively small two-bond (2)D(CH) couplings at high precision. Measurements are demonstrated for a 24-nt stem-loop RNA sequence, uniformly enriched in (13)C, and aligned in Pf1. The recently described pseudo-3D method is used to provide homonuclear (1)H-(1)H decoupling, which minimizes cross-correlation effects and optimizes resolution. Up to seven (1)H-(13)C and (13)C-(13)C couplings are measured for pyrimidines (U and C), including (1)D(C5H5), (1)D(C6H6), (2)D(C5H6), (2)D(C6H5), (1)D(C5C4), (1)D(C5C6), and (2)D(C4H5). For adenine, four base couplings ((1)D(C2H2), (1)D(C8H8), (1)D(C4C5), and (1)D(C5C6)) are readily measured whereas for guanine only three couplings are accessible at high relative accuracy ((1)D(C8H8), (1)D(C4C5), and (1)D(C5C6)). Only three dipolar couplings are linearly independent in planar structures such as nucleic acid bases, permitting cross validation of the data and evaluation of their accuracies. For the vast majority of dipolar couplings, the error is found to be less than +/-3% of their possible range, indicating that the measurement accuracy is not limiting when using these couplings as restraints in structure calculations. Reported isotropic values of the one- and two-bond J couplings cluster very tightly for each type of nucleotide.

  14. Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 as important regulators of the pharmacokinetics of substrate drugs.

    PubMed

    Maeda, Kazuya

    2015-01-01

    Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions.

  15. Aspirin Hydrolysis in Plasma Is a Variable Function of Butyrylcholinesterase and Platelet-activating Factor Acetylhydrolase 1b2 (PAFAH1b2)*

    PubMed Central

    Zhou, Gang; Marathe, Gopal K.; Hartiala, Jaana; Hazen, Stanley L.; Allayee, Hooman; Tang, W. H. Wilson; McIntyre, Thomas M.

    2013-01-01

    Aspirin is rapidly hydrolyzed within erythrocytes by a heterodimer of PAFAH1b2/PAFAH1b3 but also in plasma by an unidentified activity. Hydrolysis in both compartments was variable, with a 12-fold variation in plasma among 2226 Cleveland Clinic GeneBank patients. Platelet inhibition by aspirin was suppressed in plasma that rapidly hydrolyzed aspirin. Plasma aspirin hydrolysis was significantly higher in patients with coronary artery disease compared with control subjects (16.5 ± 4.4 versus 15.1 ± 3.7 nmol/ml/min; p = 3.4 × 10−8). A genome-wide association study of 2054 GeneBank subjects identified a single locus immediately adjacent to the BCHE (butyrylcholinesterase) gene associated with plasma aspirin hydrolytic activity (lead SNP, rs6445035; p = 9.1 × 10−17). However, its penetrance was low, and plasma from an individual with an inactivating mutation in BCHE still effectively hydrolyzed aspirin. A second aspirin hydrolase was identified in plasma, the purification of which showed it to be homomeric PAFAH1b2. This is distinct from the erythrocyte PAFAH1b2/PAFAH1b3 heterodimer. Inhibitors showed that both butyrylcholinesterase (BChE) and PAFAH1b2 contribute to aspirin hydrolysis in plasma, with variation primarily reflecting non-genetic variation of BChE activity. Therefore, aspirin is hydrolyzed in plasma by two enzymes, BChE and a new extracellular form of platelet-activating factor acetylhydrolase, PAFAH1b2. Hydrolytic effectiveness varies widely primarily from non-genetic variation of BChE activity that affects aspirin bioavailability in blood and the ability of aspirin to inhibit platelet aggregation. PMID:23508960

  16. Evaluation of the RL05 GRACE atmosphere and ocean dealiasing level 1B (AOD1B) product with precise orbit and altimetry analysis

    NASA Astrophysics Data System (ADS)

    Fagiolini, Elisa; Rudenko, Sergei; Esselborn, Saskia; Schöne, Tilo; Dobslaw, Henryk; Flechtner, Frank

    2015-04-01

    GRACE Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) product is intended to serve as a background model for a wide range of satellite missions. The main usage of AOD1B is the removal of high-frequency non-tidal mass variations due to short-term (daily and sub-daily) mass transport in the atmosphere and oceans AOD1B shall avoid aliasing of these high frequency signals into monthly gravity models derived from modern gravity missions (CHAMP, GRACE or GRACE-FO) and shall help to derive consistent orbit solutions for altimetry and SLR satellites. The latest AOD1B Release 05 (RL05) is provided for the period Jan 1st, 2001 till today and updated on an approximately weekly basis. It includes several improvements over the ocean due to an updated parametrization and spatial resolution of the oceanic part contributed by the Ocean Model for Circulation and Tides (OMCT). For the atmospheric part, as well as for the ocean response to atmospheric pressure, the necessary input data is extracted from the operational analyses of the European Centre for Medium Range Weather Forecast (ECMWF). Recently, we successfully extended backward to 1976 the last AOD1B RL05, based on ERA-Interim and ERA-40 (ECMWF Re-Analysis) input data. The new time series are stable and free from discontinuities caused by changes in the ECMWF input model. Some results of the evaluation of the new and previous releases of the AOD1B product for precise orbit determination (POD) of altimetry satellites ERS-1 (1991-1996), ERS-2 (1995-2006), TOPEX-Poseidon (1992-2005), Envisat (2002-2012) and Jason-1 (2002-2012) at the time intervals given and altimetry analysis are presented.

  17. Engineering 1D Quantum Stripes from Superlattices of 2D Layered Materials.

    PubMed

    Gruenewald, John H; Kim, Jungho; Kim, Heung Sik; Johnson, Jared M; Hwang, Jinwoo; Souri, Maryam; Terzic, Jasminka; Chang, Seo Hyoung; Said, Ayman; Brill, Joseph W; Cao, Gang; Kee, Hae-Young; Seo, Sung S Ambrose

    2017-01-01

    Dimensional tunability from two dimensions to one dimension is demonstrated for the first time using an artificial superlattice method in synthesizing 1D stripes from 2D layered materials. The 1D confinement of layered Sr2 IrO4 induces distinct 1D quantum-confined electronic states, as observed from optical spectroscopy and resonant inelastic X-ray scattering. This 1D superlattice approach is generalizable to a wide range of layered materials.

  18. Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

    PubMed Central

    De Vas, Matias G.; Kopp, Janel L.; Heliot, Claire; Sander, Maike; Cereghini, Silvia; Haumaitre, Cécile

    2015-01-01

    Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3+ endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5. PMID:25715395

  19. Cyp1b1 Regulates Ocular Fissure Closure Through a Retinoic Acid–Independent Pathway

    PubMed Central

    Williams, Antionette L.; Eason, Jessica; Chawla, Bahaar; Bohnsack, Brenda L.

    2017-01-01

    Purpose Mutations in the CYP1B1 gene are the most commonly identified genetic causes of primary infantile-onset glaucoma. Despite this disease association, the role of CYP1B1 in eye development and its in vivo substrate remain unknown. In the present study, we used zebrafish to elucidate the mechanism by which cyp1b1 regulates eye development. Methods Zebrafish eye and neural crest development were analyzed using live imaging of transgenic zebrafish embryos, in situ hybridization, immunostaining, TUNEL assay, and methylacrylate sections. Cyp1b1 and retinoic acid (RA) levels were genetically (morpholino oligonucleotide antisense and mRNA) and pharmacologically manipulated to examine gene function. Results Using zebrafish, we observed that cyp1b1 was expressed in a specific spatiotemporal pattern in the ocular fissures of the developing zebrafish retina and regulated fissure patency. Decreased Cyp1b1 resulted in the premature breakdown of laminin in the ventral fissure and altered subsequent neural crest migration into the anterior segment. In contrast, cyp1b1 overexpression inhibited cell survival in the ventral ocular fissure and prevented fissure closure via an RA-independent pathway. Cyp1b1 overexpression also inhibited the ocular expression of vsx2, pax6a, and pax6b and increased the extraocular expression of shha. Importantly, embryos injected with human wild-type but not mutant CYP1B1 mRNA also showed colobomas, demonstrating the evolutionary and functional conservation of gene function between species. Conclusions Cyp1b1 regulation of ocular fissure closure indirectly affects neural crest migration and development through an RA-independent pathway. These studies provide insight into the role of Cyp1b1 in eye development and further elucidate the pathogenesis of primary infantile-onset glaucoma. PMID:28192799

  20. Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors.

    PubMed

    De Vas, Matias G; Kopp, Janel L; Heliot, Claire; Sander, Maike; Cereghini, Silvia; Haumaitre, Cécile

    2015-03-01

    Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3(+) endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5.

  1. Beyond Oncolytics: E1B55K-Deleted Adenovirus as a Vaccine Delivery Vector

    PubMed Central

    Thomas, Michael A.; Nyanhete, Tinashe; Tuero, Iskra; Venzon, David; Robert-Guroff, Marjorie

    2016-01-01

    Type 5 human adenoviruses (Ad5) deleted of genes encoding the early region 1B 55-kDa (E1B55K) protein including Onyx-015 (dl1520) and H101 are best known for their oncolytic potential. As a vaccine vector the E1B55K deletion may allow for the insertion of a transgene nearly 1,000 base pairs larger than now possible. This has the potential of extending the application for which the vectors are clinically known. However, the immune priming ability of E1B55K-deleted vectors is unknown, undermining our ability to gauge their usefulness in vaccine applications. For this reason, we created an E1B55K-deleted Ad5 vector expressing full-length single chain HIVBaLgp120 attached to a flexible linker and the first two domains of rhesus CD4 (rhFLSC) in exchange for the E3 region. In cell-based experiments the E1B55K-deleted vector promoted higher levels of innate immune signals including chemokines, cytokines, and the NKG2D ligands MIC A/B compared to an E1B55K wild-type vector expressing the same immunogen. Based on these results we evaluated the immune priming ability of the E1B55K-deleted vector in mice. The E1B55K-deleted vector promoted similar levels of Ad5-, HIVgp120, and rhFLSC-specific cellular and humoral immune responses as the E1B55K wild-type vector. In pre-clinical HIV-vaccine studies the wild-type vector has been employed as part of a very effective prime-boost strategy. This study demonstrates that E1B55K-deleted adenoviruses may serve as effective vaccine delivery vectors. PMID:27391605

  2. Preliminary abatement device evaluation: 1D-2D KGM cyclone design

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cyclones are predominately used in controlling cotton gin particulate matter (PM) emissions. The most commonly used cyclone designs are the 2D-2D and 1D-3D; however other designs such as the 1D-2D KGM have or are currently being used. A 1D-2D cyclone has a barrel length equal to the barrel diamete...

  3. Large Area Synthesis of 1D-MoSe2 Using Molecular Beam Epitaxy.

    PubMed

    Poh, Sock Mui; Tan, Sherman J R; Zhao, Xiaoxu; Chen, Zhongxin; Abdelwahab, Ibrahim; Fu, Deyi; Xu, Hai; Bao, Yang; Zhou, Wu; Loh, Kian Ping

    2017-01-23

    Large area synthesis of 1D-MoSe2 nanoribbons on both insulating and conducting substrates via molecular beam epitaxy is presented. Dimensional controlled growth of 2D, 1D-MoSe2 , and 1D-2D-MoSe2 hybrid heterostructure is achieved by tuning the growth temperature or Mo:Se precursor ratio.

  4. PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms.

    PubMed

    Wu, Bo; Guo, Bo-Min; Kang, Jie; Deng, Xian-Zhao; Fan, You-Ben; Zhang, Xiao-Ping; Ai, Kai-Xing

    2016-03-01

    Protein phosphatase, Mg(2+)/Mn(2+) dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in human PC tissues and cell lines and their irrespective noncancerous controls. We subsequently investigated the functional role of PPM1D in the migration, invasion, and apoptosis of MIA PaCa-2 and PANC-1 PC cells in vitro and explored the signaling pathways involved. Furthermore, we examined the role of PPM1D in PC tumorigenesis in vivo. Our results showed that PPM1D is overexpressed in human PC tissues and cell lines and significantly correlated with tumor growth and metastasis. PPM1D promotes PC cell migration and invasion via potentiation of the Wnt/β-catenin pathway through downregulation of apoptosis-stimulating of p53 protein 2 (ASPP2). In contrast to PPM1D, our results showed that ASPP2 is downregulated in PC tissues. Additionally, PPM1D suppresses PC cell apoptosis via inhibition of the p38 MAPK/p53 pathway through both dephosphorylation of p38 MAPK and downregulation of ASPP2. Furthermore, PPM1D promotes PC tumor growth in vivo. Our results demonstrated that PPM1D is an oncogene in PC.

  5. 18 CFR 1b.13 - Powers of persons conducting formal investigations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Powers of persons conducting formal investigations. 1b.13 Section 1b.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS §...

  6. 18 CFR 1b.13 - Powers of persons conducting formal investigations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Powers of persons conducting formal investigations. 1b.13 Section 1b.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS §...

  7. Tumor-specific expression of cytochrome P450 CYP1B1.

    PubMed

    Murray, G I; Taylor, M C; McFadyen, M C; McKay, J A; Greenlee, W F; Burke, M D; Melvin, W T

    1997-07-15

    Cytochrome P450 CYP1B1 is a recently cloned dioxin-inducible form of the cytochrome P450 family of xenobiotic metabolizing enzymes. An antibody raised against a peptide specific for CYP1B1 was found to recognize CYP1B1 expressed in human lymphoblastoid cells but not to recognize other forms of cytochrome P450, particularly CYP1A1 and CYP1A2. Using this antibody, the cellular distribution and localization of CYP1B1 were investigated by immunohistochemistry in a range of malignant tumors and corresponding normal tissues. CYP1B1 was found to be expressed at a high frequency in a wide range of human cancers of different histogenetic types, including cancers of the breast, colon, lung, esophagus, skin, lymph node, brain, and testis. There was no detectable immunostaining for CYP1B1 in normal tissues. These results provide the basis for the development of novel methods of cancer diagnosis based on the identification of CYP1B1 in tumor cells and the development of anticancer drugs that are selectively activated in tumors by CYP1B1.

  8. 18 CFR 2.1b - Availability in contested cases of information acquired by staff investigation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Availability in contested cases of information acquired by staff investigation. 2.1b Section 2.1b Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES GENERAL...

  9. 18 CFR 1b.13 - Powers of persons conducting formal investigations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Powers of persons conducting formal investigations. 1b.13 Section 1b.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS §...

  10. 18 CFR 2.1b - Availability in contested cases of information acquired by staff investigation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Availability in contested cases of information acquired by staff investigation. 2.1b Section 2.1b Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES GENERAL...

  11. 18 CFR 1b.13 - Powers of persons conducting formal investigations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Powers of persons conducting formal investigations. 1b.13 Section 1b.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS §...

  12. 18 CFR 1b.13 - Powers of persons conducting formal investigations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Powers of persons conducting formal investigations. 1b.13 Section 1b.13 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS §...

  13. 18 CFR 2.1b - Availability in contested cases of information acquired by staff investigation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Availability in contested cases of information acquired by staff investigation. 2.1b Section 2.1b Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES GENERAL...

  14. Extending the Impact of RAC1b Overexpression to Follicular Thyroid Carcinomas

    PubMed Central

    Faria, Márcia; Capinha, Liliana; Simões-Pereira, Joana; Bugalho, Maria João; Silva, Ana Luísa

    2016-01-01

    RAC1b is a hyperactive variant of the small GTPase RAC1 known to be a relevant molecular player in different cancers. Previous studies from our group lead to the evidence that its overexpression in papillary thyroid carcinoma (PTC) is associated with an unfavorable prognosis. In the present study, we intended to extend the analysis of RAC1b expression to thyroid follicular neoplasms and to seek for clinical correlations. RAC1b expression levels were determined by RT-qPCR in thyroid follicular tumor samples comprising 23 follicular thyroid carcinomas (FTCs) and 33 follicular thyroid adenomas (FTAs). RAC1b was found to be overexpressed in 33% of carcinomas while no RAC1b overexpression was documented among follicular adenomas. Patients with a diagnosis of FTC were divided into two groups based on longitudinal evolution and final outcome. RAC1b overexpression was significantly associated with both the presence of distant metastases (P = 0.01) and poorer clinical outcome (P = 0.01) suggesting that, similarly to that previously found in PTCs, RAC1b overexpression in FTCs is also associated with worse outcomes. Furthermore, the absence of RAC1b overexpression in follicular adenomas hints its potential as a molecular marker likely to contribute, in conjunction with other putative markers, to the preoperative differential diagnosis of thyroid follicular lesions. PMID:27127508

  15. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 12 2010-07-01 2010-07-01 true Add-on Control Systems Compliance Options 1B Table 1B to Subpart DDDD of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... CATEGORIES National Emission Standards for Hazardous Air Pollutants: Plywood and Composite Wood Products...

  16. Selective binding modes and allosteric inhibitory effects of lupane triterpenes on protein tyrosine phosphatase 1B

    PubMed Central

    Jin, Tiantian; Yu, Haibo; Huang, Xu-Feng

    2016-01-01

    Protein Tyrosine Phosphatase 1B (PTP1B) has been recognized as a promising therapeutic target for treating obesity, diabetes, and certain cancers for over a decade. Previous drug design has focused on inhibitors targeting the active site of PTP1B. However, this has not been successful because the active site is positively charged and conserved among the protein tyrosine phosphatases. Therefore, it is important to develop PTP1B inhibitors with alternative inhibitory strategies. Using computational studies including molecular docking, molecular dynamics simulations, and binding free energy calculations, we found that lupane triterpenes selectively inhibited PTP1B by targeting its more hydrophobic and less conserved allosteric site. These findings were verified using two enzymatic assays. Furthermore, the cell culture studies showed that lupeol and betulinic acid inhibited the PTP1B activity stimulated by TNFα in neurons. Our study indicates that lupane triterpenes are selective PTP1B allosteric inhibitors with significant potential for treating those diseases with elevated PTP1B activity. PMID:26865097

  17. 40 CFR Table 1b to Subpart Dddd of... - Add-on Control Systems Compliance Options

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 12 2011-07-01 2009-07-01 true Add-on Control Systems Compliance.... 63, Subpt. DDDD, Table 1B Table 1B to Subpart DDDD of Part 63—Add-on Control Systems Compliance... compliance options by using an emissions control system . . . Fiberboard mat dryer heated zones (at...

  18. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

    PubMed Central

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R.; Choy, Meng S.; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D.; Tonks, Nicholas K.

    2015-01-01

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG–binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2–/y) mice and improved behavior in female heterozygous (Mecp2–/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs. PMID:26214522

  19. 20 CFR 655.736 - What are H-1B-dependent employers and willful violators?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... required to make determinations of H-1B-dependency status? Every employer that intends to file an LCA... H-1B-dependent employer or willful violator may use an LCA filed before January 19, 2001, and during... in paragraph (c)(1) of this section), then that status must be reflected on the employer's LCA...

  20. 20 CFR 655.736 - What are H-1B-dependent employers and willful violators?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... required to make determinations of H-1B-dependency status? Every employer that intends to file an LCA... H-1B-dependent employer or willful violator may use an LCA filed before January 19, 2001, and during... in paragraph (c)(1) of this section), then that status must be reflected on the employer's LCA...

  1. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome.

    PubMed

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R; Choy, Meng S; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D; Tonks, Nicholas K

    2015-08-03

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2-/y) mice and improved behavior in female heterozygous (Mecp2-/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs.

  2. New cis-regulatory elements in the Rht-D1b locus region of wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fifteen gene-containing BACs with accumulated length of 1.82-Mb from the Rht-D1b locus region weresequenced and compared in detail with the orthologous regions of rice, sorghum, and maize. Our results show that Rht-D1b represents a conserved genomic region as implied by high gene sequence identity...

  3. Manifold functions of the Nail-Patella Syndrome gene Lmx1b in vertebrate development.

    PubMed

    Dai, Jin-Xia; Johnson, Randy L; Ding, Yu-Qiang

    2009-04-01

    The LIM (Lin-1, Isl-1 and Mec-3)-homeodomain transcription factor 1 beta (Lmx1b) is widely expressed in vertebrate embryos, and is implicated in the development of diverse structures such as limbs, kidneys, eyes and brains. LMX1B mutations in humans cause an autosomal dominant inherited disease called nail-patella syndrome (NPS), which is characterized by abnormalities of the arms and legs as well as kidney disease and glaucoma. Expression of Lmx1b in the dorsal compartment of growing limb buds is critical for specification of dorsal limb cell fates and consequently dorsoventral patterning of limbs. In addition, Lmx1b is involved in the differentiation of anterior eye structures, formation of the glomerular basement membrane in kidneys and development of the skeleton, especially calvarial bones. In the central nervous system, Lmx1b controls the inductive activity of isthmic organizer, differentiation and maintenance of central serotonergic neurons, as well as the differentiation and migration of spinal dorsal horn neurons. Although details of the genetic programs involved in these developmental events are largely unknown, it is suggested that Lmx1b plays central roles in fate determination or cell differentiation in these tissues. Sustained expression of Lmx1b in the postnatal and mature mouse brain suggests that it also plays important roles in brain maturation and in the regulation of normal brain functions. This review aims to highlight recent insights into the many activities of Lmx1b in vertebrates.

  4. Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson Disease

    PubMed Central

    Levic, Daniel S.; Minkel, JR; Wang, Wen-Der; Rybski, Witold M.; Melville, David B.; Knapik, Ela W.

    2015-01-01

    Anderson Disease (ANDD) or Chylomicron Retention Disease (CMRD) is a rare, hereditary lipid malabsorption syndrome associated with mutations in the SAR1B gene that is characterized by failure to thrive and hypocholesterolemia. Although the SAR1B structure has been resolved and its role in formation of coat protein II (COPII) coated carriers is well established, little is known about the requirement for SAR1B during embryogenesis. To address this question, we have developed a zebrafish model of Sar1b deficiency based on antisense oligonucleotide knockdown. We show that zebrafish sar1b is highly conserved among vertebrates, broadly expressed during development, and enriched in the digestive tract organs, brain and craniofacial skeleton. Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b deficient embryos accumulate in enterocytes. Transgenic expression analysis revealed that Sar1b is required for growth of exocrine pancreas and liver. Furthermore, we found abnormal differentiation and maturation of craniofacial cartilage associated with defects in procollagen II secretion, and absence of select, neuroD-positive neurons of the midbrain and hindbrain. The model presented here will help to systematically dissect developmental roles of Sar1b and to discover molecular and cellular mechanisms leading to organ-specific ANDD pathology. PMID:25559265

  5. Immunolocalization of CYP1B1 in normal, human, fetal and adult eyes.

    PubMed

    Doshi, Manali; Marcus, Craig; Bejjani, Bassem A; Edward, Deepak P

    2006-01-01

    CYP1B1 is a cytochrome P450 enzyme implicated in autosomal recessive primary congenital glaucoma (PCG). The mechanism and function of CYP1B1 in the development of the PCG phenotype is unknown. Previously, investigators have reported detection of Cyp1b1 mRNA in the ciliary body and epithelium and neuroepithelium in the developing mouse eye, employing in situ hybridization techniques. Similarly, additional investigators have detected CYP1B1 mRNA in the iris, ciliary body, non-pigmented ciliary epithelial line, cornea, retinal-pigment epithelium, and retina in the human adult eye, using Northern blotting. This study was designed to immunolocalize CYP1B1 protein in the various ocular structures of normal, human fetal and adult eyes. Normal fetal and adult eyes were immunolabeled with a polyclonal antibody against human CYP1B1 using indirect immunofluorescence, and then compared with appropriate controls. The intensity of immunolabeling of the various ocular structures was assessed by qualitative and semi-quantitative techniques. In the anterior segment anti-CYP1B1 immunoreactivity (IR) was detected early in fetal development in the primitive ciliary epithelium. As well, the most intense CYP1B1 IR was in the non-pigmented ciliary epithelium. In addition, CYP1B1 IR was also present in the corneal epithelium and keratocytes, both layers of the iris pigmented epithelium, and retina. However, CYP1B1 IR was absent in the trabecular meshwork in all of the samples. In general, CYP1B1 immunolabeling in the human fetal eyes was more intense when compared to adult eyes. CYP1B1 IR was primarily immunolocalized to the non-pigmented ciliary epithelium and early in fetal development. In addition, CYP1B1 IR was not detected in the trabecular meshwork. These findings suggest that the abnormalities in the development of the trabecular meshwork in PCG may result from diminished or absent metabolism of important endogenous substrates in the ciliary epithelium due to non-functional CYP1B1

  6. Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

    PubMed Central

    2010-01-01

    Background The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. Methods CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. Results Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. Conclusions CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment. PMID:20875115

  7. Inhibition of protein tyrosine phosphatase 1B by lignans from Myristica fragrans.

    PubMed

    Yang, Senugmi; Na, Min Kyun; Jang, Jun Pil; Kim, Kyung Ah; Kim, Bo Yeon; Sung, Nak Ju; Oh, Won Keun; Ahn, Jong Seog

    2006-08-01

    Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been proposed as one of the drug targets for treating type 2 diabetes and obesity. Bioassay-guided fractionation of a MeOH extract of the semen of Myristica fragrans Houtt. (Myristicaceae) afforded PTP1B inhibitory compounds, meso-dihydroguaiaretic acid (1) and otobaphenol (2). Compounds 1 and 2 inhibited PTP1B with IC(50) values of 19.6 +/- 0.3 and 48.9 +/- 0.5 microM, respectively, in the manner of non-competitive inhibitors. Treatment with compound 1 on 32D cells overexpressing the insulin receptor (IR) resulted in a dose-dependent increase in the tyrosine phosphorylation of IR. These results indicate that compound 1 can act as an enhancing agent in intracellular insulin signaling, possibly through the inhibition of PTP1B activity.

  8. [Structure and function of heavy metal transporter P(1B)-ATPase in plant: a review].

    PubMed

    Zhang, Yuxiu; Zhang, Yuanya; Sun, Tao; Chai, Tuanyao

    2010-06-01

    The regulation of the heavy-metal accumulation in vivo for plant survival is very complex. The metal cation transporter plays key roles in the metabolic process. P(1B)-ATPases are the only subgroup of P-ATPases that contribute to heavy metal homeostasis presented in most organisms. Arabidopsis thaliana contains eight genes encoding P(1B)-ATPases. The current reports show that the functions of P(1B)-ATPases are involved in maintaining metal homeostasis, transporting and detoxification in plants. P(1B)-ATPases not only mediated metal ion mobilization and uptake in roots, but also contribute to the metal transport, storage and tolerance in shoots, especially in heavy metal hyperaccumulators. In this paper, we reviewed and discussed the evolution, classification, structure and function of P(1B)-ATPases in plants. HMAs-transgenic manipulation could be a feasible approach for phytoremediation and mineral nutrition fortification.

  9. Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

    PubMed Central

    Ni, Wenjun; Ji, Jia; Dai, Zunyan; Papp, Audrey; Johnson, Amy J.; Ahn, Sunjoo; Farley, Katherine L.; Lin, Thomas S.; Dalton, James T.; Li, Xiaobai; Jarjoura, David; Byrd, John C.; Sadee, Wolfgang; Grever, Michael R.; Phelps, Mitch A.

    2010-01-01

    Background Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy. Methodology/Principal Findings Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent. Conclusions/Significance Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other

  10. Hereditary and histologic characteristics of the CF1/b cac mouse cataract model.

    PubMed

    Kondo, Tomohiro; Nagai, Hiroaki; Kawashima, Takamune; Taniguchi, Yusuke; Koyabu, Nozomu; Takeshita, Ai; Kusakabe, Ken-Takeshi; Okada, Toshiya

    2014-10-01

    A substrain of mice originating from the CF1 strain (an outbred colony) reared at Osaka Prefecture University (CF1/b cac mice) develops cataracts beginning at 14 d old. Affected mice were fully viable and fertile and had developed cataracts by 22 d of age. The incidence of cataracts did not differ between male and female mice. Histologically, 14-wk-old CF1/b cac mice showed vacuolated lens epithelial cells, swollen lens fibers, many pyknotic nuclei, and vacuolation of the lens cortex. To elucidate the mode of inheritance, we analyzed heterozygous mutants hybrids generated from CF1/b cac and wildtype BALB/c mice and the offspring of the backcrossed heterozygous mutants. None of the heterozygous mutants was affected, but the ratio of affected to unaffected mice was 1:3 among the offspring of the heterozygous mutants. The initial genomewide screen of 20 affected backcrossed offspring (CF1/b cac × [CF1/b cac × BALB/c]) indicated that the mutant gene resides on chromosome 16. For further mapping, we used affected progeny of CF1/b cac × (CF1/b cac × MSM/Ms) mice. We concluded that the cataracts in CF1/b cac mice are inherited through an autosomal recessive mutation and that the mutant gene is located on mouse chromosome 16 between D16Mit5 and D16Mit92 and between D16Mit92 and D16Mit201. The mapping of the mutant gene of the CF1/b cac mice to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the CF1/b cac phenotype.

  11. Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling

    PubMed Central

    Vasileiou, Georgia; Ekici, Arif B.; Uebe, Steffen; Zweier, Christiane; Hoyer, Juliane; Engels, Hartmut; Behrens, Jürgen; Reis, André; Hadjihannas, Michel V.

    2015-01-01

    The link of chromatin remodeling to both neurodevelopment and cancer has recently been highlighted by the identification of mutations affecting BAF chromatin-remodeling components, such as ARID1B, in individuals with intellectual disability and cancer. However, the underlying molecular mechanism(s) remains unknown. Here, we show that ARID1B is a repressor of Wnt/β-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/β-catenin target genes are upregulated. Using cellular models of low and high Wnt/β-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/β-catenin target genes and Wnt/β-catenin-dependent transcriptional reporters in a β-catenin-dependent manner. Reciprocally, forced expression of ARID1B inhibits Wnt/β-catenin signaling downstream of the β-catenin destruction complex. Both endogenous and exogenous ARID1B associate with β-catenin and repress Wnt/β-catenin-mediated transcription through the BAF core subunit BRG1. Accordingly, mutations in ARID1B leading to partial or complete deletion of its BRG1-binding domain, as is often observed in intellectual disability and cancers, compromise association with β-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/β-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through β-catenin. The data suggest that aberrations in chromatin-remodeling factors, such as ARID1B, might contribute to neurodevelopmental abnormalities and cancer through deregulation of developmental and oncogenic pathways, such as the Wnt/β-catenin signaling pathway. PMID:26340334

  12. Cytochrome P450 CYP1B1 activity in renal cell carcinoma.

    PubMed

    McFadyen, M C E; Melvin, W T; Murray, G I

    2004-08-31

    Renal cell carcinoma (RCC) is the most common malignancy of the kidney and has a poor prognosis due to its late presentation and resistance to current anticancer drugs. One mechanism of drug resistance, which is potentially amenable to therapeutic intervention, is based on studies in our laboratory. CYP1B1 is a cytochrome P450 enzyme overexpressed in a variety of malignant tumours. Our studies are now elucidating a functional role for CYP1B1 in drug resistance. Cytochrome P450 reductase (P450R) is required for optimal metabolic activity of CYP1B1. Both CYP1B1 and P450R can catalyse the biotransformation of anticancer drugs at the site of the tumour. In this investigation, we determined the expression of CYP1B1 and P450R in samples of normal kidney and RCC (11 paired normal and tumour and a further 15 tumour samples). The O-deethylation of ethoxyresorufin to resorufin was used to measure CYP1B1 activity in RCC. Cytochrome P450 reductase activity was determined by following the reduction of cytochrome c at 550 nm. The key finding of this study was the presence of active CYP1B1 in 70% of RCC. Coincubation with the CYP1B1 inhibitor alpha-naphthoflavone (10 nM) inhibited this activity. No corresponding CYP1B1 activity was detected in any of the normal tissue examined (n=11). Measurable levels of active P450R were determined in all normal (n=11) and tumour samples (n=26). The presence of detectable CYP1B1, which is capable of metabolising anticancer drugs in tumour cells, highlights a novel target for therapeutic intervention.

  13. A functional null mutation of SCN1B in a patient with Dravet syndrome.

    PubMed

    Patino, Gustavo A; Claes, Lieve R F; Lopez-Santiago, Luis F; Slat, Emily A; Dondeti, Raja S R; Chen, Chunling; O'Malley, Heather A; Gray, Charles B B; Miyazaki, Haruko; Nukina, Nobuyuki; Oyama, Fumitaka; De Jonghe, Peter; Isom, Lori L

    2009-08-26

    Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-) versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.

  14. The alpha(1D)-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction.

    PubMed

    Tanoue, Akito; Nasa, Yoshihisa; Koshimizu, Takaaki; Shinoura, Hitomi; Oshikawa, Sayuri; Kawai, Takayuki; Sunada, Sachie; Takeo, Satoshi; Tsujimoto, Gozoh

    2002-03-01

    To investigate the physiological role of the alpha(1D)-adrenergic receptor (alpha(1D)-AR) subtype, we created mice lacking the alpha(1D)-AR (alpha(1D)(-/-)) by gene targeting and characterized their cardiovascular function. In alpha(1D)-/- mice, the RT-PCR did not detect any transcript of the alpha(1D)-AR in any tissue examined, and there was no apparent upregulation of other alpha(1)-AR subtypes. Radioligand binding studies showed that alpha(1)-AR binding capacity in the aorta was lost, while that in the heart was unaltered in alpha(1D)-/- mice. Non-anesthetized alpha(1D)-/- mice maintained significantly lower basal systolic and mean arterial blood pressure conditions, relative to wild-type mice, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. Besides hypotension, the pressor responses to phenylephrine and norepinephrine were decreased by 30-40% in alpha(1D)-/- mice. Furthermore, the contractile response of the aorta and the pressor response of isolated perfused mesenteric arterial beds to alpha(1)-AR stimulation were markedly reduced in alpha(1D)-/- mice. We conclude that the alpha(1D)-AR participates directly in sympathetic regulation of systemic blood pressure by vasoconstriction.

  15. Subtyping of Y-chromosomal haplogroup E-M78 (E1b1b1a) by SNP assay and its forensic application.

    PubMed

    Caratti, S; Gino, S; Torre, C; Robino, C

    2009-07-01

    The continual discovery of new single-nucleotide polymorphisms (SNPs) has led to an increased resolution of the Y chromosome phylogeny. Some of these Y-SNPs have shown to be restricted to small geographical regions and therefore may prove useful in the forensic field as tools for the prediction of population of origin of unknown casework samples. Here, we describe a system for the molecular dissection of haplogroup E-M78 (E1b1b1a), consisting of multiplex polymerase chain reaction and minisequencing of M78 and nine population-informative Y-SNPs (M148, M224, V12, V13, V19, V22, V27, V32, V65) in a single reaction. Sensitivity and admixture studies demonstrated that the SNP protocol allows robust genotyping from as little as 50 pg of male DNA, even in the presence of 500-fold amounts of female DNA. In order to evaluate the suitability of E1b1b1a, subhaplogrouping for population-of-origin prediction, the distribution of E-M78 and its derived variants was determined in an Italian population sample (n = 326).

  16. 20 CFR 655.705 - What Federal agencies are involved in the H-1B and H-1B1 programs, and what are the...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... EMPLOYMENT OF FOREIGN WORKERS IN THE UNITED STATES Labor Condition Applications and Requirements for... offer a position filled by an H-1B nonimmigrant to an equally or better qualified United States worker... authorization to work in the United States for that employer or, in the case of a nonimmigrant...

  17. Pathogenesis-Related Protein 1b1 (PR1b1) Is a Major Tomato Fruit Protein Responsive to Chilling Temperature and Upregulated in High Polyamine Transgenic Genotypes

    PubMed Central

    Fatima, Tahira; Topuz, Muhamet; Bernadec, Anne; Sicher, Richard; Handa, Avtar K.; Mattoo, Autar K.

    2016-01-01

    Plants execute an array of mechanisms in response to stress which include upregulation of defense-related proteins and changes in specific metabolites. Polyamines – putrescine (Put), spermidine (Spd), and spermine (Spm) – are metabolites commonly found associated with abiotic stresses such as chilling stress. We have generated two transgenic tomato lines (556HO and 579HO) that express yeast S-adenosylmethionine decarboxylase and specifically accumulate Spd and Spm in fruits in comparison to fruits from control (556AZ) plants (Mehta et al., 2002). Tomato fruits undergo chilling injury at temperatures below 13°C. The high Spd and Spm tomato together with the control azygous line were utilized to address role(s) of polyamines in chilling-injury signaling. Exposure to chilling temperature (2°C) led to several-fold increase in the Put content in all the lines. Upon re-warming of the fruits at 20°C, the levels of Spd and Spm increased further in the fruit of the two transgenic lines, the higher levels remaining stable for 15 days after re-warming as compared to the fruit from the control line. Profiling their steady state proteins before and after re-warming highlighted a protein of ∼14 kD. Using proteomics approach, protein sequencing and immunoblotting, the ∼14-kD protein was identified as the pathogenesis related protein 1b1 (PR1b1). The PR1b1 protein accumulated transiently in the control fruit whose level was barely detectable at d 15 post-warming while in the fruit from both the 556HO and 579HO transgenic lines PR1b1 abundance increased and remained stable till d 15 post warming. PR1b1 gene transcripts were found low in the control fruit with a visible accumulation only on d 15 post warming; however, in both the transgenic lines it accumulated and increased soon after rewarming being several-fold higher on day 2 while in 556HO line this increase continued until d 6 than the control fruit. The chilling-induced increase in PR1b1 protein seems independent

  18. Hypotonic stimuli enhance proton-gated currents of acid-sensing ion channel-1b

    SciTech Connect

    Ugawa, Shinya Ishida, Yusuke; Ueda, Takashi; Yu, Yong; Shimada, Shoichi

    2008-03-14

    Acid-sensing ion channels (ASICs) are strong candidates for mammalian mechanoreceptors. We investigated whether mouse acid-sensing ion channel-1b (ASIC1b) is sensitive to mechanical stimuli using oocyte electrophysiology, because ASIC1b is located in the mechanosensory stereocilia of cochlear hair cells. Hypotonic stimuli that induced membrane stretch of oocytes evoked no significant current in ASIC1b-expressing oocytes at pH 7.5. However, acid (pH 4.0 or 5.0)-evoked currents in the oocytes were substantially enhanced by the hypotonicity, showing mechanosensitivity of ASIC1b and possible mechanogating of the channel in the presence of other components. Interestingly, the ASIC1b channel was permeable to K{sup +} (a principal charge carrier for cochlear sensory transduction) and the affinity of the channel for amiloride (IC{sub 50} (inhibition constant) = approximately 48.3 {mu}M) was quite similar to that described for the mouse hair cell mechanotransducer current. Taken together, these data raise the possibility that ASIC1b participates in cochlear mechanoelectrical transduction.

  19. Polycomb Group Targeting through Different Binding Partners of RING1B C-Terminal Domain

    PubMed Central

    Wang, Renjing; Taylor, Alexander B.; Leal, Belinda Z.; Chadwell, Linda V.; Ilangovan, Udayar; Robinson, Angela K.; Schirf, Virgil; Hart, P. John; Lafer, Eileen M.; Demeler, Borries; Hinck, Andrew P.; McEwen, Donald G.; Kim, Chongwoo A.

    2015-01-01

    SUMMARY RING1B, a Polycomb Group (PcG) protein, binds methylated chromatin through its association with another PcG protein called Polycomb (Pc). However, RING1B can associate with nonmethylated chromatin suggesting an alternate mechanism for RING1B interaction with chromatin. Here, we demonstrate that two proteins with little sequence identity between them, the Pc cbox domain and RYBP, bind the same surface on the C-terminal domain of RING1B (C-RING1B). Pc cbox and RYBP each fold into a nearly identical, intermolecular beta sheet with C-RING1B and a loop structure which are completely different in the two proteins. Both the beta sheet and loop are required for stable binding and transcription repression. Further, a mutation engineered to disrupt binding on the Drosophila dRING1 protein prevents chromatin association and PcG function in vivo. These results suggest that PcG targeting to different chromatin locations relies, in part, on binding partners of C-RING1B that are diverse in sequence and structure. PMID:20696397

  20. Using mass spectrometry to study the photo-affinity labeling of protein tyrosine phosphatase 1B

    NASA Astrophysics Data System (ADS)

    Leriche, Tammy; Skorey, Kathryn; Roy, Patrick; McKay, Dan; Bateman, Kevin P.

    2004-11-01

    Protein tyrosine phosphatase 1B (PTP1B) is a potential target for the treatment of Type II diabetes and several companies are developing small molecule inhibitors of this enzyme. Part of the characterization of these compounds as PTP1B inhibitors is the understanding of how they bind in the enzyme active site. The use of photo-activated inhibitors that target the active site can provide such insight. This paper describes the characterization of a photoprobe directed at the active site of PTP1B. Mass spectrometry revealed the specific binding of the probe to the intact protein. Digestion of the labeled protein followed by LC-MS and LC-MS/MS was used to show that the photoprobe binds to a specific active site amino acid. This was confirmed by comparison with the X-ray structure of PTP1B with a PTP1B inhibitor. The probe labels a conserved acidic residue (Asp) that is required for catalytic activity. This photoprobe may prove to be a useful tool for the development of a PTP1B inhibitor or for the study of PTPs in general.

  1. Altered motor activity of alternative splice variants of the mammalian kinesin-3 protein KIF1B.

    PubMed

    Matsushita, Masafumi; Yamamoto, Ruri; Mitsui, Keiji; Kanazawa, Hiroshi

    2009-11-01

    Several mammalian kinesin motor proteins exist as multiple isoforms that arise from alternative splicing of a single gene. However, the roles of many motor protein splice variants remain unclear. The kinesin-3 motor protein KIF1B has alternatively spliced isoforms distinguished by the presence or absence of insertion sequences in the conserved amino-terminal region of the protein. The insertions are located in the loop region containing the lysine-rich cluster, also known as the K-loop, and in the hinge region adjacent to the motor domain. To clarify the functions of these alternative splice variants of KIF1B, we examined the biochemical properties of recombinant KIF1B with and without insertion sequences. In a microtubule-dependent ATPase assay, KIF1B variants that contained both insertions had higher activity and affinity for microtubules than KIF1B variants that contained no insertions. Mutational analysis of the K-loop insertion revealed that variants with a longer insertion sequence at this site had higher activity. However, the velocity of movement in motility assays was similar between KIF1B with and without insertion sequences. Our results indicate that splicing isoforms of KIF1B that vary in their insertion sequences have different motor activities.

  2. Mutation of POC1B in a severe syndromic retinal ciliopathy

    PubMed Central

    Beck, Bodo B.; Phillips, Jennifer B.; Bartram, Malte P.; Wegner, Jeremy; Thoenes, Michaela; Pannes, Andrea; Sampson, Josephina; Heller, Raoul; Göbel, Heike; Koerber, Friederike; Neugebauer, Antje; Hedergott, Andrea; Nürnberg, Gudrun; Nürnberg, Peter; Thiele, Holger; Altmüller, Janine; Toliat, Mohammad R.; Staubach, Simon; Boycott, Kym M.; Valente, Enza Maria; Janecke, Andreas R.; Eisenberger, Tobias; Bergmann, Carsten; Tebbe, Lars; Wang, Yang; Wu, Yundong; Fry, Andrew M.; Westerfield, Monte; Wolfrum, Uwe; Bolz, Hanno J.

    2014-01-01

    We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease. Targeted NGS for excluding mutations in known LCA and JBTS genes, homozygosity mapping and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with non-syndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe polycystic kidney disease. PMID:25044745

  3. Expression and localization of aquaporin 1b during oocyte development in the Japanese eel (Anguilla japonica)

    PubMed Central

    2011-01-01

    To elucidate the molecular mechanisms underling hydration during oocyte maturation, we characterized the structure of Japanese eel (Anguilla japonica) novel-water selective aquaporin 1 (AQP1b) that thought to be involved in oocyte hydration. The aqp1b cDNA encodes a 263 amino acid protein that includes the six potential transmembrane domains and two Asn-Pro-Ala motifs. Reverse transcription-polymerase chain reaction showed transcription of Japanese eel aqp1b in ovary and testis but not in the other tissues. In situ hybridization studies with the eel aqp1b cRNA probe revealed intense eel aqp1b signal in the oocytes at the perinucleolus stage and the signals became faint during the process of oocyte development. Light microscopic immunocytochemical analysis of ovary revealed that the Japanese eel AQP1b was expressed in the cytoplasm around the yolk globules which were located in the peripheral region of oocytes during the primary yolk globule stage; thereafter, the immunoreactivity was observed throughout the cytoplasm of oocyte as vitellogenesis progressed. The immunoreactivity became localized around the large membrane-limited yolk masses which were formed by the fusion of yolk globules during the oocyte maturation phase. These results together indicate that AQP1b, which is synthesized in the oocyte during the process of oocyte growth, is essential for mediating water uptake into eel oocytes. PMID:21615964

  4. Flavones Inhibit the Activity of AKR1B10, a Promising Therapeutic Target for Cancer Treatment.

    PubMed

    Zemanova, Lucie; Hofman, Jakub; Novotna, Eva; Musilek, Kamil; Lundova, Tereza; Havrankova, Jana; Hostalkova, Anna; Chlebek, Jakub; Cahlikova, Lucie; Wsol, Vladimír

    2015-11-25

    AKR1B10 is an NADPH-dependent reductase that plays an important function in several physiological reactions such as the conversion of retinal to retinol, reduction of isoprenyl aldehydes, and biotransformation of procarcinogens and drugs. A growing body of evidence points to the important role of the enzyme in the development of several types of cancer (e.g., breast, hepatocellular), in which it is highly overexpressed. AKR1B10 is regarded as a therapeutic target for the treatment of these diseases, and potent and specific inhibitors may be promising therapeutic agents. Several inhibitors of AKR1B10 have been described, but the area of natural plant products has been investigated sparingly. In the present study almost 40 diverse phenolic compounds and alkaloids were examined for their ability to inhibit the recombinant AKR1B10 enzyme. The most potent inhibitors-apigenin, luteolin, and 7-hydroxyflavone-were further characterized in terms of IC50, selectivity, and mode of action. Molecular docking studies were also conducted, which identified putative binding residues important for the interaction. In addition, cellular studies demonstrated a significant inhibition of the AKR1B10-mediated reduction of daunorubicin in intact cells by these inhibitors without a considerable cytotoxic effect. Although these compounds are moderately potent and selective inhibitors of AKR1B10, they constitute a new structural type of AKR1B10 inhibitor and may serve as a template for the development of better inhibitors.

  5. HNF1B alterations associated with congenital anomalies of the kidney and urinary tract.

    PubMed

    Nakayama, Makiko; Nozu, Kandai; Goto, Yuki; Kamei, Koichi; Ito, Shuichi; Sato, Hidenori; Emi, Mitsuru; Nakanishi, Koichi; Tsuchiya, Shigeru; Iijima, Kazumoto

    2010-06-01

    Hepatocyte nuclear factor 1beta (HNF1beta) abnormalities have been recognized to cause congenital anomalies of the kidney and urinary tract (CAKUT), predominantly affecting bilateral renal malformations. To further understand the spectrum of HNF1beta related phenotypes, we performed HNF1B gene mutation and deletion analyses in Japanese patients with renal hypodysplasia (n = 31), unilateral multicystic dysplastic kidney (MCDK; n = 14) and others (n = 5). We identified HNF1B alterations in 5 out of 50 patients (10%). De novo heterozygous complete deletions of HNF1B were found in 3 patients with unilateral MCDK. Two of the patients showed contralateral hypodysplasia, whereas the other patient showed a radiologically normal contralateral kidney with normal renal function. Copy number variation analyses showed 1.4 Mb microdeletions involving the whole HNF1B gene with breakpoints in flanking segmental duplications. We also identified 1 novel truncated mutation (1007insC) and another missense mutation (226G>T) in patients with bilateral hypodysplasia. HNF1B alterations leading to haploinsufficiency affect a diverse spectrum of CAKUT. The existence of a patient with unilateral MCDK with normal renal function might provide genetic insight into the etiology of these substantial populations of only unilateral MCDK. The recurrent microdeletions encompassing HNF1B could have a significant impact on the mechanism of HNF1B deletions.

  6. Targeting the disordered C-terminus of PTP1B with an allosteric inhibitor

    PubMed Central

    Krishnan, Navasona; Koveal, Dorothy; Miller, Daniel H.; Xue, Bin; Akshinthala, Sai Dipikaa; Kragelj, Jaka; Jensen, Malene Ringkjøbing; Gauss, Carla-Maria; Page, Rebecca; Blackledge, Martin; Muthuswamy, Senthil K.; Peti, Wolfgang; Tonks, Nicholas K.

    2014-01-01

    PTP1B, a validated therapeutic target for diabetes and obesity, plays a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We defined a novel mechanism of allosteric inhibition that targets the C-terminal, non-catalytic segment of PTP1B. We present the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small molecule inhibitor, MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules. PMID:24845231

  7. Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor☆

    PubMed Central

    Tsou, Ryan C.; Rak, Kimberly S.; Zimmer, Derek J.; Bence, Kendra K.

    2014-01-01

    Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of central metabolic signaling, and mice with whole brain-, leptin receptor (LepRb) expressing cell-, or proopiomelanocortin neuron-specific PTP1B-deficiency are lean, leptin hypersensitive, and display improved glucose homeostasis. However, whether the metabolic effects of central PTP1B-deficiency are due to action within the hypothalamus remains unclear. Moreover, whether or not these effects are exclusively due to enhanced leptin signaling is unknown. Here we report that mice with hypothalamic PTP1B-deficiency (Nkx2.1-PTP1B–/–) display decreased body weight and adiposity on high-fat diet with no associated improvements in glucose tolerance. Consistent with previous reports, we find that hypothalamic deletion of the LepRb in mice (Nkx2.1-LepRb–/–) results in extreme hyperphagia and obesity. Interestingly, deletion of hypothalamic PTP1B and LepRb (Nkx2.1-PTP1B–/–:LepRb–/–) does not rescue the hyperphagia or obesity of Nkx2.1-LepRb–/– mice, suggesting that hypothalamic PTP1B contributes to the central control of energy balance through a leptin receptor-dependent pathway. PMID:24749060

  8. Inhibition of Carnitine Palymitoyltransferase1b Induces Cardiac Hypertrophy and Mortality in Mice

    PubMed Central

    Haynie, KR; Vandanmagsar, B; Wicks, SE; Zhang, J; Mynatt, RL

    2014-01-01

    Recent reports suggest that short-term pharmacological Cpt1 inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. While this appears promising for the treatment of diabetes these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart and skeletal muscle specific deletion of the Cpt1b, Cpt1bHM−/−. These mice seem to develop normally with similar bodyweights as control mice. However, by 15 weeks of age the Cpt1bHM−/− mice begin to die. The hearts of Cpt1bHM−/− mice were 4-times the size of controls. Cpt1bHM−/− mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. PMID:24330405

  9. Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice.

    PubMed

    Haynie, K R; Vandanmagsar, B; Wicks, S E; Zhang, J; Mynatt, R L

    2014-08-01

    Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart- and skeletal muscle-specific deletion of the Cpt1b, Cpt1b(HM-/-). These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1b(HM-/-) mice. The hearts of Cpt1b(HM-/-) mice were four times the size of controls. Cpt1b(HM-/-) mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable.

  10. Expression and localization of aquaporin 1b during oocyte development in the Japanese eel (Anguilla japonica).

    PubMed

    Kagawa, Hirohiko; Kishi, Takafumi; Gen, Koichiro; Kazeto, Yukinori; Tosaka, Ryota; Matsubara, Hajime; Matsubara, Takahiro; Sawaguchi, Sayumi

    2011-05-27

    To elucidate the molecular mechanisms underling hydration during oocyte maturation, we characterized the structure of Japanese eel (Anguilla japonica) novel-water selective aquaporin 1 (AQP1b) that thought to be involved in oocyte hydration. The aqp1b cDNA encodes a 263 amino acid protein that includes the six potential transmembrane domains and two Asn-Pro-Ala motifs. Reverse transcription-polymerase chain reaction showed transcription of Japanese eel aqp1b in ovary and testis but not in the other tissues. In situ hybridization studies with the eel aqp1b cRNA probe revealed intense eel aqp1b signal in the oocytes at the perinucleolus stage and the signals became faint during the process of oocyte development. Light microscopic immunocytochemical analysis of ovary revealed that the Japanese eel AQP1b was expressed in the cytoplasm around the yolk globules which were located in the peripheral region of oocytes during the primary yolk globule stage; thereafter, the immunoreactivity was observed throughout the cytoplasm of oocyte as vitellogenesis progressed. The immunoreactivity became localized around the large membrane-limited yolk masses which were formed by the fusion of yolk globules during the oocyte maturation phase. These results together indicate that AQP1b, which is synthesized in the oocyte during the process of oocyte growth, is essential for mediating water uptake into eel oocytes.

  11. Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo*

    PubMed Central

    Lopez-Santiago, Luis F.; Brackenbury, William J.; Chen, Chunling; Isom, Lori L.

    2011-01-01

    Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons, VGSC β2 subunits, encoded by Scn2b, selectively regulate TTX-S α subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by β1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK. PMID:21555511

  12. The serine/threonine phosphatase PPM1B (PP2Cβ) selectively modulates PPARγ activity.

    PubMed

    Tasdelen, Ismayil; van Beekum, Olivier; Gorbenko, Olena; Fleskens, Veerle; van den Broek, Niels J F; Koppen, Arjen; Hamers, Nicole; Berger, Ruud; Coffer, Paul J; Brenkman, Arjan B; Kalkhoven, Eric

    2013-04-01

    Reversible phosphorylation is a widespread molecular mechanism to regulate the function of cellular proteins, including transcription factors. Phosphorylation of the nuclear receptor PPARγ (peroxisome-proliferator-activated receptor γ) at two conserved serine residue (Ser(112) and Ser(273)) results in an altered transcriptional activity of this transcription factor. So far, only a very limited number of cellular enzymatic activities has been described which can dephosphorylate nuclear receptors. In the present study we used immunoprecipitation assays coupled to tandem MS analysis to identify novel PPARγ-regulating proteins. We identified the serine/threonine phosphatase PPM1B [PP (protein phosphatase), Mg(2+)/Mn(2+) dependent, 1B; also known as PP2Cβ] as a novel PPARγ-interacting protein. Endogenous PPM1B protein is localized in the nucleus of mature 3T3-L1 adipocytes where it can bind to PPARγ. Furthermore we show that PPM1B can directly dephosphorylate PPARγ, both in intact cells and in vitro. In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112). Finally, we show that knockdown of PPM1B in 3T3-L1 adipocytes blunts the expression of some PPARγ target genes while leaving others unaltered. These findings qualify the phosphatase PPM1B as a novel selective modulator of PPARγ activity.

  13. Coumarins from Angelica decursiva inhibit α-glucosidase activity and protein tyrosine phosphatase 1B.

    PubMed

    Ali, Md Yousof; Jannat, Susoma; Jung, Hyun Ah; Jeong, Hyong Oh; Chung, Hae Young; Choi, Jae Sue

    2016-05-25

    In the present study, we investigated the anti-diabetic potential of six natural coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), decursinol (3), decursidin (4), umbelliferone 6-carboxylic acid (5), and 2'-isopropyl psoralene (6) isolated from Angelica decursiva and evaluated their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO(-)-mediated protein tyrosine nitration. Coumarins 1-6 showed potent PTP1B and α-glucosidase inhibitory activities with ranges of IC50 values of 5.39-58.90 μM and 65.29-172.10 μM, respectively. In the kinetic study for PTP1B enzyme inhibition, compounds 1, 5, and 6 were competitive, whereas 2 and 4 showed mixed type, and 3 displayed noncompetitive type inhibition. For α-glucosidase enzyme inhibition, compounds 1 and 3 exhibited good mixed-type, while 2, 5, and 6 showed noncompetitive and 4 displayed competitive type inhibition. Furthermore, these coumarins also effectively suppressed ONOO(-)-mediated tyrosine nitration in a dose-dependent manner. To further investigate PTP1B inhibition, we generated a 3D structure of PTP1B using Autodock 4.2 and simulated the binding of compounds 1-6. Docking simulations showed that different residues of PTP1B interacted with different functional groups of compounds 1-6 through hydrogen and hydrophobic interactions. In addition, the binding energies of compounds 1-6 were negative, suggesting that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of PTP1B, thereby resulting in more effective PTP1B inhibition. These results demonstrate that the whole plant of A. decursiva and its coumarins are useful as potential functional food ingredients for the prevention and treatment of type 2 diabetes.

  14. Oxidation of PAH trans-Dihydrodiols by Human Aldo-Keto Reductase AKR1B10

    PubMed Central

    Quinn, Amy M.; Harvey, Ronald G.; Penning, Trevor M.

    2009-01-01

    AKR1B10 has been identified as a potential biomarker for human non-small cell lung carcinoma and as a tobacco exposure and response gene. AKR1B10 functions as an efficient retinal reductase in vitro, and may regulate retinoic acid homeostasis. However, the possibility that this enzyme is able to activate polycyclic aromatic hydrocarbon (PAH) trans-dihydrodiols to form reactive and redox-active o-quinones has not been investigated to date. AKR1B10 was found to oxidize a wide range of PAH trans-dihydrodiol substrates in vitro to yield PAH o-quinones. Reactions of AKR1B10 proceeded with improper stereochemistry, since it was specific for the minor (+)-benzo[a]pyrene-7S,8S-dihydrodiol diastereomer formed in vivo. However, AKR1B10 displayed reasonable activity in the oxidation of both the (−)-R,R and (+)-S,S stereoisomers of benzo[g]chrysene-11,12-dihydrodiol and oxidized the potentially relevant, albeit minor, (+)-benz[a]anthracene-3S,4S-dihydrodiol metabolite. We find that AKR1B10 is therefore likely to play a contributing role in the activation of PAH trans-dihydrodiols in human lung. AKR1B10 retinal reductase activity was confirmed in vitro and found to be 5- to 150-fold greater than the oxidation of PAH trans-dihydrodiols examined. AKR1B10 was highly expressed at the mRNA and protein levels in human lung adenocarcinoma A549 cells, and robust retinal reductase activity was measured in lysates of these cells. The much greater catalytic efficiency of retinal reduction compared to PAH trans-dihydrodiol metabolism suggests AKR1B10 may play a greater role in lung carcinogenesis through dysregulation of retinoic acid homeostasis than through oxidation of PAH trans-dihydrodiols. PMID:18788756

  15. Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance

    PubMed Central

    Kim, Teayoun; He, Lan; Johnson, Maria S.; Li, Yan; Zeng, Ling; Ding, Yishu; Long, Qinqiang; Moore, John F.; Sharer, Jon D.; Nagy, Tim R.; Young, Martin E.; Wood, Philip A.; Yang, Qinglin

    2014-01-01

    Background Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. Methods We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b+/−) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. Results We found that Cpt1b+/− mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b+/− mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b+/− skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b+/− but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. Conclusion The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy. PMID:25309812

  16. Tobacco smoke induces CYP1B1 in the aerodigestive tract.

    PubMed

    Port, Jeffrey L; Yamaguchi, Kentaro; Du, Baoheng; De Lorenzo, Mariana; Chang, Mindy; Heerdt, Paul M; Kopelovich, Levy; Marcus, Craig B; Altorki, Nasser K; Subbaramaiah, Kotha; Dannenberg, Andrew J

    2004-11-01

    Several members of the P450 family, including cytochrome P450 1B1 (CYP1B1), can convert tobacco smoke (TS) procarcinogens, including benzo[a]pyrene (B[a]P), to carcinogenic intermediates. In this study we investigated the effects of TS condensate and B[a]P on the expression of CYP1B1 in vitro and in vivo. CYP1B1 mRNA and protein were induced by both TS condensate and B[a]P in cell lines derived from the human aerodigestive tract. Treatment with TS condensate stimulated binding of the aryl hydrocarbon receptor (AhR) to an oligonucleotide containing a canonical xenobiotic response element (XRE) site and induced XRE-luciferase activity. These findings are consistent with prior evidence that polycyclic aromatic hydrocarbons, known ligands of the AhR, stimulate CYP1B1 transcription by an XRE-dependent mechanism. To determine whether these in vitro findings applied in vivo, both murine and human studies were carried out. Short-term exposure to TS induced CYP1B1 in the tongue, esophagus, lung and colon of experimental mice. In contrast, CYP1B1 was not induced by TS in the aorta of these mice. Levels of CYP1B1 mRNA were also elevated in the bronchial mucosa of human tobacco smokers versus never smokers (P < 0.05). Taken together, these results support a role for CYP1B1 in TS-induced carcinogenesis in the aerodigestive tract.

  17. Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats.

    PubMed

    Borges, Beatriz de Carvalho; Rorato, Rodrigo C; Uchoa, Ernane Torres; Marangon, Paula B; Elias, Carol F; Antunes-Rodrigues, Jose; Elias, Lucila L K

    2015-01-01

    Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 μg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 μl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity.

  18. SUMOylation of the ING1b tumor suppressor regulates gene transcription

    PubMed Central

    Satpathy, Shankha; Guérillon, Claire; Kim, Tae-Sun; Bigot, Nicolas; Thakur, Satbir; Bonni, Shirin; Riabowol, Karl; Pedeux, Rémy

    2014-01-01

    The INhibitor of Growth (ING) proteins are encoded as multiple isoforms in five ING genes (ING1 –5) and act as type II tumor suppressors. They are growth inhibitory when overexpressed and are frequently mislocalized or downregulated in several forms of cancer. ING1 and ING2 are stoichiometric members of histone deacetylase complexes, whereas ING3–5 are stoichiometric components of different histone acetyltransferase complexes. The INGs target these complexes to histone marks, thus acting as epigenetic regulators. ING proteins affect angiogenesis, apoptosis, DNA repair, metastasis and senescence, but how the proteins themselves are regulated is not yet clear. Here, we find a small ubiquitin-like modification (SUMOylation) of the ING1b protein and identify lysine 193 (K193) as the preferred ING1b SUMO acceptor site. We also show that PIAS4 is the E3 SUMO ligase responsible for ING1b SUMOylation on K193. Sequence alignment reveals that the SUMO consensus site on ING1b contains a phosphorylation-dependent SUMOylation motif (PDSM) and our data indicate that the SUMOylation on K193 is enhanced by the S199D phosphomimic mutant. Using an ING1b protein mutated at the major SUMOylation site (ING1b E195A), we further demonstrate that ING1b SUMOylation regulates the binding of ING1b to the ISG15 and DGCR8 promoters, consequently regulating ISG15 and DGCR8 transcription. These results suggest a role for ING1b SUMOylation in the regulation of gene transcription. PMID:24903338

  19. Cooperative Stimulation of Megakaryocytic Differentiation by Gfi1b Gene Targets Kindlin3 and Talin1

    PubMed Central

    Singh, Divya; Upadhyay, Ghanshyam; Sengupta, Ananya; Biplob, Mohammed A.; Chakyayil, Shaleen; George, Tiji; Saleque, Shireen

    2016-01-01

    Understanding the production and differentiation of megakaryocytes from progenitors is crucial for realizing the biology and functions of these vital cells. Previous gene ablation studies demonstrated the essential role of the transcriptional repressor Gfi1b (growth factor independence 1b) in the generation of both erythroid and megakaryocytic cells. However, our recent work has demonstrated the down-regulation of this factor during megakaryocytic differentiation. In this study we identify two new gene targets of Gfi1b, the cytoskeletal proteins Kindlin3 and Talin1, and demonstrate the inverse expression and functions of these cytoskeletal targets relative to Gfi1b, during megakaryocytic differentiation. Both kindlin3 and talin1 promoters exhibit dose dependent Gfi1b and LSD1 (lysine specific demethylase 1; a Gfi1b cofactor) enrichment in megakaryocytes and repression in non-hematopoietic cells. Accordingly the expression of these genes is elevated in gfi1b mutant and LSD1 inhibited hematopoietic cells, while during megakaryocytic differentiation, declining Gfi1b levels fostered the reciprocal upregulation of these cytoskeletal factors. Concordantly, manipulation of Kindlin3 and Talin1 expression demonstrated positive correlation with megakaryocytic differentiation with over-expression stimulating, and inhibition diminishing, this process. Co-operativity between these factors and integrins in promoting differentiation was further underscored by physical interactions between them and integrinβ3/CD61 and by stimulation of differentiation by the Talin1 head domain, which is necessary and sufficient for integrin activation. Therefore this study demonstrates the significance of Gfi1b regulated Kindlin3-Talin1 expression in driving megakaryocytic differentiation and highlights the contribution of cytoskeletal agents in the developmental progression of these platelet progenitors. PMID:27768697

  20. Serotonin 1B Receptor Gene (HTR1B) Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys.

    PubMed

    Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David J; Dadds, Mark R

    2015-01-01

    The serotonin system is thought to play a role in the aetiology of callous-unemotional (CU) traits in children. Previous research identified a functional single nucleotide polymorphism (SNP) from the promoter region of the serotonin 1B receptor gene as being associated with CU traits in boys with antisocial behaviour problems. This research tested the hypothesis that CU traits are associated with reduced methylation of the promoter region of the serotonin 1B receptor gene due to the influence of methylation on gene expression. Participants (N = 117) were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered a saliva sample from which the genotype of a SNP from the promoter region of the serotonin 1B receptor gene and the methylation levels of 30 CpG sites from 3 CpG regions surrounding the location of this polymorphism were assayed. Lower levels of serotonin 1B receptor gene methylation were associated with higher levels of CU traits. This relationship, however, was found to be moderated by genotype and carried exclusively by two CpG sites for which levels of methylation were negatively associated with overall methylation levels in this region of the gene. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of CU traits. Furthermore, the results suggest that there may be two pathways to CU traits that involve methylation of the serotonin 1B receptor gene; one that is driven by a genotypic risk and another that is associated with risk for generally increased levels of methylation. Future research that aims to replicate and further investigate these results is required.

  1. Genetic variation of Cytochrome P450 1B1 (CYP1B1) and risk of breast cancer among Polish women.

    PubMed

    Gaudet, Mia M; Chanock, Stephen; Lissowska, Jolanta; Berndt, Sonja I; Yang, Xiaohong Rose; Peplonska, Beata; Brinton, Louise A; Welch, Robert; Yeager, Meredith; Bardin-Mikolajczak, Alicja; Sherman, Mark E; Sutter, Thomas R; Garcia-Closas, Montserrat

    2006-08-01

    Four single nucleotide polymorphisms (SNPs) in CYP1B1 (Ex2 + 143 C > G, Ex2 + 356 G > T, Ex3 + 251 G > C, Ex3 + 315 A > G) cause amino acid changes (R48G, A119S, L432V and N453S, respectively) and are associated with increased formation of catechol estrogens; however, epidemiologic evidence only weakly supports an association between these variants and breast cancer risk. Because genetic variability conferring increased susceptibility could exist beyond these putative functional variants, we comprehensively examined the common genetic variability within CYP1B1. A total of eight haplotype-tagging (ht)SNPs (including Ex3 + 315 A > G), in addition to two putatively functional SNPs (Ex2 + 143 C > G and Ex3 + 251 G > C), were selected and genotyped in a large case-control study of Polish women (1995 cases and 2296 controls). Haplotypes were estimated using the expectation-maximization algorithm, and overall differences in the haplotype distribution between cases and controls were assessed using a global score test. We also evaluated levels of tumor CYP1B1 protein expression in a subset of 841 cases by immunohistochemistry, and their association with genetic variants. In the Polish population, we observed two linkage disequilibrium (LD)-defined blocks. Neither haplotypes (global P-value of 0.99 and 0.67 for each block of LD, respectively), nor individual SNPs (including three putatively functional SNPs) were associated with breast cancer risk. CYP1B1 was expressed in most tumor tissues (98%), and the level of expression was not related to the studied genetic variants. We found little evidence for modification of the estimated effect of haplotypes or individual SNPs by age, family history of breast cancer, or tumor hormone receptor status. The present study provides strong evidence against the existence of a substantial overall association between common genetic variation in CYP1B1 and breast cancer risk.

  2. CYP1B1 expression in ovarian cancer in the laying hen Gallus domesticus

    PubMed Central

    Zhuge, Yan; Lagman, Jo Ann J.; Ansenberger, Kristine; Mahon, Cassandra J.; Daikoku, Takiko; Dey, Sudhansu K.; Bahr, Janice M.; Hales, Dale B.

    2009-01-01

    Objectives Ovarian carcinoma is the most lethal gynecological malignancy. The genetic and molecular mechanisms that cause it still remain largely unknown. CYP1B1 is a cytochrome P450 enzyme that catalyzes the conversion of estrogens to genotoxic catechol estrogens which may cause DNA mutations and initiate ovarian epithelial cancer. Our objectives were to evaluate CYP1B1 expression, distribution and localization in the hen ovary and to determine if there is an increased CYP1B1 expression associated with, and possibly involved in the initiation of ovarian cancer. Methods Two groups of hens were used: 1. young (50 weeks of age; devoid of cancer) and 2. old (165 weeks of age; divided into two groups: age-matched normal and ovarian cancer). CYP1B1 mRNA and protein expression were analyzed in cancerous ovaries, ovaries of age-matched normal and/or young hens by quantitative real-time PCR (qRT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). RNA was extracted from tissue preserved in RNAlater for qRT-PCR. Tissue frozen in liquid nitrogen was used for ISH. Tissue fixed in neutral buffered formalin was subjected to IHC. Results Higher expression of CYP1B1 mRNA was observed in cancerous ovaries as compared to ovaries of young and age-matched normal hens by qRT-PCR. ISH and IHC confirmed that the expression of CYP1B1 was much higher in ovarian tumors compared to ovaries of age-matched normal hens. CYP1B1 mRNA and protein were distributed extensively throughout the carcinoma, while primarily localized to the granulosa layer surrounding the follicle in age-matched normal hens. IHC also showed nuclear localization of CYP1B1. Highly expressed CYP1B1 was found in POF-3 from young and age-matched normal hens as compared to POF-1 and POF-2 by qRT-PCR. No significant difference was found in the expression of CYP1B1 between the distal (site of rupture) and the proximal (site of attachment to the ovary) of POF-1 from young and age-matched normal hens. Conclusions High

  3. Otx2 Requires Lmx1b to Control the Development of Mesodiencephalic Dopaminergic Neurons

    PubMed Central

    Sherf, Orna; Nashelsky Zolotov, Limor; Liser, Keren; Tilleman, Hadas; Jovanovic, Vukasin M.; Zega, Ksenija; Jukic, Marin M.; Brodski, Claude

    2015-01-01

    Studying the development of mesodiencephalic dopaminergic (mdDA) neurons provides an important basis for better understanding dopamine-associated brain functions and disorders and is critical for establishing cell replacement therapy for Parkinson’s disease. The transcription factors Otx2 and Lmx1b play a key role in the development of mdDA neurons. However, little is known about the genes downstream of Otx2 and Lmx1b in the pathways controlling the formation of mdDA neurons in vivo. Here we report on our investigation of Lmx1b as downstream target of Otx2 in the formation of mdDA neurons. Mouse mutants expressing Otx2 under the control of the En1 promoter (En1+/Otx2) showed increased Otx2 expression in the mid-hindbrain region, resulting in upregulation of Lmx1b and expansion of mdDA neurons there. In contrast, Lmx1b-/- mice showed decreased expression of Otx2 and impairments in several aspects of mdDA neuronal formation. To study the functional interaction between Otx2 and Lmx1b, we generated compound mutants in which Otx2 expression was restored in mice lacking Lmx1b (En1+/Otx2;Lmx1b-/-). In these animals Otx2 was not sufficient to rescue any of the aberrations in the formation of mdDA neurons caused by the loss of Lmx1b, but rescued the loss of ocular motor neurons. Gene expression studies in Lmx1b-/- embryos indicated that in these mutants Wnt1, En1 and Fgf8 expression are induced but subsequently lost in the mdDA precursor domain and the mid-hindbrain organizer in a specific, spatio-temporal manner. In summary, we demonstrate that Otx2 critically depends on Lmx1b for the formation of mdDA neurons, but not for the generation of ocular motor neurons. Moreover, our data suggest that Lmx1b precisely maintains the expression pattern of Wnt1, Fgf8 and En1, which are essential for mid-hindbrain organizer function and the formation of mdDA neurons. PMID:26444681

  4. XPB Induces C1D Expression to Counteract UV-Induced Apoptosis

    PubMed Central

    Li, Guang; Liu, Juhong; Abu-Asab, Mones; Masabumi, Shibuya; Maru, Yoshiro

    2010-01-01

    Although C1D has been shown to be involved in DNA double-strand breaks repair, how C1D expression was induced and the mechanism(s) by which C1D facilitates DNA repair in mammalian cells remain poorly understood. We and others have previously shown that expression of XPB protein efficiently compensated the UV-irradiation sensitive phenotype of 27-1 cells which lacks functional XPB. To further explore XPB-regulated genes that could be involved in UV-induced DNA repair, Differential Display analysis of mRNA level from CHO-9, 27-1 and 27-1 complemented with wild-type XPB were performed and C1D gene was identified as one of the major genes whose expression was significantly up-regulated by restoring XPB function. We found that XPB is essential to induce C1D transcription after UV-irradiation. The increase of C1D expression effectively compensates the UV-induced proteolysis of C1D and thus maintains cellular C1D level to cope with DNA damage inflicted by UV-irradiation. We further showed that although insufficient to rescue 27-1 cells from UV-induced apoptosis by itself, C1D facilitates XPB DNA repair through direct interaction with XPB. Our findings provided direct evidence that C1D is associated with DNA repair complex and may promote repair of UV-induced DNA damage. PMID:20530579

  5. Gfi1 and Gfi1b Repress Rag Transcription in Plasmacytoid Dendritic Cells In Vitro

    PubMed Central

    Chow, Kwan T.; Schulz, Danae; McWhirter, Sarah M.; Schlissel, Mark S.

    2013-01-01

    Growth factor independence genes (Gfi1 and Gfi1b) repress recombination activating genes (Rag) transcription in developing B lymphocytes. Because all blood lineages originate from hematopoietic stem cells (HSCs) and different lineage progenitors have been shown to share transcription factor networks prior to cell fate commitment, we hypothesized that GFI family proteins may also play a role in repressing Rag transcription or a global lymphoid transcriptional program in other blood lineages. We tested the level of Rag transcription in various blood cells when Gfi1 and Gfi1b were deleted, and observed an upregulation of Rag expression in plasmacytoid dendritic cells (pDCs). Using microarray analysis, we observed that Gfi1 and Gfi1b do not regulate a lymphoid or pDC-specific transcriptional program. This study establishes a role for Gfi1 and Gfi1b in Rag regulation in a non-B lineage cell type. PMID:24086657

  6. The new powder diffractometer D1B of the Institut Laue Langevin

    NASA Astrophysics Data System (ADS)

    Puente Orench, I.; Clergeau, J. F.; Martínez, S.; Olmos, M.; Fabelo, O.; Campo, J.

    2014-11-01

    D1B is a medium resolution high flux powder diffractometer located at the Institut Laue Langevin, ILL. D1B a suitable instrument for studying a large variety of polycrystalline materials. D1B runs since 1998 as a CRG (collaborating research group) instrument, being exploited by the CNRS (Centre National de la Recherche Scientifique, France) and CSIC (Consejo Superior de Investigaciones Cientificas, Spain). In 2008 the Spanish CRG started an updating program which included a new detector and a radial oscillating collimator (ROC). The detector, which has a sensitive height of 100mm, covers an angular range of 128°. Its 1280 gold wires provide a neutron detection point every 0.1°. The ROC is made of 198 gadolinium- based absorbing collimation blades, regular placed every 0.67°. Here the present characteristics of D1B are reviewed and the different experimental performances will be presented.

  7. [Research progress on the relationship between SLCO1B1 gene and neonatal jaundice].

    PubMed

    Lu, An-Feng; Zhong, Dan-Ni

    2014-11-01

    Organic anion transporter 2 (OATP2) is an uptake transporter located on the basolateral membrane of human hepatocytes. It mediates the transportation of various organic solutes including bilirubin and impacts bilirubin metabolism. It is encoded by the gene of solute carrier organic anion transporter family member 1B1 and the gene variants that inhibit hepatic bilirubin uptake function may reduce the normal functional level of bilirubin elimination and result in neonatal hyperbilirubinemia. In recent years, some studies have indicated that variants of SLCO1B1 are associated with neonatal jaundice. This article reviews the research advance in SLCO1B1 with respect to the structure and function and the relationship between SLCO1B1 mutations and neonatal jaundice.

  8. AP-1/σ1B-adaptin mediates endosomal synaptic vesicle recycling, learning and memory

    PubMed Central

    Glyvuk, Nataliya; Tsytsyura, Yaroslav; Geumann, Constanze; D'Hooge, Rudi; Hüve, Jana; Kratzke, Manuel; Baltes, Jennifer; Böning, Daniel; Klingauf, Jürgen; Schu, Peter

    2010-01-01

    Synaptic vesicle recycling involves AP-2/clathrin-mediated endocytosis, but it is not known whether the endosomal pathway is also required. Mice deficient in the tissue-specific AP-1–σ1B complex have impaired synaptic vesicle recycling in hippocampal synapses. The ubiquitously expressed AP-1–σ1A complex mediates protein sorting between the trans-Golgi network and early endosomes. Vertebrates express three σ1 subunit isoforms: A, B and C. The expressions of σ1A and σ1B are highest in the brain. Synaptic vesicle reformation in cultured neurons from σ1B-deficient mice is reduced upon stimulation, and large endosomal intermediates accumulate. The σ1B-deficient mice have reduced motor coordination and severely impaired long-term spatial memory. These data reveal a molecular mechanism for a severe human X-chromosome-linked mental retardation. PMID:20203623

  9. Prediction and verification of novel peptide targets of protein tyrosine phosphatase 1B.

    PubMed

    Li, Xun; Köhn, Maja

    2016-08-01

    Phosphotyrosine peptides are useful starting points for inhibitor design and for the search for protein tyrosine phosphatase (PTP) phosphoprotein substrates. To identify novel phosphopeptide substrates of PTP1B, we developed a computational prediction protocol based on a virtual library of protein sequences with known phosphotyrosine sites. To these we applied sequence-based methods, biologically meaningful filters and molecular docking. Five peptides were selected for biochemical testing of their potential as PTP1B substrates. All five peptides were equally good substrates for PTP1B compared to a known peptide substrate whereas appropriate control peptides were not recognized, showing that our protocol can be used to identify novel peptide substrates of PTP1B.

  10. VIEW OF ROOM 1B, LOOKING TOWARDS SIDE 3 OF THE ...

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

    VIEW OF ROOM 1B, LOOKING TOWARDS SIDE 3 OF THE MLP - Cape Canaveral Air Force Station, Launch Complex 39, Mobile Launcher Platforms, Launcher Road, East of Kennedy Parkway North, Cape Canaveral, Brevard County, FL

  11. Tandem repeats modify the structure of the canine CD1D gene.

    PubMed

    Looringh van Beeck, F A; Leegwater, P A J; Herrmann, T; Broere, F; Rutten, V P M G; Willemse, T; Van Rhijn, I

    2013-06-01

    Among the CD1 proteins that present lipid antigens to T cells, CD1d is the only one that stimulates a population of T cells with an invariant T-cell receptor known as NKT cells. Sequencing of a 722 nucleotide gap in the dog (Canis lupus familiaris) genome revealed that the canine CD1D gene lacks a sequence homologous to exon 2 of human CD1D, coding for the start codon and signal peptide. Also, the canine CD1D gene contains three different short tandem repeats that disrupt the expected gene structure. Because canine CD1D cDNA lacks sequences homologous to human exon 2 and 3, the functionality of canine CD1d protein may be affected, and this could have consequences for the development and activation of canine NKT cells.

  12. MODIS technical report series. Volume 3: MODIS airborne simulator level 1B data user's guide

    NASA Technical Reports Server (NTRS)

    Gumley, Liam E.; Hubanks, Paul A.; Masuoka, Edward J.

    1994-01-01

    The purpose of this document is to describe the characteristics of moderate resolution imaging spectroradiometer (MODIS) airborne simulator level 1B data, the calibration and geolocation methods used in processing, the structure and format of the level 1B data files, and methods for accessing the data. The MODIS airborne simulator is a scanning spectrometer which flies on a NASA ER-2 and provides spectral information similar to that which will be provided by the MODIS.

  13. Targeting Sulfotransferase (SULT) 2B1b as a Regulator of Cholesterol Metabolism in Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0588 TITLE: Targeting Sulfotransferase (SULT) 2B1b as a regulator of Cholesterol Metabolism in Prostate Cancer...October 2015 30Sep2014 - 29Sep2015 W81XWH-14-1-0588Targeting Sulfotransferase (SULT) 2B1b as a regulator of Cholesterol Metabolism in Prostate...epidemiological and experimental evidence establishes alterations in cholesterol metabolism as a key driver of prostate cancer (PCa) aggressiveness

  14. Structure and Promoter Characterization of Aldo-Keto Reductase Family 1 B10 Gene

    PubMed Central

    Liu, Ziwen; Zhong, Linlin; Krishack, Paulette A; Robbins, Sarah; Cao, Julia X; Zhao, Yupei; Chung, Stephen; Cao, Deliang

    2009-01-01

    Aldo-keto reductase family 1 member B10 (AKR1B10) is overexpressed in human hepatocellular carcinoma, lung squamous carcinoma, and lung adenocarcinoma in smokers. Our recent studies have showed that AKR1B10 plays a critical role in the growth and proliferation of cancer cells by detoxifying reactive carbonyls and regulating fatty acid biosynthesis. However, little is known about the regulatory mechanisms of AKR1B10 expression. In this study, we determined the structure of AKR1B10 gene and characterized its promoter. The results demonstrated that AKR1B10 consists of 10 exons and 9 introns, stretching approximately 13.8 kb. A 5′-RACE study determined the transcriptional start site of AKR1B10 at 320 bp upstream of the ATG translational start codon. A TATA-like (TAATAA) and a CAAT box are present from −145 to −140 bp and −193 to −190 bp upstream of the transcriptional start site, respectively. Motif analysis recognized multiple putative oncogenic and tumor suppressor protein binding sites in the AKR1B10 promoter, including c-Ets-1, C/EBP, AP-1, and p53, but osmolytic response elements were not found. A -4,091 bp of the 5′-flanking fragment of the AKR1B10 gene was capable of driving GFP and luciferase reporter gene expression in HepG2 cells derived from human hepatocellular carcinoma; progressive 5′-deletions revealed that a −255 bp fragment possesses full promoter activity. PMID:19236911

  15. Decreased blood pressure response in mice deficient of the α1b-adrenergic receptor

    PubMed Central

    Cavalli, Antonella; Lattion, Anne-Laure; Hummler, Edith; Nenniger, Monique; Pedrazzini, Thierry; Aubert, Jean-François; Michel, Martin C.; Yang, Ming; Lembo, Giuseppe; Vecchione, Carmine; Mostardini, Marina; Schmidt, Andrea; Beermann, Friedrich; Cotecchia, Susanna

    1997-01-01

    To investigate the functional role of different α1-adrenergic receptor (α1-AR) subtypes in vivo, we have applied a gene targeting approach to create a mouse model lacking the α1b-AR (α1b−/−). Reverse transcription–PCR and ligand binding studies were combined to elucidate the expression of the α1-AR subtypes in various tissues of α1b +/+ and −/− mice. Total α1-AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex of the α1b −/− as compared with +/+ mice. Because of the large decrease of α1-AR in the heart and the loss of the α1b-AR mRNA in the aorta of the α1b−/− mice, the in vivo blood pressure and in vitro aorta contractile responses to α1-agonists were investigated in α1b +/+ and −/− mice. Our findings provide strong evidence that the α1b-AR is a mediator of the blood pressure and the aorta contractile responses induced by α1 agonists. This was demonstrated by the finding that the mean arterial blood pressure response to phenylephrine was decreased by 45% in α1b −/− as compared with +/+ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in α1b−/− mice. The α1b-AR knockout mouse model provides a potentially useful tool to elucidate the functional specificity of different α1-AR subtypes, to better understand the effects of adrenergic drugs, and to investigate the multiple mechanisms involved in the control of blood pressure. PMID:9326654

  16. Immunomodulation with Recombinant Interferon-γ1b in Pulmonary Tuberculosis

    PubMed Central

    Dawson, Rod; Condos, Rany; Tse, Doris; Huie, Maryann L.; Ress, Stanley; Tseng, Chi-Hong; Brauns, Clint; Weiden, Michael; Hoshino, Yoshihiko; Bateman, Eric; Rom, William N.

    2009-01-01

    Background Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-γ1b (rIFN-γb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. Methodology/Principal Findings We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-γ1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1β, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-γ1b group from baseline to week 16. Both rIFN-γ1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-γ1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-γ1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-γ1b versus DOTS alone. Conclusion Recombinant interferon-γ1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. Trial Registration ClinicalTrials.gov NCT00201123 PMID:19753300

  17. Digenic Inheritance of Early-Onset Glaucoma: CYP1B1, a Potential Modifier Gene

    PubMed Central

    Vincent, Andrea L.; Billingsley, Gail; Buys, Yvonne; Levin, Alex V.; Priston, Megan; Trope, Graham; Williams-Lyn, Donna; Héon, Elise

    2002-01-01

    “Early-onset glaucoma” refers to genetically heterogeneous conditions for which glaucoma manifests at age 5–40 years and for which only a small subset is molecularly characterized. We studied the role of MYOC, CYP1B1, and PITX2 in a population (n=60) affected with juvenile or early-onset glaucoma from the greater Toronto area. By a combination of single-strand conformation polymorphism and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) of the 60 individuals, CYP1B1 mutations were detected in 3 (5%) of the 60 individuals, and no PITX2 mutations were detected. The range of phenotypic expression associated with MYOC and CYP1B1 mutations was greater than expected. MYOC mutations included cases of juvenile glaucoma with or without pigmentary glaucoma and mixed-mechanism glaucoma. CYP1B1 mutations involved cases of juvenile open-angle glaucoma, as well as cases of congenital glaucoma. The study of a family with autosomal dominant glaucoma showed the segregation of both MYOC and CYP1B1 mutations with disease; however, in this family, the mean age at onset of carriers of the MYOC mutation alone was 51 years (range 48–64 years), whereas carriers of both the MYOC and CYP1B1 mutations had an average age at onset of 27 years (range 23–38 years) (P=.001). This work emphasizes the genetic heterogeneity of juvenile glaucoma and suggests, for the first time, that (1) congenital glaucoma and juvenile glaucoma are allelic variants and (2) the spectrum of expression of MYOC and CYP1B1 mutations is greater than expected. We also propose that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway. PMID:11774072

  18. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    SciTech Connect

    Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

    2010-04-01

    This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

  19. Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11.

    PubMed

    Eriksson, T M; Alvarsson, A; Stan, T L; Zhang, X; Hascup, K N; Hascup, E R; Kehr, J; Gerhardt, G A; Warner-Schmidt, J; Arango-Lievano, M; Kaplitt, M G; Ogren, S O; Greengard, P; Svenningsson, P

    2013-10-01

    Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

  20. Examination of 1D Solar Cell Model Limitations Using 3D SPICE Modeling: Preprint

    SciTech Connect

    McMahon, W. E.; Olson, J. M.; Geisz, J. F.; Friedman, D. J.

    2012-06-01

    To examine the limitations of one-dimensional (1D) solar cell modeling, 3D SPICE-based modeling is used to examine in detail the validity of the 1D assumptions as a function of sheet resistance for a model cell. The internal voltages and current densities produced by this modeling give additional insight into the differences between the 1D and 3D models.

  1. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation.

    PubMed Central

    Meyers, S; Lenny, N; Hiebert, S W

    1995-01-01

    The AML-1/CBF beta transcription factor complex is targeted by both the t(8;21) and the inv(16) chromosomal alterations, which are frequently observed in acute myelogenous leukemia. AML-1 is a site-specific DNA-binding protein that recognizes the enhancer core motif TGTGGT. The t(8;21) translocation fuses the first 177 amino acids of AML-1 to MTG8 (also known as ETO), generating a chimeric protein that retains the DNA-binding domain of AML-1. Analysis of endogenous AML-1 DNA-binding complexes suggested the presence of at least two AML-1 isoforms. Accordingly, we screened a human B-cell cDNA library and isolated a larger, potentially alternatively spliced, form of AML1, termed AML1B. AML-1B is a protein of 53 kDa that binds to a consensus AML-1-binding site and complexes with CBF beta. Subcellular fractionation experiments demonstrated that both AML-1 and AML-1/ETO are efficiently extracted from the nucleus under ionic conditions but that AML-1B is localized to a salt-resistant nuclear compartment. Analysis of the transcriptional activities of AML-1, AML-1B, and AML-1/ETO demonstrated that only AML-1B activates transcription from the T-cell receptor beta enhancer. Mixing experiments indicated that AML-1/ETO can efficiently block AML-1B-dependent transcriptional activation, suggesting that the t(8;21) translocation creates a dominant interfering protein. PMID:7891692

  2. Prodrug delivery of novel PTP1B inhibitors to enhance insulin signalling.

    PubMed

    Erbe, D V; Klaman, L D; Wilson, D P; Wan, Z-K; Kirincich, S J; Will, S; Xu, X; Kung, L; Wang, S; Tam, S; Lee, J; Tobin, J F

    2009-06-01

    A growing percentage of the population is resistant to two key hormones - insulin and leptin - as a result of increased obesity, often leading to significant health consequences such as type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of signalling by both of these hormones, so that inhibitors of this enzyme may provide promise for correcting endocrine abnormalities in both diabetes and obesity. As with other tyrosine phosphatases, identification of viable drug candidates targeting PTP1B has been elusive because of the nature of its active site. Beginning with novel phosphotyrosine mimetics, we have designed some of the most potent PTP1B inhibitors. However, their highly acidic structures limit intrinsic permeability and pharmacokinetics. Ester prodrugs of these inhibitors improve their drug-like properties with the goal of delivering these nanomolar inhibitors to the cytoplasm of cells within target tissues. In addition to identifying prodrugs that is able to deliver active drugs into cells to inhibit PTP1B and increase insulin signalling, these compounds were further modified to gain a variety of cleavage properties for targeting activity in vivo. One such prodrug candidate improved insulin sensitivity in ob/ob mice, with lowered fasting blood glucose levels seen in the context of lowered fasting insulin levels following 4 days of intraperitoneal dosing. The results presented in this study highlight the potential for design of orally active drug candidates targeting PTP1B, while also delineating the considerable challenges remaining.

  3. SMC1B is present in mammalian somatic cells and interacts with mitotic cohesin proteins

    PubMed Central

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Amato, Clelia; Tinti, Mara; Tana, Luigi; Frattini, Annalisa; Delia, Domenico; Krantz, Ian D.; Jessberger, Rolf; Musio, Antonio

    2015-01-01

    Cohesin is an evolutionarily conserved protein complex that plays a role in many biological processes: it ensures faithful chromosome segregation, regulates gene expression and preserves genome stability. In mammalian cells, the mitotic cohesin complex consists of two structural maintenance of chromosome proteins, SMC1A and SMC3, the kleisin protein RAD21 and a fourth subunit either STAG1 or STAG2. Meiotic paralogs in mammals were reported for SMC1A, RAD21 and STAG1/STAG2 and are called SMC1B, REC8 and STAG3 respectively. It is believed that SMC1B is only a meiotic-specific cohesin member, required for sister chromatid pairing and for preventing telomere shortening. Here we show that SMC1B is also expressed in somatic mammalian cells and is a member of a mitotic cohesin complex. In addition, SMC1B safeguards genome stability following irradiation whereas its ablation has no effect on chromosome segregation. Finally, unexpectedly SMC1B depletion impairs gene transcription, particularly at genes mapping to clusters such as HOX and PCDHB. Genome-wide analyses show that cluster genes changing in expression are enriched for cohesin-SMC1B binding. PMID:26673124

  4. Terra and Aqua moderate-resolution imaging spectroradiometer collection 6 level 1B algorithm

    NASA Astrophysics Data System (ADS)

    Toller, Gary; Xiong, Xiaoxiong; Sun, Junqiang; Wenny, Brian N.; Geng, Xu; Kuyper, James; Angal, Amit; Chen, Hongda; Madhavan, Sriharsha; Wu, Aisheng

    2013-01-01

    The moderate-resolution imaging spectroradiometer (MODIS) was launched on the Terra spacecraft on Dec.18, 1999 and on Aquaon May 4, 2002. The data acquired by these instruments have contributed to the long-term climate data record for more than a decade and represent a key component of NASA's Earth observing system. Each MODIS instrument observes nearly the whole Earth each day, enabling the scientific characterization of the land, ocean, and atmosphere. The MODIS Level 1B (L1B) algorithms input uncalibrated geo-located observations and convert instrument response into calibrated reflectance and radiance, which are used to generate science data products. The instrument characterization needed to run the L1B code is currently implemented using time-dependent lookup tables. The MODIS characterization support team, working closely with the MODIS Science Team, has improved the product quality with each data reprocessing. We provide an overview of the new L1B algorithm release, designated collection 6. Recent improvements made as a consequence of on-orbit calibration, on-orbit analyses, and operational considerations are described. Instrument performance and the expected impact of L1B changes on the collection 6 L1B products are discussed.

  5. 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B.

    PubMed

    Zhi, Ying; Gao, Li-Xin; Jin, Yi; Tang, Chun-Lan; Li, Jing-Ya; Li, Jia; Long, Ya-Qiu

    2014-07-15

    Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

  6. Structure of a BMI-1-Ring1B Polycomb Group Ubiquitin Ligase Complex

    SciTech Connect

    Li,Z.; Cao, R.; Wang, M.; Myers, M.; Zhang, Y.; Xu, R.

    2006-01-01

    Polycomb group (PcG) proteins Bmi-1 and Ring1B are core subunits of the PRC1 complex which plays important roles in the regulation of Hox gene expression, X-chromosome inactivation, tumorigenesis and stem cell self-renewal. The RING finger protein Ring1B is an E3 ligase that participates in the ubiquitination of lysine 119 of histone H2A, and the binding of Bmi-1 stimulates the E3 ligase activity. We have mapped the regions of Bmi-1 and Ring1B required for efficient ubiquitin transfer and determined a 2.5 Angstroms structure of the Bmi-1-Ring1B core domain complex. The structure reveals that Ring1B 'hugs' Bmi-1 through extensive RING domain contacts and its N-terminal tail wraps around Bmi-1. The two regions of interaction have a synergistic effect on the E3 ligase activity. Our analyses suggest a model where the Bmi-1-Ring1B complex stabilizes the interaction between the E2 enzyme and the nucleosomal substrate to allow efficient ubiquitin transfer.

  7. Preparation and characterization of Ni-P/Ni3.1B composite alloy coatings

    NASA Astrophysics Data System (ADS)

    Wang, Yurong; He, Jiawei; Wang, Wenchang; Shi, Jianhua; Mitsuzaki, Naotoshi; Chen, Zhidong

    2014-02-01

    The preparation of Ni-P/Ni3.1B composite alloy coating on the surface of copper was achieved by co-deposition of Ni3.1B nanoparticles with Ni-P coating during electroless plating. Ni-P-B alloy coating was obtained by heat-treating the as-plated Ni-P/Ni3.1B composite coating. The effect of the concentration of sodium alginate, borax, thiourea, Ni3.1B, temperature, and pH value on the deposition rate and B content were investigated and determined to be: 30 g L-1, 10 g L-1, 2 mg L-1, 20 mg L-1, 70 °C and 9.0 , respectively. Sodium alginate and thiourea were played as surfactant for coating Ni3.1B nanoparticles and stabilizer for the plating bath, respectively. Ni-P/Ni3.1B composite coating had good performance such as corrosion resistance and solderability.

  8. Knockdown of Lingo1b protein promotes myelination and oligodendrocyte differentiation in zebrafish.

    PubMed

    Yin, Wu; Hu, Bing

    2014-01-01

    Demyelinating diseases include multiple sclerosis, which is a neurodegenerative disease characterized by immune attacks on the central nervous system (CNS), resulting in myelin sheath damage and axonal loss. Leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitory protein (Nogo) receptor-interacting protein-1 (LINGO-1) have been identified as a negative regulator of oligodendrocytes differentiation. Targeted LINGO-1 inhibition promotes neuron survival, axon regeneration, oligodendrocyte differentiation, and remyelination in diverse animal models. Although studies in rodent models have extended our understanding of LINGO-1, its roles in neural development and myelination in zebrafish (Danio rerio) are not yet clear. In this study, we cloned the zebrafish homolog of the human LINGO-1 and found that lingo1b regulated myelination and oligodendrocyte differentiation. The expression of lingo1b started 1 (mRNA) and 2 (protein) days post-fertilization (dpf) in the CNS. Morpholino oligonucleotide knockdown of lingo1b resulted in developmental abnormalities, including less dark pigment, small eyes, and a curly spinal cord. The lack of lingo1b enhanced myelination and oligodendrocyte differentiation during embryogenesis. Furthermore, immunohistochemistry and movement analysis showed that lingo1b was involved in the axon development of primary motor neurons. These results suggested that Lingo1b protein functions as a negative regulator of myelination and oligodendrocyte differentiation during zebrafish development.

  9. Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer

    PubMed Central

    McFadyen, M C E; Cruickshank, M E; Miller, I D; McLeod, H L; Melvin, W T; Haites, N E; Parkin, D; Murray, G I

    2001-01-01

    Ovarian cancer is the most frequent cause of death from gynaecological malignancies world wide. Little improvement has been made in the long-term outcome of this disease, with the 5-year survival of patients only 30%. This poor prognosis is due to the late presentation of the disease and to the unpredictable response of ovarian cancer to chemotherapy. The cytochrome P450 enzymes are a superfamily of haemoproteins, known to be involved in the metabolic activation and/or detoxification of a number of anti-cancer drugs. CYP1B1 is a tumour-related form of cytochrome P450 which is over expressed in a wide variety of primary tumours of different histological type. The presence of CYP1B1 may be of importance in the modulation of these tumours to anti-cancer drugs. We have conducted a comprehensive immunohistochemical investigation, into the presence of cytochrome P450 CYP1B1 in primary and metastatic ovarian cancer. The key findings of this study are the increased expression of CYP1B1 in the majority of ovarian cancers investigated (92%), with a strong correlation demonstrated between CYP1B1 expression in both primary and metastatic ovarian cancer (P= 0.005 Spearman's rank correlation test). In contrast no detectable CYP1B1 was found in normal ovary. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11461084

  10. [Polymorphisms of CYP1B1 and COMT in breast and endometrial cancer].

    PubMed

    Zimarina, T C; Kristensen, V N; Imianitov, E N; Bershteĭn, L M

    2004-01-01

    CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine a variation of enzymic activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu and COMT polymorphism Val158Met in 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34-4.43, p = 0.000) and endometrial (OR = 2.43, CI 1.72-3.44, p = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58-3.01, p = 0.000 in breast cancer and OR = 2.52, CI 1.78-3.56, p = 0.000 in endometrial cancer. Risk of endometrial, but not breast, cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen reactivity of the endometrium as compared with the mammary gland.

  11. Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice

    PubMed Central

    Kraus, Anna E.; Gale, Daniel; White, Gilbert C.; VanSluys, Jillian

    2008-01-01

    Angiogenesis is the main mechanism of vascular remodeling during late development and, after birth, in wound healing. Perturbations of angiogenesis occur in cancer, diabetes, ischemia, and inflammation. While much progress has been made in identifying factors that control angiogenesis, the understanding of the precise molecular mechanisms involved is incomplete. Here we identify a small GTPase, Rap1b, as a positive regulator of angiogenesis. Rap1b-deficient mice had a decreased level of Matrigel plug and neonatal retinal neovascularization, and aortas isolated from Rap1b-deficient animals had a reduced microvessel sprouting response to 2 major physiological regulators of angiogenesis: vascular endothelial growth factor (VEGF) and basic fibroblasts growth factor (bFGF), indicating an intrinsic defect in endothelial cells. Proliferation of retinal endothelial cells in situ and in vitro migration of lung endothelial cells isolated from Rap1b-deficient mice were inhibited. At the molecular level, activation of 2 MAP kinases, p38 MAPK and p42/44 ERK, important regulators of endothelial migration and proliferation, was decreased in Rap1b-deficient endothelial cells in response to VEGF stimulation. These studies provide evidence that Rap1b is required for normal angiogenesis and reveal a novel role of Rap1 in regulation of proangiogenic signaling in endothelial cells. PMID:17993608

  12. Association of PTP1B with Outcomes of Breast Cancer Patients Who Underwent Neoadjuvant Chemotherapy

    PubMed Central

    Rivera Franco, Monica M.; Leon Rodriguez, Eucario; Martinez Benitez, Braulio; Villanueva Rodriguez, Luisa G.; de la Luz Sevilla Gonzalez, Maria; Armengol Alonso, Alejandra

    2016-01-01

    PTP1B is involved in the oncogenesis of breast cancer. In addition, neoadjuvant therapy has been widely used in breast cancer; thus, a measurement to assess survival improvement could be pathological complete response (pCR). Our objective was to associate PTP1B overexpression with outcomes of breast cancer patients who underwent neoadjuvant chemotherapy. Forty-six specimens were included. Diagnostic biopsies were immunostained using anti-PTP1B antibody. Expression was categorized as negative (<5%) and overexpression (≥5%). Patients’ responses were graded according to the Miller–Payne system. Sixty-three percent of patients overexpressed PTP1B. There was no significant association between PTP1B overexpression and pCR (P = 0.2). However, when associated with intrinsic subtypes, overexpression was higher in human epidermal growth factor receptor 2-positive-enriched specimens (P = 0.02). Ten-year progression-free survival showed no differences. Our preliminary results do not show an association between PTP1B over-expression and pCR; however, given the limited sample and heterogeneous treatment in our cohort, this hypothesis cannot be excluded. PMID:27840578

  13. Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer.

    PubMed

    McFadyen, M C; Cruickshank, M E; Miller, I D; McLeod, H L; Melvin, W T; Haites, N E; Parkin, D; Murray, G I

    2001-07-20

    Ovarian cancer is the most frequent cause of death from gynaecological malignancies world wide. Little improvement has been made in the long-term outcome of this disease, with the 5-year survival of patients only 30%. This poor prognosis is due to the late presentation of the disease and to the unpredictable response of ovarian cancer to chemotherapy. The cytochrome P450 enzymes are a superfamily of haemoproteins, known to be involved in the metabolic activation and/or detoxification of a number of anti-cancer drugs. CYP1B1 is a tumour-related form of cytochrome P450 which is over expressed in a wide variety of primary tumours of different histological type. The presence of CYP1B1 may be of importance in the modulation of these tumours to anti-cancer drugs. We have conducted a comprehensive immunohistochemical investigation, into the presence of cytochrome P450 CYP1B1 in primary and metastatic ovarian cancer. The key findings of this study are the increased expression of CYP1B1 in the majority of ovarian cancers investigated (92%), with a strong correlation demonstrated between CYP1B1 expression in both primary and metastatic ovarian cancer (P = 0.005 Spearman's rank correlation test). In contrast no detectable CYP1B1 was found in normal ovary.

  14. Tunable Design of Structural Colors Produced by Pseudo-1D Photonic Crystals of Graphene Oxide.

    PubMed

    Tong, Liping; Qi, Wei; Wang, Mengfan; Huang, Renliang; Su, Rongxin; He, Zhimin

    2016-07-01

    It is broadly observed that graphene oxide (GO) films appear transparent with a thickness of about several nanometers, whereas they appear dark brown or almost black with thickness of more than 1 μm. The basic color mechanism of GO film on a sub-micrometer scale, however, is not well understood. This study reports on GO pseudo-1D photonic crystals (p1D-PhCs) exhibiting tunable structural colors in the visible wavelength range owing to its 1D Bragg nanostructures. Striking structural colors of GO p1D-PhCs could be tuned by simply changing either the volume or concentration of the aqueous GO dispersion during vacuum filtration. Moreover, the quantitative relationship between thickness and reflection wavelength of GO p1D-PhCs has been revealed, thereby providing a theoretical basis to rationally design structural colors of GO p1D-PhCs. The spectral response of GO p1D-PhCs to humidity is also obtained clearly showing the wavelength shift of GO p1D-PhCs at differently relative humidity values and thus encouraging the integration of structural color printing and the humidity-responsive property of GO p1D-PhCs to develop a visible and fast-responsive anti-counterfeiting label. The results pave the way for a variety of potential applications of GO in optics, structural color printing, sensing, and anti-counterfeiting.

  15. Comparison of genetic variations of the SLCO1B1, SLCO1B3, and SLCO2B1 genes among five ethnic groups.

    PubMed

    Namgoong, Suhg; Cheong, Hyun Sub; Kim, Ji On; Kim, Lyoung Hyo; Na, Han Sung; Koh, In Song; Chung, Myeon Woo; Shin, Hyoung Doo

    2015-11-01

    Organic anion-transporting polypeptide (OATP; gene symbol, SLCO) transporters are generally involved in the uptake of multiple drugs and their metabolites at most epithelial barriers. The pattern of single-nucleotide polymorphisms (SNPs) in these transporters may be determinants of interindividual variability in drug disposition and response. The objective of this study was to define the distribution of SNPs of three SLCO genes, SLCO1B1, SLCO1B3, and SLCO2B1, in a Korean population and other ethnic groups. The study was screened using the Illumina GoldenGate assay for genomic DNA from 450 interethnic subjects, including 11 pharmacogenetic core variants and 76 HapMap tagging SNPs. The genotype distribution of the Korean population was similar to East Asian populations, but significantly different from African American and European American cohorts. These interethnic differences will be useful information for prospective studies, including genetic association and pharmacogenetic studies of drug metabolism by SLCO families.

  16. Naringin attenuates the cytotoxicity of hepatotoxin microcystin-LR by the curious mechanisms to OATP1B1- and OATP1B3-expressing cells.

    PubMed

    Takumi, Shota; Ikema, Satoshi; Hanyu, Tamami; Shima, Yusuke; Kurimoto, Takashi; Shiozaki, Kazuhiro; Sugiyama, Yasumasa; Park, Ho-Dong; Ando, Seiichi; Furukawa, Tatsuhiko; Komatsu, Masaharu

    2015-03-01

    Microcystin-LR, which is an inhibitor of serine/threonine protein phosphatase (PP)1 and PP2A, induces liver injury by its selective uptake system into the hepatocyte. It is also thought that microcystin-LR induces reactive oxygen species (ROS). We tried to establish the chemical prevention of microcystin-LR poisoning. We investigated the effect of grapefruit flavanone glycoside naringin on cytotoxicity of microcystin-LR using human hepatocyte uptake transporter OATP1B3-expressing HEK293-OATP1B3 cells. We found cytotoxicity of microcystin-LR was attenuated by naringin in a dose dependent manner. The inhibition magnitude of total cellular serine/threonine protein phosphatase activity induced by microcystin-LR was suppressed by naringin. In addition, uptake of microcystin-LR into HEK293-OATP1B3 cells was inhibited by naringin. Furthermore, microcystin-LR induced phosphorylation of p53 was inhibited by naringin. Regardless of the difference in the exposure pattern of pre-processing and post-processing of naringin, the toxicity of microcystin-LR was comparable. These results suggested that naringin is promising remedy as well as preventive medicine for liver damage with microcystin-LR. In addition, involvement of ROS production after exposure to the sublethal concentrations of microcystin-LR in the onset of cytotoxicity was negligible. Therefore, inhibition of microcystin-LR uptake and the pathway other than ROS production would be involved in the effect of naringin on the attenuation of microcystin-LR toxicity.

  17. Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes

    PubMed Central

    Reis, Linda M.; Tyler, Rebecca C.; Weh, Eric; Hendee, Kathryn E.; Kariminejad, Ariana; Abdul-Rahman, Omar; Ben-Omran, Tawfeg; Manning, Melanie A.; Yesilyurt, Ahmet; McCarty, Catherine A.; Kitchner, Terrie E.; Costakos, Deborah

    2016-01-01

    Purpose The CYP1B1 gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in CYP1B1 have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG). Methods We examined CYP1B1 in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined. Results Recessive pathogenic variants in CYP1B1 were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with CYP1B1. Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the CYP1B1-positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant

  18. Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis

    PubMed Central

    Jankovic, Slobodan M

    2010-01-01

    Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%–15%) or relapsing-remitting (85%–90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection s